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1. When discordant insulin and C-peptide levels lead to a medical diagnosis in a patient with transient hypoglycemia: Varying degrees of interference of insulin-antibody complexes on three insulin immunoassays

Author

Jordan Teoli, Karim Chikh, Ryme Jouini-Bouhamri, Sybil Charriere, Nicole Fabien, and Véronique Raverot

Subjects
Case report, Insulin autoimmune syndrome, Hyperinsulinism, Immunoassay, Assay interference, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Background: Determining the cause of hypoglycemia partly relies on blood insulin and C-peptide assays. Although the pancreatic secretion of these peptides is equimolar, discrepancies in their concentrations may occur. Case presentation: We report the case of a 73-year-old woman with type 2 diabetes mellitus (T2DM) and a history of gastric bypass. The T2DM was initially treated with insulin analogs, which were interrupted due to transient hypoglycemia episodes three years before hospitalization in our endocrinology department. During this hospitalization, the most common etiologies of hypoglycemia were excluded. Fasting insulin level was high (190 mIU/L, reference values (RV): 5–25) on Architect i2000 (an assay recognizing insulin analogs) despite normal blood C-peptide (4.5 μg/L, RV: 0.8–5.2) and slight hypoglycemia (4.5 mmol/L, RV: 4.6–6.1). Insulin level using the Elecsys assay (an assay with low sensitivity to insulin analogs) was very high (>1000 mIU/L, RV: 2.6–24.9). This pattern was observed on several samples, including some taken during a fasting test. Insulin level was only slightly increased using the Mercodia iso-insulin ELISA kit (an assay recognizing insulin analogs). These results excluded an exogenous insulin intake and were suggestive of an interference on insulin assays. To explore the latter possibility, free anti-insulin antibodies were measured and found strongly positive. The presence of interfering insulin-antibody complexes was further investigated using gel filtration chromatography, polyethylene glycol precipitation, and dilution test. Based on these findings, an insulin autoimmune syndrome (IAS) was suspected to cause the hypoglycemic episodes observed. Conclusion: Although a discrepancy between blood insulin and C-peptide levels points to insulin analog intake, IAS should also be considered, particularly in a patient with transient hypoglycemia. IAS is characterized by the presence of insulin-antibody complexes, which can induce varying degrees of interference on insulin immunoassays and may lead to discordant insulin and C-peptide levels according to the insulin immunoassay used.

Published
2024
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2. Paraneoplastic Neurologic Syndromes Associated With Merkel Cell Carcinoma.

Author

Ciano-Petersen, Nicolás Lundahl, Muñiz-Castrillo, Sergio, Villagrán-García, Macarena, Farina, Antonio, Vogrig, Alberto, Wucher, Valentin, Le Duy Do, Birzu, Cristina, Goncalves, David, Flabeau, Olivier, Duwicquet, Coline, Benard, Adrien, Nicole, Fabien, Rogemond, Veronique, Picard, Geraldine, Joubert, Bastien, and Honnorat, Jerome

Published
2024
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4. Early-onset autoimmunity associated with SOCS1 haploinsufficiency

Author

Jérôme Hadjadj, Carla Noemi Castro, Maud Tusseau, Marie-Claude Stolzenberg, Fabienne Mazerolles, Nathalie Aladjidi, Martin Armstrong, Houman Ashrafian, Ioana Cutcutache, Georg Ebetsberger-Dachs, Katherine S. Elliott, Isabelle Durieu, Nicole Fabien, Mathieu Fusaro, Maximilian Heeg, Yohan Schmitt, Marc Bras, Julian C. Knight, Jean-Christophe Lega, Gaetan Lesca, Anne-Laure Mathieu, Marion Moreews, Baptiste Moreira, Audrey Nosbaum, Matthew Page, Cécile Picard, T. Ronan Leahy, Isabelle Rouvet, Ethel Ryan, Damien Sanlaville, Klaus Schwarz, Andrew Skelton, Jean-Francois Viallard, Sebastien Viel, Marine Villard, Isabelle Callebaut, Capucine Picard, Thierry Walzer, Stephan Ehl, Alain Fischer, Bénédicte Neven, Alexandre Belot, and Frédéric Rieux-Laucat

Subjects
Science
Abstract

SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.

Published
2020
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5. Infection Risk in Patients with Dermatomyositis Associated with Anti-MDA5 Antibodies: A Historical Cohort Study

Author

Anne-Claire Billet, Thomas Barba, Frédéric Coutant, Nicole Fabien, Laurent Perard, Pascal Sève, Jean-Christophe Lega, Cécile-Audrey Durel, Laure Gallay, and Arnaud Hot

Subjects
dermatomyositis with anti-MDA5 autoantibodies, infectious complications, prophylaxis, Biology (General), QH301-705.5
Abstract

Objective: Dermatomyositis associated with anti-MDA5 autoantibodies (DM-MDA5+) is a rare autoimmune disease usually characterized by skin involvement, often-severe lung involvement, and general features. Several reports of infections have been described, sometimes early after the introduction of immunosuppressive therapy. We studied the infection risk in a DM-MDA5+ population. Methods: A retrospective cohort study comparing the number and type of infections during the follow-up of 19 patients with DM-MDA5+ and 37 patients with another type of inflammatory myopathy was analyzed. Patients in both groups were matched on initial immunosuppressive therapy. We described and compared significant infectious complications (SIC) in each group. Results: Patients DM-MDA5+ had more SIC: 27 events in the DM-MDA5+ group versus 6 in the controls (HR 7.08, 95% CI 2.50–20.04, p < 0.0001). The number of SIC per patient was higher in DM-MDA5+ (1.4 ± 1.57 vs. 0.16 ± 0.44, p < 0.001). These were mainly lung (n = 13, 48%) and skin infections (n = 6, 22%), more often infections of an undetermined infectious agent (n = 11, 41%) or of bacterial origin (n = 9, 33%). A few cases of opportunistic infections were reported. The median duration of follow-up without SIC event in the DM-MDA5+ cohort was 3.5 months. Conclusion: Patients with DM-MDA5+ have an increased infection risk compared to others inflammatory myopathies irrespective of immunosuppressive therapy exposure. These results highlight the importance of monitoring for infection during patient follow-up.

Published
2022
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6. Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies

Author

Anaïs Nombel, Nicole Fabien, and Frédéric Coutant

Subjects
myositis, dermatomyositis, idiopathic inflammatory myopathies, MDA5, COVID-19, SARS-CoV-2, Immunologic diseases. Allergy, RC581-607
Abstract

Anti-MDA5 dermatomyositis is a rare systemic autoimmune disease, historically described in Japanese patients with clinically amyopathic dermatomyositis and life-threatening rapidly progressive interstitial lung disease. Subsequently, the complete clinical spectrum of the disease was enriched by skin, articular and vascular manifestations. Depending on the predominance of these symptoms, three distinct clinical phenotypes with different prognosis are now defined. To date, the only known molecular component shared by the three entities are specific antibodies targeting MDA5, a cytosolic protein essential for antiviral host immune responses. Several biological tools have emerged to detect these antibodies, with drawbacks and limitations for each of them. However, the identification of this highly specific serological marker of the disease raises the question of its role in the pathogenesis. Although current knowledge on the pathogenic mechanisms that take place in the disease are still in their enfancy, several lines of evidence support a central role of interferon-mediated vasculopathy in the development of skin and lung lesions, as well as a possible pathogenic involvement of anti-MDA5 antibodies. Here, we review the clinical and biological evidences in favor of these hypothesis, and we discuss the contribution of emerging therapies that shed some light on the pathogenesis of the disease.

Published
2021
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7. Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies

Author

Anaïs Nombel, Jean-Jacques Pin, Nicole Fabien, Pierre Miossec, and Frédéric Coutant

Subjects
myositis, dermatomyositis, idiopathic inflammatory myopathies, autoantibody, MDA5, indirect immunofluorescence, Biology (General), QH301-705.5
Abstract

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease’s activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA.

Published
2022
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8. Antibodies against type I interferon: detection and association with severe clinical outcome in COVID‐19 patients

Author

David Goncalves, Mehdi Mezidi, Paul Bastard, Magali Perret, Kahina Saker, Nicole Fabien, Rémi Pescarmona, Christine Lombard, Thierry Walzer, Jean‐Laurent Casanova, Alexandre Belot, Jean‐Christophe Richard, and Sophie Trouillet‐Assant

Subjects
autoantibodies, COVID‐19, intensive care unit, SARS‐CoV‐2 virus, type I interferon, viral infection, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Objectives Impairment of type I interferon (IFN‐I) immunity has been reported in critically ill COVID‐19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto‐Abs) against IFN‐I. We set out to improve the detection and the quantification of IFN‐I auto‐Abs in a cohort of critically ill COVID‐19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease. Methods The concentration of anti‐IFN‐α2 Abs was determined in the serum of 84 critically ill COVID‐19 patients who were admitted to ICU in Hospices Civils de Lyon, France, using a commercially available kit (Thermo Fisher, Catalog #BMS217). Results A total of 21 of 84 (25%) critically ill COVID‐19 patients had circulating anti‐IFN‐α2 Abs above cut‐off (> 34 ng mL−1). Among them, 15 of 21 had Abs with neutralising activity against IFN‐α2, that is 15 of 84 (18%) critically ill patients. In addition, we noticed an impairment of the IFN‐I response in the majority of patients with neutralising anti‐IFN‐α2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralising anti‐IFN‐α2 auto‐Abs. We detected anti‐IFN‐α2 auto‐Abs in COVID‐19 patients' sera throughout their ICU stay. Finally, we also found auto‐Abs against multiple subtypes of IFN‐I including IFN‐ω. Conclusions We reported that 18% of critically ill COVID‐19 patients were positive for IFN‐I auto‐Abs, whereas all mild COVID‐19 patients were negative, confirming that the presence of these antibodies is associated with a higher risk of developing a critical COVID‐19 form.

Published
2021
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9. Idiopathic inflammatory myopathies and the lung

Author

Jean-Christophe Lega, Quitterie Reynaud, Alexandre Belot, Nicole Fabien, Isabelle Durieu, and Vincent Cottin

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Idiopathic inflammatory myositis (IIM) is a group of rare connective tissue diseases (CTDs) characterised by muscular and extramuscular signs, in which lung involvement is a challenging issue. Interstitial lung disease (ILD) is the hallmark of pulmonary involvement in IIM, and causes morbidity and mortality, resulting in an estimated excess mortality of 50% in some series. Except for inclusion body myositis, these extrapulmonary disorders are associated with the general and visceral involvement frequently found in other CTDs including fever, Raynaud's phenomenon, arthralgia, nonspecific cutaneous modifications and ILD, for which the prevalence is estimated to be up to 65%. Substantial heterogeneity exists within the spectrum of IIMs, and each condition is associated with various frequencies and subtypes of pulmonary involvement. This heterogeneity is partly related to the presence of various autoantibodies encompassing anti-synthetase, anti-MDA5 and anti-PM/Scl. ILD is present in all subsets of IIM including juvenile myositis, but is more frequent in dermatomyositis and overlap myositis. IIM can also be associated with other presentations of respiratory involvement, namely pulmonary arterial hypertension, pleural disease, infections, drug-induced toxicity, malignancy and respiratory muscle weakness. Here, we critically review the current knowledge about adult and juvenile myositis-associated lung disease with a detailed description of therapeutics for chronic and rapidly progressive ILD.

Published
2015
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10. Evaluation of a novel particle-based multi-analyte technology for the detection of anti-fibrillarin antibodies

Author

David Goncalves, Nicole Fabien, Grace Kim, Fabrece Roup, Chelsea Bentow, Boaz Palterer, Marvin J. Fritzler, Michael Mahler, and Danilo Villalta

Subjects
0301 basic medicine, Male, Chromosomal Proteins, Non-Histone, Inflammatory bowel disease, Gastroenterology, Serology, 0302 clinical medicine, Child, Fluorescent Antibody Technique, Indirect, Aged, 80 and over, Immunoassay, medicine.diagnostic_test, biology, IIf, Middle Aged, Prognosis, Healthy Volunteers, Rheumatoid arthritis, Antibodies, Antinuclear, Systemic sclerosis, Female, Original Article, Antibody, Adult, medicine.medical_specialty, Adolescent, Immunology, Multi-analyte, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Aged, Autoantibodies, 030203 arthritis & rheumatology, Autoimmune disease, Scleroderma, Systemic, business.industry, Autoantibody, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, biology.protein, Feasibility Studies, Reagent Kits, Diagnostic, business
Abstract

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease associated with several anti-nuclear antibodies (ANA), including those in the classification criteria (anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA Pol III). However, the presence of less common antibodies such as anti-fibrillarin (U3-RNP) that generate a clumpy nucleolar pattern by HEp-2 indirect immunofluorescence assay (IFA, ICAP AC-9) are considered disease specific and are with clinical subsets of SSc, therefore playing a role in diagnosis and prognosis. A specific and sensitive anti-fibrillarin assay would be an important addition to serological diagnosis and evaluation of SSc. The goal of this study was to evaluate a new particle-based multi-analyte technology (PMAT) for the measurement of anti-fibrillarin antibodies. A total of 149 patient samples were collected including 47 samples from France (Lyon and Paris, n = 32) and Italy (Careggi Hospital, Florence, n = 15) selected based on AC-9 HEp-2 IFA staining (> 1:640, clumpy nucleolar pattern) and 102 non-SSc controls (inflammatory bowel disease (IBD) n = 20, Sjögren’s syndrome (SjS) n = 20, infectious disease (ID) n = 7, systemic lupus erythematosus (SLE) n = 17, rheumatoid arthritis (RA) n = 17, and healthy individuals (HI) n = 21). All samples were tested on the anti-fibrillarin PMAT assay (research use only, Inova Diagnostics, USA). Additionally, the 47 anti-fibrillarin positive samples were also tested on PMAT assays for detecting other autoantibodies in ANA-associated rheumatic diseases (AARD). Anti-fibrillarin antibody data performed by fluorescence enzyme immunoassay (FEIA, Thermo Fisher, Germany) was available for 34 samples. The anti-fibrillarin PMAT assay was positive in 31/32 (96.9%, France) and 12/15 (80.0%, Italy) of samples preselected based on the AC-9 IIF pattern (difference p = 0.09). Collectively, the PMAT assay showed 91.5% (95% confidence interval (CI): 80.1–96.6%) sensitivity with 100.0% (95% CI: 96.4–100.0%) specificity in non-SSc controls. Strong agreement was found between PMAT and FEIA with 100.0% positive qualitative agreement (34/34) and quantitative agreement (Spearman’s rho = 0.89, 95% CI: 0.77.9–0.95%, p

Published
2021

12. Repository of intra-and inter-run variations of quantitative autoantibody assays: A European multicenter study

Author

Marie-Agnès Dragon-Durey, Nicola Bizzaro, Marie Senant, Hristina Andreeva, Dimitrios P. Bogdanos, Carolien Bonroy, Xavier Bossuyt, Catharina Eriksson, Nicole Fabien, Ingmar Heijnen, Manfred Herold, Lucile Musset, Liisa Kuhi, Marcos Lopez-Hoyos, Tímea Berki, Caroline Roozendaal, Ulrich Sack, Tatjana Sundic, Lorna Taylor, Andrea Tesija Kuna, Jan Damoiseaux, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, and Central Diagnostic Lab

Subjects
Quality Control, Biochemistry (medical), Clinical Biochemistry, inter-run variation, General Medicine, quality assurance, Clinical Laboratory Services, Reference Standards, VALIDATION, QUALITY-CONTROL, internal quality control, laboratory accreditation, Humans, precision, immunoassay, Laboratories, intra-run variation, Autoantibodies
Abstract

Objectives No reference data are available on repositories to measure precision of autoantibody assays. The scope of this study was to document inter- and intra-run variations of quantitative autoantibody assays based on a real-world large international data set. Methods Members of the European Autoimmunity Standardisation Initiative (EASI) group collected the data of intra- and inter-run variability obtained with assays quantifying 15 different autoantibodies in voluntary participating laboratories from their country. We analyzed the impact on the assay performances of the type of immunoassay, the number of measurements used to calculate the coefficient of variation (CVs), the nature and the autoantibody level of the internal quality control (IQC). Results Data were obtained from 64 laboratories from 15 European countries between February and October 2021. We analyzed 686 and 1,331 values of intra- and inter-run CVs, respectively. Both CVs were significantly dependent on: the method of immunoassay, the level of IQC with higher imprecision observed when the antibody levels were lower than 2-fold the threshold for positivity, and the nature of the IQC with commercial IQCs having lower CVs than patients-derived IQCs. Our analyses also show that the type of autoantibody has low impact on the assay’ performances and that 15 measurements are sufficient to establish reliable intra- and inter-run variations. Conclusions This study provides for the first time an international repository yielding values of intra- and inter-run variation for quantitative autoantibody assays. These data could be useful for ISO 15189 accreditation requirements and will allow clinical diagnostic laboratories to assure quality of patient results.

Published
2022

13. Isolated positive anti-SS-B autoantibodies are not related to clinical features of systemic autoimmune diseases: Results from a routine population survey.

Author

Sabine Jardel, Nicole Fabien, Arnaud Hot, Sandra Vukusic, Jacques Tebib, Vincent Cottin, Pascal Sève, Maurice Laville, Alexandre Belot, Isabelle Durieu, Lorna Garnier, Frédéric Coutant, Quitterie Reynaud, and Jean Christophe Lega

Subjects
Medicine, Science
Abstract

To assess in clinical practice the frequency and diagnosis associated with the SS-B-positive/SS-A negative autoantibody profile.We analyzed a one-year consecutive population of 624 patients referred by clinicians to the immunology laboratory to investigate anti-SS-A and/or anti-SS-B autoantibodies, who were detected using luminex technology. Data were analyzed for patients with isolated anti-SS-B autoantibodies. The clinical characteristics and diagnosis of connective tissue diseases (CTD) were retrieved according to the international criteria.Among 1173 sera positive for anti-SS-A and/or anti-SS-B autoantibodies from 624 patients, we identified 84 patients (13.5%) that had isolated anti-SS-B. Among the 75 patients positive for anti-SS-B with known clinical data, 15 were diagnosed with a CTD (20%) including 4 systemic lupus erythematosus (5%), 4 rheumatoid arthritis (5%), 2 idiopathic inflammatory myositis (3%), 1 primary Sjögren's syndrome pSS (1%), 1 systemic sclerosis (1%), 2 undefined CTD (3%), and 1 mixed CTD (1%). Among the 60 other patients, 18 had non-CTD autoimmune diseases and 42 had non-autoimmune diseases. Within the CTD population, the presence of isolated anti-SS-B was not significantly associated to characteristic indicating a specific syndrome. There was no association between diagnosis of CTD and level of anti-SS-B autoantibodies (p = 0.70). Arthralgia was the more frequent sign and encountered in 10 patients (67%), of whom 3 had arthritis.The presence of anti-SS-B, without anti-SS-A autoantibodies using luminex technology, was not associated with CTD, especially pSS, in daily clinical practice. Our data suggests that the SS-B serological profile is not contributive for the classification criteria of pSS.

Published
2017
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14. miRNA-375 a Sensor of Glucotoxicity Is Altered in the Serum of Children with Newly Diagnosed Type 1 Diabetes

Author

Lucien Marchand, Audrey Jalabert, Emmanuelle Meugnier, Kathleen Van den Hende, Nicole Fabien, Marc Nicolino, Anne-Marie Madec, Charles Thivolet, and Sophie Rome

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array. Results. The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies. Conclusion. Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.

Published
2016
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15. Precision of autoantibody assays in clinical diagnostic laboratories: What is the reality?

Author

Laurence Guis-Cabanne, Georges Chyderiotis, Marie Senant, Jan Damoiseaux, Marie-Agnès Dragon-Durey, Lucile Musset, Nicole Fabien, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cerballiance, Unité fonctionnelle d’Auto-immunité et Immunochimie [CHU Pitié-Salpêtrière], Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Eurofins Biomnis, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Paris Cité (UPCité), CCSD, Accord Elsevier, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, and Faculteit FHML Centraal

Subjects
Quality Control, 030213 general clinical medicine, medicine.medical_specialty, Percentile, Internal quality control, Coefficient of variation, [SDV]Life Sciences [q-bio], Clinical Biochemistry, No reference, Antibody level, 030204 cardiovascular system & hematology, Sensitivity and Specificity, Accreditation, Autoimmune Diseases, 03 medical and health sciences, LIMITS, 0302 clinical medicine, Autoantibody, QUALITY-CONTROL, Surveys and Questionnaires, medicine, Humans, Measurement precision, Medical physics, CLASSIFICATION CRITERIA, Laboratory accreditation, Clinical care, Autoantibodies, Immunoassay, Clinical Laboratory Techniques, business.industry, Reproducibility of Results, General Medicine, Reference Standards, Analytic performances, 3. Good health, Internal quality, [SDV] Life Sciences [q-bio], BIOLOGICAL VARIATION, France, business
Abstract

Background: ISO 15189 accreditation remains a challenge for specialized laboratories. In the field of autoimmunity, beside the crucial problem of absence of standardization, laboratories have to manage the analytical performances of the large panel of assays in terms of sensitivity and specificity, but also on their measurement precision for which no reference values are available on biorepositories.Methods: As an initiative of the French EASI (European Autoimmunity Standardization Initiative) group, French clinical diagnostic laboratories were requested to participate in a survey aiming to analyze the coefficients of variation (CVs) of intra-run and inter-run variability obtained with assays quantifying 14 different autoantibodies. Two performance goals corresponding to the 90th percentile and the 50th percentile (lowest CV values reached by 90% and 50% of laboratories respectively) defined for three levels of concentration were calculated. The impact on the assay performances of the number of measurements, of the nature of the internal quality control (IQC) and the type of immunoassay, was also analyzed.Results: 414 and 616 values of intra-run and inter-run CVs were collected, respectively. The 50th percentile performance goals were comprised between 1.0% and 8.9% for the intra-run CVs, and between 1.8% and 14.6% for the inter-run CVs. At 90th percentile, the performance goals were comprised between 3.2% and 13.5% for the intra-run CVs, and between 7.3% and 30.8% for the inter-run CVs. CVs calculated from 10 values were similar to those obtained from more values. Higher imprecision was observed when the antibody levels of the IQC was lower than 2 fold the positive threshold. Commercial IQCs gave lower CVs than IQCs derived from patient samples.Conclusion: Our results allow proposing some acceptability limits for the precision performances of the autoantibody assays, compatible with the reality of life in diagnostic laboratories and clinical care.

Published
2020
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16. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author

Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract

Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Published
2020
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17. DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity

Author

Françoise Poitevin, Sonia Lounis, Cécile Picard, Marine Villard, Christophe Malcus, Alexandre Belot, Mathieu Fusaro, Capucine Picard, Sébastien Viel, Debora Jorge Cordeiro, Emmanuel Martin, Sylvain Latour, David Goncalves, Benjamin Fournier, Anne-Laure Mathieu, Magali Perret, Nicole Fabien, Marion Moreews, Yves Bertrand, Thierry Walzer, Maud Tusseau, Nathalie Garnier, Alexandra Gauthier, Emilie Chopin, Christelle Lenoir, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Viremia, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Immunology and Allergy, Immunodeficiency, ComputingMilieux_MISCELLANEOUS, business.industry, Immune dysregulation, medicine.disease, Epstein–Barr virus, 3. Good health, Lymphoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols, medicine.symptom, business
Abstract

By studying four siblings with a null homozygous mutation in DEF6, we show that DEF6 deficiency is a new inherited immune dysregulation disorder with variable expressivity from autoimmunity/inflammation to EBV-associated viremia/lymphoproliferation/lymphoma without extra-hematopoietic manifestations.

Published
2020
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18. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes

Author

Benoît Déchelotte, Christine Lombard, Véronique Rogemond, Sergio Muñiz-Castrillo, Géraldine Picard, Jérôme Honnorat, Nicole Fabien, Alberto Vogrig, Anne-Laurie Pinto, Bastien Joubert, and Virginie Desestret

Subjects
0301 basic medicine, Onconeural antibodies, medicine.medical_specialty, Immunoblotting, Paraneoplastic Neurologic Syndromes, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Western blot, Predictive Value of Tests, Internal medicine, Clinical information, medicine, Humans, Autoantibodies, Retrospective Studies, Indirect immunofluorescence, biology, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, Blot, 030104 developmental biology, HEK293 Cells, Neurology, biology.protein, Neurology (clinical), Antibody, business, 030217 neurology & neurosurgery, Paraneoplastic Syndromes, Nervous System
Abstract

ObjectiveTo investigate the diagnostic yield of commercial immunodots to detect onconeural antibodies associated with paraneoplastic neurologic syndromes (PNSs), we analyzed the proportion of confirmed positive results using alternative techniques.MethodsSera (n = 5,300) of patients with suspected PNS were tested by PNS+2 blot (Ravo Diagnostika; January 2016–May 2017) or EUROLINE PNS 12 Ag (Euroimmun; July 2017–November 2018). Positive samples were further explored by in-house indirect immunofluorescence and a third in-house technique (Western blot or cell-based assay) using recombinant protein. Those found negative by these 2 techniques were considered as nonconfirmed. We analyzed the relationship between band intensity and final confirmation. Clinical data were collected for all confirmed results and nonconfirmed EUROLINE immunodots.ResultsPNS+2 blot was positive in 128/1,658 (7.7%) sera and confirmed in 47/128 (36.7%). EUROLINE was positive in 186/3,626 (5.1%) and confirmed in 56/186 (30.1%). Confirmation was highly variable among the antibodies tested, from 7.2% (PNS+2 blot) and 5.8% (EUROLINE) for anti-Yo to 88.2% (PNS+2 blot) and 65.0% (EUROLINE) for anti-Hu. None of the 27 weak positive sera by EUROLINE was confirmed. Band intensity in confirmed cases was variable among the antibodies from strong positive for all anti-Yo (n = 3) and anti-Hu (n = 11) to positive (n = 19) or strong positive (n = 9) for anti-SOX1. Among patients with a nonconfirmed EUROLINE result and available clinical information, all had an alternative diagnosis, and only 6.7% had cancer.ConclusionsImmunodots may be useful for PNS screening, but a threshold should be established for each antibody, and clinical information and confirmation by other techniques are essential.Classification of evidenceThe study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.

Published
2020

19. Immune responses elicited in tertiary lymphoid tissues display distinctive features.

Author

Olivier Thaunat, Stéphanie Graff-Dubois, Sophie Brouard, Chantal Gautreau, Aditi Varthaman, Nicole Fabien, Anne-Christine Field, Liliane Louedec, Jianping Dai, Etienne Joly, Emmanuel Morelon, Jean-Paul Soulillou, Jean-Baptiste Michel, and Antonino Nicoletti

Subjects
Medicine, Science
Abstract

During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also "stochastic," since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts.

Published
2010
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20. Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

Author

Alexandre Belot, Gillian I Rice, Sulliman Ommar Omarjee, Quentin Rouchon, Eve M D Smith, Marion Moreews, Maud Tusseau, Cécile Frachette, Raphael Bournhonesque, Nicole Thielens, Christine Gaboriaud, Isabelle Rouvet, Emilie Chopin, Akihiro Hoshino, Sylvain Latour, Bruno Ranchin, Rolando Cimaz, Paula Romagnani, Christophe Malcus, Nicole Fabien, Marie-Nathalie Sarda, Behrouz Kassai, Jean-Christophe Lega, Stéphane Decramer, Pauline Abou-Jaoude, Ian N Bruce, Thomas Simonet, Claire Bardel, Pierre Antoine Rollat-Farnier, Sebastien Viel, Héloise Reumaux, James O'Sullivan, Thierry Walzer, Anne-Laure Mathieu, Gaelle Marenne, Thomas Ludwig, Emmanuelle Genin, Jamie Ellingford, Brigitte Bader-Meunier, Tracy A Briggs, Michael W Beresford, Yanick J Crow, Dominique Campion, Jean-Francois Dartigues, Jean-François Deleuze, Jean-Charles Lambert, Richard Redon, Emma Allain-Launay, Kenza Bouayed, Stephane Burtey, Aurélia Carbasse, Véronique Despert, Olivier Fain, Michel Fischbach, Hugues Flodrops, Caroline Galeotti, Eric Hachulla, Yves Hatchuel, Jean-Francois Kleinmann, Isabelle Kone-Paut, Aurélia Lanteri, Irène Lemelle, Hélène Maillard, François Maurier, Ulrich Meinzer, Isabelle Melki, Sandrine Morell-Dubois, Anne Pagnier, Maryam Piram, Charlotte Samaille, Jean Sibilia, Olivia Weill, Eslam Al-Abadi, Kate Armon, Kathryn Bailey, Michael Beresford, Mary Brennan, Coziana Ciurtin, Janet Gardner-Medwin, Kirsty Haslam, Daniel Hawley, Alice Leahy, Valentina Leone, Devesh Mewar, Rob Moots, Clarissa Pilkington, Athimalaipet Ramanan, Satyapal Rangaraj, Annie Ratcliffe, Philip Riley, Ethan Sen, Arani Sridhar, Nick Wilkinson, Fiona Wood, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Academic Unit of Medical Genetic, University of Manchester [Manchester], Reproduction et développement des plantes (RDP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Hospices Civils de Lyon (HCL), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL], Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital and University of Florence, Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France, parent, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Pédiatrique [Jeanne de Flandre], Hôpital Jeanne de Flandre [Lille], Genetic Medicine, University of Manchester [Manchester]-Faculty of Human and Medical Sciences, Spanish National Cancer Research Centre, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Bordeaux (UB), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM), Service Pédiatrique [Rennes], CHU Pontchaillou [Rennes], Service de Médecine Interne [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), service pédiatrique de dialyse et de transplantation rénales, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 'Personal Protection Against Vectors' working group (PPAV), PPAV working group, CHU Strasbourg, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Pédiatrie [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de médecine interne, Hôpital Sainte-Blandine-Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Paediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases [Paris], Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie Générale et Rhumatologie Pédiatrique, Service de rhumatologie [Strasbourg], Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], University of Edinburgh, Analyse et Traitement Informatique de la Langue Française (ATILF), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Firenze = University of Florence (UniFI), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche de l'institut du thorax (ITX-lab), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Proband, [SDV]Life Sciences [q-bio], Immunology, Population, Genome-wide association study, Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Rheumatology, immune system diseases, Genotype, medicine, Immunology and Allergy, 1000 Genomes Project, education, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetic association, 030203 arthritis & rheumatology, Genetics, 0303 health sciences, education.field_of_study, Systemic lupus erythematosus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], medicine.disease, 3. Good health, Mendelian inheritance, symbols
Abstract

Summary Background Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE. Methods For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium. Findings After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10−11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution. Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity. Funding European Research Council.

Published
2020
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21. Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3(+) T cells in a patient with IPEX syndrome

Author

Bernard Flourié, Stéphane Nancey, Nicole Fabien, Marine Sarfati, Gilles Boschetti, Fabienne Coury, Alain Lachaux, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Hematopoietic stem cell transplantation, medicine.disease_cause, Anti-TNF, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Medicine, Enteropathy, 030212 general & internal medicine, Sacroiliitis, 030203 arthritis & rheumatology, business.industry, FOXP3, Immunosuppression, Regulatory T cells, Immune dysregulation, IPEX syndrome, medicine.disease, 3. Good health, Transplantation, [SDV] Life Sciences [q-bio], Foxp3, Immunology, Primary immunodeficiency, business
Abstract

International audience; Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.

Published
2020
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22. The IgG2 Isotype of Anti–Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis

Author

Audrey Aussy, Isabelle Marie, Didier Bessis, Fabienne Jouen, Sophie Hue, Pierre-Julien Viailly, Jean Sibilia, Alain Meyer, Manuel Fréret, Nadège Cordel, Olivier Benveniste, Mohammed Hamidou, Denis Jullien, Pascal Joly, Jean-Luc Charuel, Yves Allenbach, Olivier Boyer, Laurent Drouot, Nicole Fabien, Brigitte Bader-Meunier, Laure Gallay, Thierry Vincent, Eric Hachulla, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Strasbourg, Physiopathologie des arthrites, Université Louis Pasteur - Strasbourg I, Service de médecine interne, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Facultat de Química (DEPARTAMENT DE QUíMICA ORGàNICA), Universitat de Barcelona (UB), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de Dermatologie et Médecine Interne [Pointe-à-Pitre, Guadeloupe], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie, Club Rhumatismes et Inflammation, Laboratoire d'Electronique et des Technologies de l'Information (CEA-LETI), Université Grenoble Alpes (UGA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Médecine Interne [Rouen], Service Physiologie, Les Hôpitaux Universitaires de Strasbourg (HUS)-Nouvel Hôpital Civil, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [Lille], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut des Neurosciences de Montpellier (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Risk Assessment, Gastroenterology, Dermatomyositis, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Risk Factors, Neoplasms, Internal medicine, Biomarkers, Tumor, Risk of mortality, Humans, Immunology and Allergy, Medicine, ComputingMilieux_MISCELLANEOUS, Aged, Autoantibodies, Proportional Hazards Models, Retrospective Studies, 030203 arthritis & rheumatology, biology, Proportional hazards model, business.industry, Autoantibody, Retrospective cohort study, Middle Aged, medicine.disease, Adult dermatomyositis, 3. Good health, 030104 developmental biology, Immunoglobulin G, Multivariate Analysis, biology.protein, Biomarker (medicine), [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Creatine kinase, business, Transcription Factors
Abstract

International audience; Objective: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM.Methods: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model.Results: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality.Conclusion: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

Published
2019
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23. Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype

Author

Charles Thivolet, Karim Chikh, Lucien Marchand, Nicole Fabien, Sophie Reffet, Julien Vouillarmet, Christine Cugnet-Anceau, Arnaud Thivolet, Stéphane Dalle, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Immune checkpoint inhibitors side-effects, Male, Durvalumab, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, Mixed meal test, Pembrolizumab, 030204 cardiovascular system & hematology, Anti-PD-L1, Gastroenterology, B7-H1 Antigen, B7-H1 Antigen/antagonists & inhibitors/*immunology, Autoimmune diabetes, 0302 clinical medicine, Endocrinology, Diabetes mellitus, Monoclonal, 80 and over, Fulminant diabetes, Programmed death ligand 1, Aged, 80 and over, Antibodies, Monoclonal, General Medicine, Middle Aged, Programmed Cell Death 1 Receptor/antagonists & inhibitors/*immunology, Pancreas, Exocrine, Alpha-cell pancreatic function, Anti-PD-1, 3. Good health, Nivolumab, Editorial, medicine.anatomical_structure, Phenotype, Female, Immunotherapy, Pancreas, Monoclonal/adverse effects, medicine.medical_specialty, Exocrine/*drug effects/metabolism/pathology, 030209 endocrinology & metabolism, Beta-cell pancreatic function, Antibodies, Monoclonal, Humanized, Antibodies, Islets of Langerhans/*drug effects/metabolism/pathology, Islets of Langerhans, 03 medical and health sciences, Internal medicine, Internal Medicine, medicine, Endocrine system, Humans, Immunotherapy/*adverse effects, Autoantibodies, Aged, Type 1 diabetes, business.industry, Pancreas volume, Programmed cell death-1, medicine.disease, Nivolumab/adverse effects, Diabetes Mellitus/*chemically induced/pathology, Ketoacidosis, Exocrine pancreatic function, Humanized/adverse effects, business, Autoantibodies/blood
Abstract

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Published
2019
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24. Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort

Author

Nathalie Bendelac, Nicole Fabien, Charles Thivolet, Lorna Garnier, Lucien Marchand, Christine Lombard, Marc Nicolino, Catherine Wright, Philippe Moulin, Marine Benoit, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, Anti-ZnT8 autoantibodies, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Disease, Biochemistry, 0302 clinical medicine, Child, Glutamate Decarboxylase, General Medicine, Predictive value, autoantigen, 3. Good health, Anti-GAD autoantibodies, Medical Laboratory Technology, Type 1 diabetes, Cohort, Adult, autoantibodies autoimmune diabetes, medicine.medical_specialty, type-1, Adolescent, glutamic-acid decarboxylase, onset, 030209 endocrinology & metabolism, Anti-IA-2, 03 medical and health sciences, Young Adult, children, Internal medicine, Diabetes mellitus, medicine, Humans, islet-cell antibodies, Autoantibodies, Retrospective Studies, Glycated Hemoglobin, business.industry, Biochemistry (medical), Autoantibody, prediction, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Clinical diagnosis, Autoimmune diabetes, zinc transporter 8, identification, business, Biomarkers, mellitus
Abstract

International audience; Aim of the study: Evaluate the added value of screening anti-ZnT8 antibodies (ZnT8A) in addition to the classical anti-GAD (GADA) and anti-IA-2 (IA-2A) antibodies for the diagnosis of type-1 diabetes (T1D) within a large cohort of both children and adults. Materials and methods: Retrospective 2-year study including 516 patients (215 children, 301 adults) who had blood tests at diabetes onset and/or for diabetes classification. ZnT8A, GADA, and IA-2A were analyzed in all samples. Results: Among those individuals included, 142 (28%) were ZnT8A-positive. A total of 228/516 suffered from T1D, of whom 110 (48%) were ZnT8A-positive and 166 (73%) GADA and/or IA-2A positive. When adding ZnT8A to GADA/IA-2A, 184 (81%) patients were positive for \textgreater= 1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with \textgreater= 1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10 years. Fourteen of the 124 patients positive for ZnT8A with a known clinical diagnosis suffered from a disease other than T1D. Conclusions: ZnT8A should be included in routine evaluation at diabetes onset and is a valuable biological marker to classify newly-diagnosed diabetics. The predictive value in our high-risk subjects has to be confirmed.

Published
2018
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25. Multiplex family with GAD65-Abs neurologic syndromes

Author

Gonzalo Montero-Martín, Marcelo Fernandez-Vina, Nicole Fabien, Véronique Rogemond, Aude Belbezier, Emmanuel Mignot, Jérôme Honnorat, and Bastien Joubert

Subjects
0301 basic medicine, Proband, endocrine system diseases, Human leukocyte antigen, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, biology, Cerebellar ataxia, business.industry, Haplotype, Limbic encephalitis, nutritional and metabolic diseases, medicine.disease, Titer, 030104 developmental biology, Neurology, Immunology, biology.protein, Neurology (clinical), Antibody, medicine.symptom, business, 030217 neurology & neurosurgery, Aunt
Abstract

Objective:Neurologic autoimmune syndromes associated with anti–glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic.Methods:We describe a niece and her aunt with GAD65-Abs neurologic syndromes. High-resolution HLA typing of Class I and Class II alleles was performed using next-generation sequencing.Results:The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects.Conclusions:This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs.

Published
2017

26. Heterogeneous clinical spectrum of anti-SRP myositis and importance of the methods of detection of anti-SRP autoantibodies: a multicentric study

Author

Nicolas Molinari, Daniel Bertin, René-Louis Humbel, Sylvain Dubucquoi, Nathalie Streichenberger, Pascale Chretien, Jean Sibilia, Thierry Vincent, Nicole Fabien, Alain Chevailler, Sophie Hue, Sophie Desplat-Jégo, Françoise Fortenfant, Nathalie Bardin, Joëlle Goetz, Daniela Lakomy, Xavier Bossuyt, Catherine Johanet, Isabelle Abreu, Jean-Christophe Lega, Cécile Picard, In Vivo NSA, Centre des Matériaux des Mines d'Alès (C2MA), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Central Laboratory of Immunology, CHU Strasbourg, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie et hématologies biologiques [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Hospices Civils de Lyon (HCL), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Département Immunologie (DéPARTEMENT IMMUNOLOGIE), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bicêtre, Physiopathologie des arthrites, Université Louis Pasteur - Strasbourg I, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)--Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Paul Brousse

Subjects
myalgia, Adult, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Immunoblotting, Immune-mediated necrotizing myopathy, Serology, 03 medical and health sciences, Necrosis, 0302 clinical medicine, Immunodot, Cell Line, Tumor, medicine, Humans, Fluorescent Antibody Technique, Indirect, Myositis, ComputingMilieux_MISCELLANEOUS, Aged, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, biology, medicine.diagnostic_test, Indirect immunofluorescence, business.industry, Autoantibody, IIf, Myalgia, Middle Aged, medicine.disease, 3. Good health, Anti-SRP antibodies, Immunoassay, biology.protein, Creatine kinase, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Antibody, business, Signal Recognition Particle, 030217 neurology & neurosurgery
Abstract

International audience; Anti-signal recognition particle (SRP) antibodies are important serological markers for the diagnosis and the prognosis of idiopathic inflammatory myopathy (IIM), especially to distinguish immune-mediated necrotizing myopathy (IMNM). This study was set up to investigate the phenotype associated with anti-SRP antibodies and to evaluate the methods for detecting these antibodies. Clinical and biological data were retrospectively obtained from 60 adult patients with anti-SRP antibodies detected by a dot immunoassay from 12 centers. Thirty-six (60 %) out of these 60 patients suffered from an IIM, and among them, 21 patients were diagnosed as IMNM. Among patients with a definite IIM, proximal weakness and myalgia were prominent symptoms at the time of diagnosis. Only few patients displayed severe extra-muscular symptoms such as cardiac involvement or severe myositis. Mean creatine kinase levels were high for all patients except for two of them. When testing by indirect immunofluorescence (IIF) on HEp2 cells, the fraction of patients displaying the typical anti-SRP fine speckled staining of the cytoplasm was higher in patients with IIM (30/36) (83 %) than in patients with non-IIM (3/24) (12.5 %) (p

Published
2016
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27. Multiple autoantibodies at onset do not accurately predict long-term pancreatic beta-cell fate in a 13-year-old obese child with immediate insulin-requiring diabetes

Author

Nicole Fabien, B.O. Roep, Charles Thivolet, Lucien Marchand, Marc Nicolino, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Beta-cell fate, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Type 1 diabetes, business.industry, Insulin, Autoantibody, General Medicine, medicine.disease, Obesity, 3. Good health, Multiple autoantibodies, Immunology, Beta cell, business
Abstract

International audience

Published
2016
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28. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children

Author

Marine Desjonquères, Nicole Fabien, Jean-Christophe Lega, Alexandre Belot, Jean-Paul Larbre, Natalia Cabrera, Agnès Duquesne, Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL], Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Immunology, Arthritis, Context (language use), Systemic Lupus Erythematosus, Dermatomyositis, Autoimmune Diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mixed connective tissue disease, Tocilizumab, Rheumatology, medicine, Immunology and Allergy, 030212 general & internal medicine, Juvenile Idiopathic Arthritis, 030203 arthritis & rheumatology, business.industry, Autoantibody, Paediatric Rheumatology, Overlap syndrome, medicine.disease, Connective tissue disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, chemistry, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, business
Abstract

International audience; Arthritis is one of the main manifestations of mixed connective tissue disease (MCTD) and overlap syndrome in children and can be responsible for functional disability. We report on 2 children with arthritis that were dramatically improved by a treatment with interleukin-6 (IL-6) blockers in the context of connective tissue disease. However, in both cases, other systemic autoimmune symptoms were not modified by the treatment and autoantibodies tend to increase, suggesting a differential effect of IL-6 inhibition on articular inflammation and systemic autoimmunity.

Published
2016
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29. Early-onset hypoparathyroidism and chronic keratitis revealing APECED

Author

E.H. Kemp, Aurélia Bertholet-Thomas, Anthony P. Weetman, Nicole Fabien, Michael Morris, Justine Bacchetta, Alexandre Belot, P. Cochat, Solange Milazzo, Ellia Mezgueldi, Department of Nephrology-Rheumatology-Dermatology Pediatric, Bron, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Synlab [Lausanne], Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Sheffield [Sheffield], Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, animal structures, hypocalcaemia, Case Reports, Disease, Keratitis, AIRE, medicine, Hypocalcaemia, Chronic mucocutaneous candidiasis, Adrenocortical Insufficiency, Past medical history, business.industry, Dystrophy, hypoparathyroidism, General Medicine, medicine.disease, Dermatology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, keratitis, Hypoparathyroidism, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, APECED
Abstract

International audience; Early diagnosis of potentially life-threatening autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is crucial, but is often delayed due to the clinical heterogeneity of the disorder. Even in the absence of the classic disease triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency, a diagnosis of APECED should be considered in children who have hypoparathyroidism and chronic keratitis, with a past medical history showing a mild and transient Candida infection.

Published
2015
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30. Long-term disease course in a patient with severe neonatal IPEX syndrome

Author

Rémi Duclaux-Loras, Sophie Collardeau-Frachon, Nicole Fabien, Alain Lachaux, Stéphane Nancey, Dominique Kaiserlian, Hepatologie Gastroentérologie et Nutrition, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Mucosal Immunity, Vaccination, and Biometrics -- Immunité des muqueuses, vaccinations et biothérapies, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [Hôpital Femme-Mère-Enfant, HCL], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Autophagie infection et immunité - Autophagy Infection Immunity (APY), Service d'Hépatologie et de Gastroentérologie [Lyon], Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Liver Cirrhosis, Pediatrics, Endoscopy, Gastrointestinal, Medicine, Enteropathy, Young adult, education.field_of_study, Gastroenterology, Genetic Diseases, X-Linked, 3. Good health, Immune System Diseases, Genetic Diseases, Combination, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cyclosporine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, Stem cell, Immunosuppressive Agents, Type 1, Glomerular Filtration Rate, Diarrhea, medicine.medical_specialty, Gastrointestinal, Prednisolone, Population, Young Adult, Pharmacotherapy, Drug Therapy, Diabetes mellitus, Diabetes Mellitus, Humans, education, Glucocorticoids, Hepatology, business.industry, Infant, Newborn, Infant, Endoscopy, IPEX syndrome, X-Linked, Mycophenolic Acid, Immunoglobulin E, medicine.disease, Newborn, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Transplantation, Diabetes Mellitus, Type 1, Immunology, business, Follow-Up Studies
Abstract

International audience; We report here on the clinical, histological and immunological findings regarding a patient with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome who was treated for the first 21 years with a combination of immunosuppressant agents (IS). The potential modalities of care and treatment options in this rare and severe immune-mediated disorder are discussed. So, long-term outcome for IPEX patients can be obtained with immunosuppressive treatment, which is important since the outcome of haematopoietic stem cell transplantation for this population is variable.

Published
2015
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31. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Author

Marie Therese Zabot, Jolan E. Walter, Anne Laure Mathieu, Marie Chansel, Gillian I. Rice, Jean-Pierre de Villartay, Luigi D. Notarangelo, Christine Ménétrier-Caux, François Plenat, Nicole Fabien, Brigitte Balme, Kari C. Nadeau, Chantal Rigal, E. Helen Kemp, Annick Lim, Christophe Malcus, Yves Bertrand, Sébastien Viel, Mirjam van der Burg, Despina Moshous, Jacques Bienvenu, A. Phan, Christine Bardin, Catharina Schuetz, Thierry Walzer, Christophe Caux, Capucine Picard, Ana Delgado, David J. Chen, Manish J. Butte, Krisztian Csomos, Isabelle Rouvet, Karin Chen, Jean François Meritet, Alexandre Belot, Héloïse Reumaux, Fanny Fouyssac, Pierre Cochat, Yanick J. Crow, Estelle Verronese, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Service d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Immunology and Inflammatory Diseases [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Department of Microbiology and Immunology [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Texas Southwestern Medical Center, University of Utah School of Medicine [Salt Lake City], Department of Pediatrics and Adolescent Medicine, Universität Ulm - Ulm University [Ulm, Allemagne], Unité Pédiatrique [Jeanne de Flandre], Hôpital Jeanne de Flandre [Lille], Service de Pathologie [CHRU Nancy], Epidémiologie, Pharmacologie, Investigation Clinique, Information médicale, Mère-Enfant (EPICIME), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Sheffield [Sheffield], Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France, parent, Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Institut Pasteur [Paris] (IP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine, St Mary's Hospital-Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Sciences Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology and Immunology, Stanford University School of Medicine [CA, USA], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], and Immunology

Subjects
Male, DNA End-Joining Repair, Skin Neoplasms, DCLRE1C, Autoimmunity, DNA-Activated Protein Kinase, medicine.disease_cause, DNA-Dependent Protein Kinase Catalytic Subunit, Immune tolerance, Mice, Immunology and Allergy, DNA-PKcs, B-Lymphocytes, Granuloma, tolerance, PRKDC, recombination-activating gene, V(D)J recombination, Nuclear Proteins, severe combined immunodeficiency, Autoimmune regulator, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adolescent, Immunology, Biology, Article, Young Adult, Th2 Cells, SDG 3 - Good Health and Well-being, medicine, Immune Tolerance, Animals, Humans, Autoantibodies, Severe combined immunodeficiency, Immunologic Deficiency Syndromes, Th1 Cells, VDJ recombination, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, V(D)J Recombination, Gene Expression Regulation, DNA-dependent protein kinase catalytic subunit, Mutation, Cancer research, Transcription Factors
Abstract

International audience; BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T~cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in~vitro. The latter defect correlated in~vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1~had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

Published
2015
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32. Idiopathic inflammatory myopathies and the lung

Author

Alexandre Belot, Isabelle Durieu, Nicole Fabien, Jean-Christophe Lega, Quitterie Reynaud, Vincent Cottin, Service de Médecine Interne Vasculaire, Hospices Civils de Lyon (HCL), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Hôpital Femme-Mère-Enfant, Département Immunologie (DéPARTEMENT IMMUNOLOGIE), Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), and Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Pathology, Time Factors, Pneumologie et système respiratoire, morbidity, Comorbidity, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Risk Factors, morbidité, Lung, maladie inflammatoire, Myositis, Interstitial lung disease, respiratory system, Prognosis, 3. Good health, inflammatory disease, maladie pulmonaire, medicine.anatomical_structure, Disease Progression, Drug Therapy, Combination, Immunosuppressive Agents, myopathy, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Malignancy, 03 medical and health sciences, Pleural disease, Predictive Value of Tests, medicine, Animals, Humans, respiratory system diseases, Pulmonology and respiratory tract, Autoantibodies, myopathie, 030203 arthritis & rheumatology, lcsh:RC705-779, business.industry, lcsh:Diseases of the respiratory system, Dermatomyositis, medicine.disease, mortality, 030228 respiratory system, Inclusion body myositis, business, Lung Diseases, Interstitial, mortalité, Biomarkers
Abstract

Idiopathic inflammatory myositis (IIM) is a group of rare connective tissue diseases (CTDs) characterised by muscular and extramuscular signs, in which lung involvement is a challenging issue. Interstitial lung disease (ILD) is the hallmark of pulmonary involvement in IIM, and causes morbidity and mortality, resulting in an estimated excess mortality of 50% in some series. Except for inclusion body myositis, these extrapulmonary disorders are associated with the general and visceral involvement frequently found in other CTDs including fever, Raynaud's phenomenon, arthralgia, nonspecific cutaneous modifications and ILD, for which the prevalence is estimated to be up to 65%. Substantial heterogeneity exists within the spectrum of IIMs, and each condition is associated with various frequencies and subtypes of pulmonary involvement. This heterogeneity is partly related to the presence of various autoantibodies encompassing anti-synthetase, anti-MDA5 and anti-PM/Scl. ILD is present in all subsets of IIM including juvenile myositis, but is more frequent in dermatomyositis and overlap myositis. IIM can also be associated with other presentations of respiratory involvement, namely pulmonary arterial hypertension, pleural disease, infections, drug-induced toxicity, malignancy and respiratory muscle weakness. Here, we critically review the current knowledge about adult and juvenile myositis-associated lung disease with a detailed description of therapeutics for chronic and rapidly progressive ILD.

Published
2015
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33. Mutations in CECR1 associated with a neutrophil signature in peripheral blood

Author

Thierry Walzer, Sophie Collardeau-Frachon, Nicole Fabien, Laurent Derex, Isabelle Durieu, Jean-Christophe Lega, Marinka Twilt, Gillian I. Rice, Alexandre Belot, Christophe Malcus, Anne Laure Mathieu, Anthony Oojageer, Julie Demaret, Paul R. Kasher, Leo A. H. Zeef, Yanick J. Crow, Evangeline Wassmer, Laura Mechtouff, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Rares, Hospices Civil de Lyon, Birmingham Children’s Hospital, Aarhus University Hospital, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Faculty of Life Sciences [Manchester], University of Manchester [Manchester], Faculty of Medical and Human Sciences, Laboratoire d'Immunologie, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Pathology and Neuropathology Department, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, Hospices Civiles de Lyon, Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adenosine Deaminase 2 Deficiency, Male, Vasculitis, Neutrophils, Adenosine Deaminase, Neutrophil signature, Aicardi-Goutières syndrome, medicine.disease_cause, ADA2, Neutrophil Activation, SAM Domain and HD Domain-Containing Protein 1, Young Adult, Rheumatology, Agammaglobulinemia, Immunology and Allergy, Medicine, Humans, Pediatrics, Perinatology, and Child Health, Child, Type I interferon, Alleles, Monomeric GTP-Binding Proteins, Mutation, Severe combined immunodeficiency, business.industry, Polyarteritis nodosa, Interferon-stimulated gene, Research, CECR1, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, SAMHD1, 3. Good health, Pediatrics, Perinatology and Child Health, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Aicardi–Goutières syndrome, Intercellular Signaling Peptides and Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, Severe Combined Immunodeficiency, Interferons, business, Systemic vasculitis, Genome-Wide Association Study
Abstract

Background A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis. Methods Considering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutières syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients. Results We identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils. Conclusions We hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process. Electronic supplementary material The online version of this article (doi:10.1186/1546-0096-12-44) contains supplementary material, which is available to authorized users.

Published
2014
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34. The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome

Author

Nicole Fabien, Vincent Cottin, Jean-François Cordier, Jean-Christophe Lega, Isabelle Durieu, Quitterie Reynaud, Stéphane Durupt, Marine Dutertre, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), PRES Université de Lyon, Rétrovirus et Pathologie Comparée, Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, systemic sclerosis, [SDV]Life Sciences [q-bio], Immunology, anti-aminoacyl-tRNA synthetase autoantibodies, anti-PM/Scl autoantibodies, Antisynthetase syndrome, Gastroenterology, Amino Acyl-tRNA Synthetases, Cohort Studies, Internal medicine, Immunology and Allergy, Medicine, Humans, Myositis, Autoantibodies, interstitial lung disease, business.industry, Autoantibody, Interstitial lung disease, Cancer, Sclerodactyly, medicine.disease, Rash, 3. Good health, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, business, myositis, Cohort study
Abstract

International audience; Objective: To describe the clinical spectrum associated with aminoacyl-transfer RNA synthetase (ARS) autoantibodies in patients with idiopathic inflammatory myositis defined according to Peter and Bohan's criteria. Methods: Cohort studies were selected from MEDLINE and Embase up to August 2013. Two investigators independently extracted data on study design, patient characteristics, and clinical features (interstitial lung disease [ILD], fever, mechanic's hands [MH], Raynaud's phenomenon [RPh], arthralgia, sclerodactyly, cancer and dermatomyositis-specific rash) according to the presence of myositis-specific (anti-aminoacyl-transfer RNA synthetase [ARS], anti-signal recognition particle [anti-SRP] and anti-Mi2) and myositis-associated (anti-PM/Scl, anti-U1-RNP and anti-Ku) autoantibodies. Results: 27 studies (3487 patients) were included in the meta-analysis. Arthralgia (75%, CI 67-81) and IW (69%, CI 63-74) were the most prevalent clinical signs associated with anti-ARS autoantibodies. Anti-Mi2 and anti-SRP autoantibodies were associated with few extramuscular signs. ARS autoantibodies were identified in 13% of patients with cancer-associated myositis (5-25). Patients with non-anti-Jo1 ARS had greater odds of presenting fever (RR 0.63, CI 0.52-0.90) and ILD (RR 0.87, CI 0.81-0.93) compared to those with anti-Jol autoantibodies. The frequencies of myositis (RR 1.60, CI 1.38-1.85), arthralgia (RR 1.52, CI 1.32-1.76) and MH (RR 1.47, CI 1.11-1.94) were almost 50% higher in patients with anti-Jo1 compared to non-anti-Jo1 ARS autoantibodies. Patients with anti-PM/Scl differed from those with anti-ARS autoantibodies by a greater prevalence of RPh (RR 0.70, CI 0.53-0.94) and sclerodactyly (RR 0.47, Cl 025-0.89). IID was less frequent in patients with anti-Ul-RNP autoantibodies (RR 3.35, CI 1.07-10.43). No difference was observed between anti-ARS and myositis-associated autoantibodies for other outcomes. Conclusions: The presence of anti-ARS autoantibodies delimits a heterogeneous subset of patients with a high prevalence of myositis, MH, arthralgia in anti-Jo1 patients, and RPh and fever in non-anti-Jo1 patients. The clinical signs of populations positive for anti-PM/Scl and anti-ARS autoantibodies largely overlap, especially with regard to ILD, challenging the clinical delimitation of the antisynthetase syndrome.

Published
2014
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35. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies

Author

Catharina Eriksson, Torsten Witte, Yehuda Shoenfeld, Johan Rönnelid, Nancy Agmon-Levin, Edward K. L. Chan, Ulrich Sack, Antonella Radice, Allan Wiik, Xavier Bossuyt, Maria José Rego Sousa, Markku Viander, Olli Vainio, Carlos Tadeu dos Santos Dias, Robert Lahita, Aresio Plaza-Lopez, L. Musset, Pier Luigi Meroni, Jan Damoiseaux, Stephan Regenass, Olof Hultgren, Marvin J. Fritzler, Renato Alberto Sinico, Munther A. Khamashta, I. Garcia-De La Torre, Cornelis Kallenberg, Merlin R. Wilson, Ricard Cervera, Daniel Bloch, Nicole Fabien, Manfred Herold, Konstantin N. Konstantinov, Angela Tincani, Luis Eduardo Coelho Andrade, University of Zurich, Shoenfeld, Yehuda, Agmon Levin, N, Damoiseaux, J, Kallenberg, C, Sack, U, Witte, T, Herold, M, Bossuyt, X, Musset, L, Cervera, R, Plaza Lopez, A, Dias, C, José Sousa, M, Radice, A, Eriksson, C, Hultgren, O, Viander, M, Khamashta, M, Regenass, S, Coelho Andrade, L, Wiik, A, Tincani, A, Rönnelid, J, Bloch, D, Fritzler, M, Chan, E, Garcia De La Torre, I, Konstantinov, K, Lahita, R, Wilson, M, Vainio, O, Fabien, N, Sinico, R, Meroni, P, Shoenfeld, Y, MUMC+: DA CDL Algemeen (9), Interne Geneeskunde, RS: NUTRIM - R4 - Gene-environment interaction, and Universitat de Barcelona

Subjects
Standardization, Anti-nuclear antibody, Extractable nuclear antigens, 2745 Rheumatology, INDIRECT IMMUNOFLUORESCENCE, Autoimmune diseases, Autoimmunity, Antígens, organization, GUIDELINES, Autoantigens, Immunology and Allergy, Sjøgren's Syndrome, Immunologic Test, SYSTEMIC-LUPUS-ERYTHEMATOSUS, HEALTHY-INDIVIDUALS, Indirect immunofluorescence, Malalties autoimmunitàries, Autoantibodie, ANA, COMMERCIAL KITS, Sjogren's syndrome, Antibodies, Antinuclear, 2723 Immunology and Allergy, Systemic Lupus Erythematosu, Human, medicine.medical_specialty, Immunology, MEDLINE, 610 Medicine & health, Immunologic Tests, Systemic Lupus Erythematosus, AUTOIMMUNE-DISEASES, General Biochemistry, Genetics and Molecular Biology, Arthritis foundation, Rheumatic Disease, Rheumatology, Autoantigen, 1300 General Biochemistry, Genetics and Molecular Biology, organization.non_profit_organization, Allergy and Immunology, Rheumatic Diseases, Terminology as Topic, SjOgren's Syndrome, medicine, Humans, DIAGNOSTIC-ACCURACY, Antigens, EXTRACTABLE NUCLEAR ANTIGENS, Autoantibodies, RHEUMATIC-DISEASES, 2403 Immunology, Biochemistry, Genetics and Molecular Biology (all), Lupus erythematosus, business.industry, Autoantibody, Family medicine, Lupus eritematós, 10033 Clinic for Immunology, Síndrome de Sjögren, Cellular antigens, business
Abstract

Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p

Published
2013

36. Development of miniaturized immunoassay: Influence of surface chemistry and comparison with enzyme-linked immunosorbent assay and Western blot

Author

Eliane Souteyrand, Dominique Rigal, Jean-Pierre Cloarec, Agnes Desbos, Emmanuelle Laurenceau, Nicole Fabien, Yves Mérieux, Yann Chevolot, Graziella El Khoury, INL - Chimie et Nanobiotechnologies (INL - C&N), Institut des Nanotechnologies de Lyon (INL), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École supérieure de Chimie Physique Electronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-École supérieure de Chimie Physique Electronique de Lyon (CPE), EFS, Hospices Civils de Lyon (HCL), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École supérieure de Chimie Physique Electronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pyran Copolymer, Autoimmune diseases, Blotting, Western, Protein Array Analysis, Biophysics, Enzyme-Linked Immunosorbent Assay, 01 natural sciences, Biochemistry, MAMVE copolymer, Histones, 03 medical and health sciences, Protein structure, Western blot, medicine, Humans, Lupus Erythematosus, Systemic, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Autoantibodies, 030304 developmental biology, Immunoassay, Detection limit, 0303 health sciences, Miniaturization, biology, medicine.diagnostic_test, Chemistry, 010401 analytical chemistry, Autoantibody, Protein microarrays, Cell Biology, [CHIM.MATE]Chemical Sciences/Material chemistry, Silanes, Molecular biology, Surface chemistry, 0104 chemical sciences, 3. Good health, Immobilized Proteins, Protein immobilization, biology.protein, Protein microarray, DNA microarray, Antibody, [CHIM.OTHE]Chemical Sciences/Other
Abstract

Protein microarray technology provides a useful approach for the simultaneous serodetection of various antibodies in low sample volumes. To implement functional protein microarrays, appropriate surface chemistry must be designed so that both the protein structure and the biological activity can be retained. In the current study, two surface chemistries for protein microarrays and immunofluorescent assays were developed. Glass slides were functionalized with N-hydroxysuccinimide (NHS) ester via a monofunctional silane or maleic anhydride-alt-methyl vinyl ether (MAMVE) copolymer to allow covalent grafting of histone proteins. Analytical performance of these microarrays was then evaluated for the detection of anti-histone autoantibodies present in the sera of patients suffering from a systemic autoimmune disease, namely systemic lupus erythematosus (SLE), and the results were compared with those of the classical enzyme-linked immunosorbent assay (ELISA) and Western blot. The detection limit of our MAMVE copolymer microarrays was 50-fold lower than that of the classical ELISA. Furthermore, 100-fold less volume of biological samples was required with these miniaturized immunoassays.

Published
2010
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37. Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: Results of a multicenter study

Author

René-Louis Humbel, Eric Ballot, P Chamouard, J Sarles, S Desplat-Jégo, Nicole Fabien, A Escande, JJ Baudon, M Veyrac, Joëlle Goetz, N O Olsson, Catherine Johanet, and Jean-Charles Grimaud

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Saccharomyces cerevisiae, Inflammatory bowel disease, Sensitivity and Specificity, Coeliac disease, Antibodies, Antineutrophil Cytoplasmic, Cohort Studies, Diagnosis, Differential, Crohn Disease, Clinical Research, Medicine, Humans, Child, Fluorescent Antibody Technique, Indirect, Antibodies, Fungal, Aged, Retrospective Studies, Indirect immunofluorescence, biology, business.industry, Gastroenterology, Inflammatory Bowel Diseases, General Medicine, Middle Aged, medicine.disease, biology.organism_classification, digestive system diseases, Pancreas, Exocrine, Celiac Disease, Cross-Sectional Studies, Multicenter study, Exocrine pancreas, Antibodies, Antinuclear, Immunology, Chronic Disease, biology.protein, Colitis, Ulcerative, Female, Antibody, business, Biomarkers
Abstract

Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-nuclear associated anti-neutrophil antibodies (NANA) and antibodies to exocrine pancreas (PAB), are serological tools for discriminating Crohn's disease (CrD) and ulcerative colitis (UC). Like CrD, coeliac disease (CoD) is an inflammatory bowel disease (IBD) associated with (auto) antibodies. Performing a multicenter study we primarily aimed to determine the performance of ASCA, NANA and PAB tests for IBD diagnosis in children and adults, and secondarily to evaluate the prevalence of these markers in CoD.Sera of 109 patients with CrD, 78 with UC, 45 with CoD and 50 healthy blood donors were retrospectively included. ASCA, NANA and PAB were detected by indirect immunofluorescence (IIF).ASCA+/NANA- profile displayed a positive predictive value of 94.2% for CrD. Detection of ASCA was correlated with a more severe clinical profile of CrD and treatment of the disease did not influence their serum levels. ASCA positivity was found in 37.9% of active CoD. PAB were found in 36.7% CrD and 13.3% CoD patients and were not correlated with clinical features of CrD, except with an early onset of the disease. Fifteen CrD patients were ASCA negative and PAB positive.ASCA and PAB detected by IIF are specific markers for CrD although their presence does not rule out a possible active CoD. The combination of ASCA, NANA and PAB tests improves the sensitivity of immunological markers for CrD. Repeating ASCA, NANA, and PAB testing during the course of CrD has no clinical value.

Published
2007

38. Clinical significance of anti-histidyl-tRNA synthetase (Jo1) Autoantibodies

Author

Jacques Ninet, Nicole Fabien, H. Rousset, Jacques Tebib, Jean-François Cordier, Emeline Gomard-Mennesson, Hospices Civils de Lyon (HCL), U851, Institut National de la Santé et de la Recherche Médicale (INSERM), Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), and ProdInra, Migration

Subjects
Male, Anti-nuclear antibody, Cells, [SDV]Life Sciences [q-bio], JO1, Fluorescent Antibody Technique, Antisynthetase syndrome, General Biochemistry, Genetics and Molecular Biology, Histidine-tRNA Ligase, AUTOIMMUNE DISEASE, 03 medical and health sciences, 0302 clinical medicine, History and Philosophy of Science, medicine, MYOSITIS, Humans, ANTISYNTHETASE SYNDROME, Myositis, 030304 developmental biology, 030203 arthritis & rheumatology, Autoimmune disease, 0303 health sciences, business.industry, ANTI-HISTIDYL-TRNA SYNTHETASE, General Neuroscience, Autoantibody, Syndrome, Middle Aged, medicine.disease, Anti-thyroid autoantibodies, 3. Good health, [SDV] Life Sciences [q-bio], Titer, Immunology, Female, AUTOANTIBODIES, business, Anti-SSA/Ro autoantibodies
Abstract

Autoimmunity, Part A Basic Principles and New Diagnostic Tools; International audience; The clinical significance of a discovery of anti-histidyl-tRNA synthetase (Jo1) autoantibodies patients was established in the early diagnosis of antisynthetase syndrome (ASS) as the common form of this pathology is characterized by interstitial lung disease (ILD), inflammatory muscle disease, and production of anti-Jo1 autoantibodies. However, the specificity of such autoantibodies has to be evaluated in daily clinical practice. In this study, the clinical and prognostic profiles of 45 patients displaying anti-Jo1 autoantibodies were determined. Among 36 patients with a titer of anti-Jo1 autoantibodies above the cutoff value suggested by the manufacturer (40 AU/mL), three different groups were identified. The first group (n = 26) suffered from a complete or incomplete ASS and showed anti-Jo1 autoantibodies mostly above 60 AU/mL. A second group (n = 7) suffered from another autoimmune disease, that is, a systemic lupus erythematosus, cutaneous lupus and rheumatoid arthritis, and Crohn's disease with anti-Jo1 autoantibodies mostly below 60 AU/mL. The third group (n = 3) did not suffer from any autoimmune disease and presented anti-Jo1 autoantibodies below 60 AU/mL. The nine doubtful cases (titer of anti-Jo1 autoantibodies of 30-39 AU/mL) were from patients with no ASS nor myositis. Only 27 out of 45 patients showed antinuclear antibodies with 15 sera showing a pattern characteristic of anti-Jo1 autoantibodies by indirect immunofluoreseence on HEp2 cells. In conclusion, this study underlines the need to search for anti-Jo1 autoantibodies even if antinuclear antibodies are negative by indirect immunofluorescence and underlines the usefulness of anti-Jo1 antibodies of titer above 60 AU/mL in the diagnosis of complete or incomplete ASS.

Published
2007
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39. When to stop in the quest of formes frustes of connective tissue disease ?

Author

Jean-François Cordier, Nicole Fabien, Jean-Christophe Lega, Vincent Cottin, ProdInra, Migration, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), BioSciences Lyon-Gerland (BLG), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), and École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
030203 arthritis & rheumatology, medicine.medical_specialty, Pathology, business.industry, [SDV]Life Sciences [q-bio], SYSTEMIC-SCLEROSIS, Autoantibody, General Medicine, SCLEROSIS SINE SCLERODERMA, INTERSTITIAL LUNG-DISEASE, medicine.disease, Connective tissue disease, Rheumatology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, medicine, FIBROSIS, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

40. Diagnostic value of anti-F-actin antibodies in a French multicenter study

Author

P Chretien-Leprince, A Escande, Joëlle Goetz, C Andre, Alain Chevailler, Eric Ballot, N O Olsson, S Jego, S Dubuquoi, Catherine Johanet, F Oksman, Marielle Sanmarco, René-Louis Humbel, Nicole Fabien, Khrestchatisky, Michel, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Adolescent, Autoimmune hepatitis, Disease, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, Age Distribution, History and Philosophy of Science, Internal medicine, Cell Line, Tumor, medicine, Animals, Humans, Multicenter Studies as Topic, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, Connective Tissue Diseases, Fluorescent Antibody Technique, Indirect, Aged, Retrospective Studies, Hepatitis, Aged, 80 and over, Chi-Square Distribution, biology, business.industry, General Neuroscience, Antibody titer, IIf, Muscle, Smooth, Middle Aged, medicine.disease, SMA, Hepatitis C, Actins, Rats, Hepatitis, Autoimmune, Antibodies, Antinuclear, Child, Preschool, biology.protein, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, Antibody, business, Viral hepatitis, Colchicine
Abstract

According to international criteria, autoimmune hepatitis (AIH) type 1 is characterized by the presence of antinuclear or anti-smooth muscle antibodies (SMA) with F-actin specificity. SMA have been found in 85% of AIH patients, but are not specific to this disease, and anti-F-actin specificity is not always verified when SMA are detected. The objective of this study was to determine the diagnostic value of anti-F-actin antibodies in a large population. A multicenter study involving 12 clinical centers was performed. Patients were selected on the basis of the presence of F-actin SMA detected by indirect immunofluorescence (IIF) on rat liver-kidney-stomach sections and was confirmed by IIF on Hep2 cells treated with colchicine, or F-actin dot-blot. The clinical status of patients was determined from their medical records. One hundred sixty-eight patients were included: 76% women, 24% men; mean age of 45 years (range, 2-88 years), with a bimodal age distribution. Sixty percent had AIH type 1, and 40% had another disease. In the group of women younger than 25 years, 90% had AIH type 1. Other pathologies associated with antiactin were other liver diseases (19%), including viral hepatitis C (7%), and non-liver diseases (21%), including connective tissue diseases (12%). Antibody titers were higher in AIH than in other diseases. Antiactin antibodies are of major diagnostic value in AIH, especially in young women; they may be found in other disease settings, but mostly at low levels.

Published
2005

41. Autoantibodies directed against the ribosomal P proteins are not only directed against a common epitope of the P0, P1 and P2 proteins

Author

Cécile Alves de Olivera, Annick Moreira, Agnes Desbos, Jean-Claude Monier, Patricia Surgey, Jean-Paul Reboud, Jacques Bienvenu, Annick Venot, Hubert Perrier, Philippe Gonzalo, Jean-Pierre Lavergne, Nicole Fabien, and Deleage, Gilbert

Subjects
Ribosomal Proteins, medicine.drug_class, Immunology, Immunoblotting, Molecular Sequence Data, Protozoan Proteins, Peptide, Biology, Monoclonal antibody, Autoantigens, Epitope, law.invention, Epitopes, Mice, Ribosomal protein, law, Antibody Specificity, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immunology and Allergy, Animals, Humans, Lupus Erythematosus, Systemic, Amino Acid Sequence, Autoantibodies, chemistry.chemical_classification, Autoantibody, Ribosomal RNA, Phosphoproteins, Molecular biology, Peptide Fragments, Recombinant Proteins, chemistry, Case-Control Studies, Monoclonal, Recombinant DNA
Abstract

The autoantibodies (aAbs) directed against the ribosomal P proteins (RPP aAbs) are known to react mainly against epitopes localized within the common C-terminal sequence of the three acidic ribosomal P proteins, P0, P1 and P2. In order to investigate the opportunity to select short recombinant peptides of this common C-terminal sequence to detect the RPP-aAbs, the location of the epitopes recognized by ribosomal proteins (RP) aAb(+)sera of systemic lupus erythematosus patients (SLE) was investigated. Immunoblotting and ELISA techniques using extracted or recombinant, entire or cleaved RPP showed that 55% of the RP aAbs were directed against the three ribosomal P0, P1, and P2 proteins. The epitopes recognized by the RPP aAbs are located not only within the C-terminal sequence common to the three proteins but also within the N-terminal sequence of the P2 or P1 protein. The other RP aAbs sera (45%) did not react with all three proteins but with some of them, and showed the following pattern: P0(+)P1(+); P1(+); P2(+); P0(+)and P1(+). They recognized epitopes located in the region of the C-terminal sequence of the protein but not common to the three proteins. In addition two out of the six monoclonal Abs produced by immunization of mice using the P1 protein did not react with the peptide N-65 or N-71 of the P2 protein or with the C-terminal sequence of the three proteins. In conclusion, this study showed that the RPP aAb in SLE patients are not only directed against epitopes within the C-terminal sequence shared by the three acidic ribosomal P proteins. In view of these data it seems necessary to be cautious in using only a C-terminal peptide of ribosomal P proteins in tests performed to detect RPP aAb in human sera.The autoantibodies (aAbs) directed against the ribosomal P proteins (RPP aAbs) are known to react mainly against epitopes localized within the common C-terminal sequence of the three acidic ribosomal P proteins, P0, P1 and P2. In order to investigate the opportunity to select short recombinant peptides of this common C-terminal sequence to detect the RPP-aAbs, the location of the epitopes recognized by ribosomal proteins (RP) aAb(+)sera of systemic lupus erythematosus patients (SLE) was investigated. Immunoblotting and ELISA techniques using extracted or recombinant, entire or cleaved RPP showed that 55% of the RP aAbs were directed against the three ribosomal P0, P1, and P2 proteins. The epitopes recognized by the RPP aAbs are located not only within the C-terminal sequence common to the three proteins but also within the N-terminal sequence of the P2 or P1 protein. The other RP aAbs sera (45%) did not react with all three proteins but with some of them, and showed the following pattern: P0(+)P1(+); P1(+); P2(+); P0(+)and P1(+). They recognized epitopes located in the region of the C-terminal sequence of the protein but not common to the three proteins. In addition two out of the six monoclonal Abs produced by immunization of mice using the P1 protein did not react with the peptide N-65 or N-71 of the P2 protein or with the C-terminal sequence of the three proteins. In conclusion, this study showed that the RPP aAb in SLE patients are not only directed against epitopes within the C-terminal sequence shared by the three acidic ribosomal P proteins. In view of these data it seems necessary to be cautious in using only a C-terminal peptide of ribosomal P proteins in tests performed to detect RPP aAb in human sera.

Published
1999

42. A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Author

Jan Holmgren, I. Bergerot, Carola Rask, Cecil Czerkinsky, Jacob Petersen, Valerie Moulin, Marianne Lindblad, Corinne Ploix, Nicole Fabien, A. Mayer, and Charles Thivolet

Subjects
Cholera Toxin, Immunoconjugates, medicine.medical_treatment, T-Lymphocytes, Administration, Oral, Nod, Islets of Langerhans, Mice, Immune system, Antigen, Cell Movement, Mice, Inbred NOD, medicine, Animals, Insulin, Vibrio cholerae, Autoimmune disease, Immunosuppression Therapy, geography, Multidisciplinary, geography.geographical_feature_category, business.industry, Biological Sciences, Toxoids, medicine.disease, Islet, Adoptive Transfer, Diabetes Mellitus, Type 1, Immunology, Female, Lymph Nodes, Beta cell, business, Insulitis
Abstract

Mucosally induced immunological tolerance is an attractive strategy for preventing or treating illnesses resulting from untoward inflammatory immune reactions against self- or non-self-antigens. Oral administration of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental autoimmune and allergic disorders. However, the approach often requires repeated feeding of large amounts of tolerogens over long periods and is only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune disease. We have recently shown that oral administration of microgram amounts of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune animals. We now report that feeding small amounts (2–20 μg) of human insulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice. The protective effect could be transferred by T cells from CTB-insulin-treated animals and was associated with reduced lesions of insulitis. Furthermore, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells from congenic Thy-1,1 mice fed with CTB-insulin demonstrated a selective recruitment of Thy-1,1 donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration. These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.

Published
1997

43. Insulin-like growth factor-1 (IGF-1) protects NOD mice from insulitis and diabetes

Author

Nicole Fabien, Charles Thivolet, V. Maguer, and I. Bergerot

Subjects
CD4-Positive T-Lymphocytes, Male, medicine.medical_specialty, Adoptive cell transfer, T cell, Immunology, Nod, CD8-Positive T-Lymphocytes, Islets of Langerhans, Mice, Mice, Inbred NOD, Internal medicine, Immunology and Allergy, Medicine, Animals, Insulin-Like Growth Factor I, Proinsulin, NOD mice, Immunity, Cellular, business.industry, Immunization, Passive, medicine.disease, Recombinant Proteins, medicine.anatomical_structure, Endocrinology, Diabetes Mellitus, Type 1, Female, Beta cell, business, Insulitis, CD8, Research Article
Abstract

SUMMARYTo evaluate the effect of IGF-1 on the autoimmune process of d cell destruction, permissive non-obese diabetic (NOD) recipients were adoptively transferred with 7 × 106 autoreactive T cells from diabetic NOD mice and were administered subcutaneously 10μ;g rhIGF-1, twice daily for 3 weeks. Administration of rhIGF-1 reduced the final incidence of successful transfers of diabetes observed in only 6/24 mice (25%) versus 12/21 (57%) in control mice. A marked reduction of insulitis during histological analysis of pancreatic glands was also observed. Mice treated with rhIGF-1 had a higher percentage of intact islets (486 ± 12% versus 16 ± 1·1%. P= 0·001) and a lower percentage of infiltrated islets. Islets from rhIGF-1-treated mice had a more intense insulin staining reflecting a higher β cell mass, but no difference was observed in the amount of insulin content of pancreatic extracts and in the amounts of mRNA transcripts for proinsulin. No difference was also observed in the titres of three islet cell antibody (ICA)-positive sera and in the pattern of A2B5 staining. Some mice developed diabetes and severe islet cell infiltration despite rhIGF-1, thus indicating that some committed T cells were still able to invade the islets and cause β cell destruction. The percentages of CD4+ and CD8+ T cells in the spleen of experimental mice were similar. To evaluate the effects of rhIGF-1 on cell trafficking in recipient mice, T cells from diabetic NOD Thy-1,2 mice injected into congenic NOD-N Thy-1,1 mice were monitored 3 weeks after adoptive cell transfer. The percentage of Thy-1,2+ T cells was significantly reduced in the spleen (10·8 ± 1·3%versus 17·2 ± 3·9%, P= 0·004) of rhIGF-1 treated mice in contrast to the thymus (68·4 ± 7·9%versus 72·87 ± 6·2%, P= 0·306), suggesting that rhIGF-1 could influence T cell trafficking to the lymphoid organs. The findings that rhIGF-1 has protective effects in autoimmune diabetes opens new perspectives for future experiments as well as for preventive strategies in human type I diabetes.

Published
1995

44. Detection of RET oncogene activation in human papillary thyroid carcinomas by in situ hybridisation

Author

Y. Barbier, P. M. Dubois, M. Grieco, Nicole Fabien, Christian Paulin, Alfredo Fusco, D. Galvain, Nicole Berger, Massimo Santoro, N., Fabien, C., Paulin, Santoro, Massimo, N., Berger, M., Grieco, D., Galvain, Y., Barbier, P. M., Duboi, Fusco, Alfredo, Fabien, N, Paulin, C, Santoro, M, Berger, N, Grieco, Michele, Galvain, D, Barbier, Y, Dubois, Pm, and Fusco, A.

Subjects
Cancer Research, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, endocrine system diseases, Molecular Sequence Data, Papillary, Messenger, In situ hybridization, analysis, Receptor Protein-Tyrosine Kinases, Thyroid Neoplasm, Biology, Proto-Oncogene Mas, analysis, RNA, Thyroid carcinoma, Mice, Proto-Oncogene Proteins, medicine, Animals, Drosophila Proteins, Humans, 3T3 Cells, Amino Acid Sequence, Animals, Carcinoma, genetics, Amino Acid Sequence, RNA, Messenger, RNA, Neoplasm, Thyroid Neoplasms, neoplasms, In Situ Hybridization, Southern blot, Oncogene, Papillary Neoplasm, Thyroid, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, 3T3 Cells, Oncogenes, Carcinoma, Papillary, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, Cancer research, Neoplasm, Neoplastic, Humans, In Situ Hybridization, Mice, Molecular Sequence Data, Oncogenes, Proto-Oncogene Proteins c-ret, Proto-Oncogene Protein, genetics, Drosophila Proteins, Gene Expression Regulation, Tyrosine kinase, Research Article
Abstract

We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, named PTC, is a novel rearranged version of the ret proto oncogene. In fact PTC is the product of the fusion of the tyrosine kinase domain of the ret proto-oncogene with the 5'-terminal region of another gene that we have named H4. The ret proto oncogene shows a pattern of expression restricted to neuroendocrine tissue. Its fusion with H4 allows the expression of the activated form in thyroid papillary carcinomas. Therefore the detection of ret transcripts is a tool to investigate ret activation in thyroid neoplasms. Here we show the detection by in situ hybridisation, of activated ret transcripts in human thyroid papillary neoplasms that were positive for PTC activation by Southern blot analysis. We did not find any ret transcripts in papillary carcinomas negative for PTC activation, nor in normal thyroid and in non-papillary thyroid neoplasias. © 1992 Macmillan Press Ltd.

Published
1992

45. Localization of tissue transglutaminase and N (epsilon)-(gamma) -glutamyl lysine in duodenal cucosa during the development of mucosal atrophy in coeliac disease.

Author

Wahiba Sakly, Badreddine Sriha, Ibtissem Ghedira, Françoise Bienvenu, Abdelkarim Ayadi, Mohamed Tahar Sfar, Alain Lachaux, Sadok Korbi, Jacques Bienvenu, and Nicole Fabien

Abstract

Abstract Expression and transamidation activity of tissue transglutaminase (tTG) may be involved in the morphological modifications leading to the mucosal atrophy observed in coeliac disease (CD). We aimed to investigate the localization of tTG within the duodenal mucosa during the development of villous atrophy. The localization and level of expression of N?-(?-glutamyl) lysine isopeptides which could reflect the transamidation activity of tTG were also analyzed. tTG and N?-(?-glutamyl) lysine were localized using an immunohistochemical technique on duodenal biopsies obtained from 75 patients with CD and 51 subjects with normal mucosa (control group). The number of cases displaying tTG-expressing cells in the basement membrane and lamina propria was significantly higher in CD patients than in the control group. Moreover, the intensity of tTG staining in these areas was higher in CD. In contrast, the number of biopsies with tTG-expressing enterocytes was significantly lower in CD than in the control group. There was no difference in N?-(?-glutamyl) lysine between the two populations. Tissue transglutaminase was differently expressed in the various areas of the mucosa according to the stage of atrophy, whereas the localization and the intensity of the labelling of N?-(?-glutamyl) lysine isopeptides did not show any modification. The preferential localization in the basement membrane and lamina propria may reflect the involvement of tTG in the development of mucosal atrophy in CD. [ABSTRACT FROM AUTHOR]

Published
2005

46. Influence of age at disease onset in the outcome of paediatric systemic lupus erythematosus.

Author

Elodie Descloux, Isabelle Durieu, Pierre Cochat, Denis Vital-Durand, Jacques Ninet, Nicole Fabien, and Rolando Cimaz

Subjects
AGE factors in disease, HEALTH outcome assessment, PEDIATRIC dermatology, SYSTEMIC lupus erythematosus, PEDIATRIC neuropsychiatry, IMMUNOSUPPRESSIVE agents, DISEASE susceptibility, DISEASE risk factors
Abstract

Objectives. The aim of this study was to investigate the influence of age at disease onset in the outcome of paediatric SLE (pSLE). Methods. Fifty-six patients with pSLE, divided into three groups (pre-pubertal, peripubertal and post-pubertal onset), were studied. The SDI (SLICC/ACR Damage Index for SLE), patients’ characteristics, disease manifestations and treatments were compared using Fishers exact test and Kruskal–Wallis test. Kaplan–Meier curves were constructed to compare the risk of damage occurrence. Results. The risk of damage (SDI 1) significantly decreased when age at disease onset increased (89% in pre-pubertal pSLE, 57% in peripubertal pSLE and 38% in post-pubertal pSLE). This excess of risk was found in all disease duration intervals studied (1–3, 3–5, 5–8, 8–10, >10 years) and at the end of follow-up. Kaplan–Meier curves indicated a higher and earlier risk of damage in younger patients. Young children showed higher frequency of autoimmune family history. The frequency of neuropsychiatric disorders and damages decreased with age at disease onset (P 0.5 mg/kg/day) and number of immunosuppressive drugs used that seem to contribute to damage significantly increased when age at disease onset decreased. Conclusions. The risk of damage is inversely correlated with age at disease onset in pSLE. The poorer outcome observed in younger children may be explained by a more severe disease expression, may be a higher infectious susceptibility, and a more aggressive therapy, particularly within the first 6 months of disease course. [ABSTRACT FROM AUTHOR]

Published
2009
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