78 results on '"Sivils KL"'
Search Results
2. How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project)
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Brito-Zerón, P., Acar-Denizli, N., Ng, Wf, Zeher, M., Rasmussen, A., Mandl, T., Seror, R., Li, X., Baldini, C., Gottenberg, Je, Danda, D., Quartuccio, L., Priori, R., Hernandez-Molina, G., Armagan, B., Kruize, Aa, Kwok, Sk, Marika Kvarnström, Praprotnik, S., Sène, D., Bartoloni, E., Solans, R., Rischmueller, M., Suzuki, Y., Isenberg, Da, Valim, V., Wiland, P., Nordmark, G., Fraile, G., Bootsma, H., Nakamura, T., Giacomelli, R., Devauchelle-Pensec, V., Knopf, A., Bombardieri, M., Trevisani, Vf, Hammenfors, D., Pasoto, Sg, Retamozo, S., Gheita, Ta, Atzeni, F., Morel, J., Vollenveider, C., Horvath, If, Sivils, Kl, Olsson, P., Vita, S., Sánchez-Guerrero, J., Kilic, L., Wahren-Herlenius, M., Mariette, X., Ramos-Casals, M., Sjögren Big Data Consortium, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Herrada, Anthony, and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,Complement C4 ,Complement C3 ,Middle Aged ,Aged ,Antibodies, Antinuclear ,Autoantibodies ,Biomarkers ,Cryoglobulins ,Female ,Humans ,Phenotype ,Prognosis ,Registries ,Rheumatoid Factor ,Sjogren's Syndrome ,Antibodies ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,Antinuclear - Abstract
International audience; OBJECTIVES:To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS).METHODS:The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays.RESULTS:By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p
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- 2018
3. Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)
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Seror, R, Bootsma, H, Saraux, A, Bowman, S, Theander, E, Brun, Jg, Baron, G, Le Guern, V, Devauchelle Pensec, V, Ramos Casals, M, Valim, V, Dörner, T, Tzioufas, A, Gottenberg, Je, Laqué, Rs, Mandl, T, Hachulla, E, Sivils, Kl, Wf, Ng, Fauchais, A, Bombardieri, S, Priori, R, BARTOLONI BOCCI, Elena, Goeb, V, Praprotnik, S, Sumida, T, Nishiyama, S, Caporali, R, Kruize, Aa, Vollenweider, C, Ravaud, P, Meiners, P, Brito Zerón, P, Vitali, C, Mariette, X, Gerli, Roberto, Kallenberg, C, De Vita, S, Demoulins, F, Montecucco, C, Tomsic, M, Scofield, H, Valesini, G., Service de rhumatologie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Rheumatology, Lund University [Lund], Education Discours Apprentissages (EDA - EA 4071), Université Paris Descartes - Paris 5 (UPD5), Klinik für Dermatologie, Venerologie und Allergologie, Department of Pathophysiology, Medical School, University of Athens, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Droit et Santé, University of Northumbria at Newcastle [United Kingdom], Service de Médecine interne A et polyclinique médicale [CHU Limoges], CHU Limoges, Service de rhumatologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), University Medical Centre, University of Tsukuba, Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Internal Medicine and section of Rheumatology, Villamarina Hospital, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Service de rhumatologie [CHU Rouen], Université de Tsukuba = University of Tsukuba, Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Immunology Groningen (TRIGR), Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Centre d'Investigation Clinique ( CIC - Brest ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Education Discours Apprentissages ( EDA - EA 4071 ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques ( CRESS - U1153 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Sorbonne Paris Cité (USPC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
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0301 basic medicine ,Genetics and Molecular Biology (all) ,Male ,[SDV]Life Sciences [q-bio] ,Health Status ,Rheumatology ,Immunology ,Biochemistry, Genetics and Molecular Biology (all) ,Immunology and Allergy ,Biochemistry ,Severity of Illness Index ,RESPONSIVENESS ,DOUBLE-BLIND ,0302 clinical medicine ,EUROPEAN LEAGUE ,Epidemiology ,Prospective Studies ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,10. No inequality ,Prospective cohort study ,Non-U.S. Gov't ,Research Support, Non-U.S. Gov't ,RANDOMIZED CONTROLLED-TRIAL ,Middle Aged ,3. Good health ,Sjogren's Syndrome ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,Patient Satisfaction ,Rheumatoid arthritis ,patient-reported indexes (ESSPRI) ,Disease Progression ,Female ,Symptom Assessment ,medicine.medical_specialty ,BELIMUMAB ,Research Support ,General Biochemistry, Genetics and Molecular Biology ,[ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,03 medical and health sciences ,Diagnostic Self Evaluation ,Patient satisfaction ,Internal medicine ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Severity of illness ,medicine ,Journal Article ,Humans ,disease activity states ,Aged ,030203 arthritis & rheumatology ,Outcomes research ,Patient perspective ,Sjøgren's Syndrome ,ROC Curve ,[ SDV ] Life Sciences [q-bio] ,EULAR primary Sjogren's syndrome disease activity ,business.industry ,RITUXIMAB TREATMENT ,medicine.disease ,EFFICACY ,RHEUMATOID-ARTHRITIS ,Clinical trial ,030104 developmental biology ,Physical therapy ,business ,ACCEPTABLE SYMPTOM STATE ,Rheumatism ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; OBJECTIVES: To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjogren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). METHODS: For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. RESULTS: Low-activity (ESSDAI/=14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI/=5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI>/=5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.
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- 2014
4. Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). in combination wiIh methotrexate
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Gseror, R, Bootsma, H, Saraux, A, Bowman, Sj, Theander, E, Brun, Jg, Baron, G, Le Guern, V, Devauchelle Pensec, V, Ramos Casals, M, Valim, V, Dörner, T, Tzioufas, A, Gottenberg, Je, Solans Laqué, R, Mandl, T, Hachulla, E, Sivils, Kl, Ng, Wf, Fauchais, Al, Bombardieri, Stefano, Priori, R, Bartoloni, E, Goeb, V, Praprotnik, S, Sumida, T, Nishiyama, S, Caporali, R, Kruize, Aa, Vollenweider, C, Ravaud, P, Meiners, P, Brito Zerón, P, Vitali, C, and Mariette, X.
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- 2014
5. Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjogren's syndrome
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Lester, S, Stokes, L, Skarratt, KK, Gu, BJ, Sivils, KL, Lessard, CJ, Wiley, JS, Rischmueller, M, Lester, S, Stokes, L, Skarratt, KK, Gu, BJ, Sivils, KL, Lessard, CJ, Wiley, JS, and Rischmueller, M
- Abstract
INTRODUCTION: The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjögren's syndrome (pSS). METHODS: Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA. RESULTS: The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro±La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G. CONCLUSIONS: The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS.
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- 2013
6. Mitochondrial Dysfunction and Fatigue in Sjögren's Disease.
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Kurien BT, Ice JA, Wood R, Pharaoh G, Cavett J, Lewis V, Bhaskaran S, Rasmussen A, Lessard CJ, Farris AD, Sivils KL, Koelsch KA, Van Remmen H, and Scofield RH
- Abstract
Objectives: Sjögren's disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species. We hypothesized that mitophagic processes are dysregulated in SjD and that dysfunctional mitochondria contribute to overall fatigue. We sought to link fatigue with mitochondrial dysfunction directly in SjD, heretofore unexamined, and further sought to assess the pathogenic extent and implications of dysregulated mitophagy in SjD., Methods: We isolated pan T cells via negative selection from the peripheral blood mononuclear cells of 17 SjD and 8 age-matched healthy subjects, all of whom completed fatigue questionnaires prior to phlebotomy. Isolated T cells were analyzed for mitochondrial oxygen consumption rate (OCR) and glycolysis using Seahorse, and linear correlations with fatigue measures were assessed. A mitophagy transcriptional signature in SjD was identified by reanalysis of whole-blood microarray data from 190 SjD and 32 healthy subjects. Differential expression analyses were performed by case/control and subgroup analyses comparing SjD patients by mitophagy transcriptional cluster against healthy subjects followed by bioinformatic interpretation using gene set enrichment analysis., Results: Basal OCR, ATP-linked respiration, maximal respiration, and reserve capacity were significantly lower in SjD compared to healthy subjects with no observed differences in non-mitochondrial respiration, basal glycolysis, or glycolytic stress. SjD lymphocytic mitochondria show structural alterations compared to healthy subjects. Fatigue scores related to pain/discomfort in SjD correlated with the altered OCR. Results from subgroup analyses by mitophagic SjD clusters revealed highly variable inter-cluster differentially expressed genes (DEGs) and expanded the number of SjD-associated gene targets by tenfold within the same dataset., Conclusion: Mitochondrial dysfunction, associated with fatigue, is a significant problem in SjD and warrants further investigation.
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- 2024
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7. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.
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Wiley MM, Khatri B, Joachims ML, Tessneer KL, Stolarczyk AM, Rasmussen A, Anaya JM, Aqrawi LA, Bae SC, Baecklund E, Björk A, Brun JG, Bucher SM, Dand N, Eloranta ML, Engelke F, Forsblad-d'Elia H, Fugmann C, Glenn SB, Gong C, Gottenberg JE, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kelly JA, Khanam S, Kim K, Kvarnström M, Mandl T, Martín J, Morris DL, Nocturne G, Norheim KB, Olsson P, Palm Ø, Pers JO, Rhodus NL, Sjöwall C, Skarstein K, Taylor KE, Tombleson P, Thorlacius GE, Venuturupalli S, Vital EM, Wallace DJ, Grundahl KM, Radfar L, Brennan MT, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Appel S, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner BM, Rischmueller M, Witte T, Farris AD, Mariette X, Shiboski CH, Wahren-Herlenius M, Alarcón-Riquelme ME, Ng WF, Sivils KL, Guthridge JM, Adrianto I, Vyse TJ, Tsao BP, Nordmark G, and Lessard CJ
- Abstract
Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1 . Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6 , CXCR5 , and lnc-PHLDB1-1 , among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues., Competing Interests: Competing Interests C.J.L.* and A.D.F. have an active collaborative research agreement with Janssen. E.B. has an active research collaboration with Pfizer. T.M. is employed as medical solutions lead in rheumatology at UCB. R.H.S. is a consultant for Jansen Pharmaceuticals. S.J.B. provided consultancy services for Abbvie, BMS, Galapagos, Iqvia, J&J, Kiniksa, and Novartis in 2020–2021. L.R. provided consultancy services for AstraZeneca. B.M.W. has active collaborative research agreements with Astellas Bio and Pfizer, Inc. M.R. received grants from Amgen, AstraZeneca, Bristol Myers-Squibb, Novartis, and Servier for clinical trials in Sjögren’s Syndrome and SLE. All other authors have reported that they have no competing interests to report.
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- 2023
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8. Author Correction: Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.
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Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME, Shiboski CH, Wahren-Herlenius M, Ng WF, Sivils KL, Adrianto I, Nordmark G, and Lessard CJ
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- 2023
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9. Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses.
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Joachims ML, Khatri B, Li C, Tessneer KL, Ice JA, Stolarczyk AM, Means N, Grundahl KM, Glenn SB, Kelly JA, Lewis DM, Radfar L, Stone DU, Guthridge JM, James JA, Scofield RH, Wiley GB, Wren JD, Gaffney PM, Montgomery CG, Sivils KL, Rasmussen A, Farris AD, Adrianto I, and Lessard CJ
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- Humans, Interferons, Calcineurin, Antiviral Agents, Autoantibodies, Immunity, Receptors, Antigen, T-Cell, RNA, Long Noncoding genetics, Sjogren's Syndrome genetics, Autoimmune Diseases
- Abstract
Objective: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD
Ro+ ) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised., Methods: Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo- ); n=27 Ro/SSA positive (SjDRo+ ) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2 fold change ≥2 or ≤0.5; padj <0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion ( LINC01871-/ - ) and in vitro stimulation assays., Results: Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, RSAD2 , in SjDRo+ (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871-/ - cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells., Conclusion: LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD., Competing Interests: Competing interests: KS is a current employee of Janssen. ADF and CJL have an active collaborative research agreement with Janssen. All other authors have reported that they have no competing interests to report., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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10. Author Correction: Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.
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Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME, Shiboski CH, Wahren-Herlenius M, Ng WF, Sivils KL, Adrianto I, Nordmark G, and Lessard CJ
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- 2022
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11. Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.
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Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME, Shiboski CH, Wahren-Herlenius M, Ng WF, Sivils KL, Adrianto I, Nordmark G, and Lessard CJ
- Subjects
- Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Sjogren's Syndrome genetics
- Abstract
Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands., (© 2022. The Author(s).)
- Published
- 2022
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12. Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor.
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Witas R, Rasmussen A, Scofield RH, Radfar L, Stone DU, Grundahl K, Lewis D, Sivils KL, Lessard CJ, Farris AD, and Nguyen CQ
- Subjects
- ADAM17 Protein metabolism, Animals, Antibodies, Antinuclear chemistry, Apoptosis, Autoantibodies metabolism, Autoimmunity, Disease Models, Animal, Female, Humans, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Phenotype, Saliva metabolism, Signal Transduction, Thymocytes metabolism, Gene Expression Regulation, Enzymologic, Sjogren's Syndrome immunology, Sjogren's Syndrome metabolism, c-Mer Tyrosine Kinase genetics
- Abstract
Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjS
S ) C57BL/6.NOD- Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.- Published
- 2021
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13. Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren's Syndrome.
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Oyelakin A, Horeth E, Song EC, Min S, Che M, Marzullo B, Lessard CJ, Rasmussen A, Radfar L, Scofield RH, Lewis DM, Stone DU, Grundahl K, De Rossi SS, Kurago Z, Farris AD, Sivils KL, Sinha S, Kramer JM, and Romano RA
- Subjects
- Case-Control Studies, Computational Biology, Epithelial Cells immunology, Female, Humans, Middle Aged, Salivary Glands, Minor immunology, Sjogren's Syndrome diagnosis, Sjogren's Syndrome immunology, Epithelial Cells metabolism, Gene Expression Profiling, Gene Regulatory Networks, Salivary Glands, Minor metabolism, Sjogren's Syndrome genetics, Transcriptome
- Abstract
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren's syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oyelakin, Horeth, Song, Min, Che, Marzullo, Lessard, Rasmussen, Radfar, Scofield, Lewis, Stone, Grundahl, De Rossi, Kurago, Farris, Sivils, Sinha, Kramer and Romano.)
- Published
- 2021
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14. Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen.
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Ghodke-Puranik Y, Imgruet M, Dorschner JM, Shrestha P, McCoy K, Kelly JA, Marion M, Guthridge JM, Langefeld CD, Harley JB, James JA, Sivils KL, and Niewold TB
- Subjects
- Ephrin-A5 genetics, Genome-Wide Association Study, Haplotypes, Humans, Lupus Erythematosus, Systemic blood, Polymorphism, Single Nucleotide, Interferon-alpha blood, Lupus Erythematosus, Systemic genetics
- Abstract
Background/purpose: High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE., Methods: We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture., Results: We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10
-6 ). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription., Conclusion: This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
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15. American Indians Have a Higher Risk of Sjögren's Syndrome and More Disease Activity Than European Americans and African Americans.
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Scofield RH, Sharma R, Pezant N, Kelly JA, Radfar L, Lewis DM, Kaufman CE, Cioli S, Harris J, Grundahl K, Rhodus NL, Wallace DJ, Weisman MH, Venuturupalli S, Brennan MT, Koelsch KA, Lessard CJ, Montgomery CG, Sivils KL, and Rasmussen A
- Subjects
- Adult, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Oklahoma epidemiology, Risk Factors, Black or African American statistics & numerical data, Indians, North American statistics & numerical data, Sjogren's Syndrome epidemiology, Sjogren's Syndrome ethnology, White People statistics & numerical data
- Abstract
Objective: To describe the clinical and serologic manifestations of Sjögren's syndrome (SS) in ethnic groups of the US., Methods: This was a cross-sectional study of 648 patients with primary SS: 20 African American (AA), 164 American Indian (AI), 426 European American (EA), and 38 patients of other races evaluated in a multidisciplinary Sjögren's International Collaborative Clinical Alliance research clinic., Results: AA subjects comprised 3.1% of the SS cohort, much lower than the percentage of AA in the state of Oklahoma (P = 3.01 × E - 05), the US (P = 2.24E - 13), or a systemic lupus erythematosus (SLE) cohort at the same institution (P = 4.26 × 10E - 27). In contrast, the percentage of AI in the SS cohort (25.3%) was much higher than expected (P = 3.17E - 09 versus SLE cohort, P = 6.36 - 26 versus Oklahoma, and P = 8.14E - 96 versus US population). The SS classification criteria were similar between AA and EA, but subjects of AI ancestry had lower rates of abnormal tear and salivary flow, as well as anti-Ro/SSA and anti-La/SSB antibodies. Paradoxically, AI had higher levels of disease activity (mean ± SD European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score 3.77 ± 4.78) in comparison to EA (2.90 ± 4.12; P = 0.011) and more extraglandular manifestations affecting mainly the articular and glandular domains. Meanwhile, AA patients were characterized by higher rates of hypergammaglobulinemia (odds ratio [OR] 1.39 [95% confidence interval (95% CI) 1.39-8.65]; P = 0.01), elevated erythrocyte sedimentation rate (ESR) (OR 3.95 [95% CI 1.46-9.95]; P = 0.009), and parotid enlargement (OR 4.40 [95% CI 1.49-13.07]; P = 0.02)., Conclusion: AI are affected at high rates with SS but present with few classical features, potentially preventing timely diagnosis. In contrast to SLE, SS is infrequent and not more severe among AA, but the triad of hypergammaglobulinemia, increased ESR, and parotid enlargement warrants extra vigilance for lymphomagenesis., (© 2019, American College of Rheumatology.)
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- 2020
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16. Sjögren's Syndrome Minor Salivary Gland CD4 + Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile.
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Joachims ML, Leehan KM, Dozmorov MG, Georgescu C, Pan Z, Lawrence C, Marlin MC, Macwana S, Rasmussen A, Radfar L, Lewis DM, Stone DU, Grundahl K, Scofield RH, Lessard CJ, Wren JD, Thompson LF, Guthridge JM, Sivils KL, Moore JS, and Farris AD
- Abstract
To assess the types of salivary gland (SG) T cells contributing to Sjögren's syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4
+ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4+ and CD8+ T cells. SG memory CD4+ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4+ CD45RA- T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8+ CD45RA- T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4+ CD45RA- T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4+ CD45RA- cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis.- Published
- 2020
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17. Unique Sjögren's syndrome patient subsets defined by molecular features.
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James JA, Guthridge JM, Chen H, Lu R, Bourn RL, Bean K, Munroe ME, Smith M, Chakravarty E, Baer AN, Noaiseh G, Parke A, Boyle K, Keyes-Elstein L, Coca A, Utset T, Genovese MC, Pascual V, Utz PJ, Holers VM, Deane KD, Sivils KL, Aberle T, Wallace DJ, McNamara J, Franchimont N, and St Clair EW
- Subjects
- Adult, Antibodies, Antinuclear immunology, Autoantibodies immunology, B-Cell Activating Factor genetics, B-Cell Activating Factor immunology, B-Cell Activating Factor metabolism, Chemokine CXCL10 genetics, Chemokine CXCL10 immunology, Chemokine CXCL10 metabolism, Chemokine CXCL13 genetics, Chemokine CXCL13 immunology, Chemokine CXCL13 metabolism, Chemokine CXCL9 genetics, Chemokine CXCL9 immunology, Chemokine CXCL9 metabolism, Cytokines genetics, Cytokines immunology, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Female, Gene Regulatory Networks, Humans, Inflammation genetics, Inflammation immunology, Inflammation metabolism, Interferons genetics, Interferons immunology, Interferons metabolism, Interleukin-1alpha genetics, Interleukin-1alpha immunology, Interleukin-1alpha metabolism, Interleukins genetics, Interleukins immunology, Interleukins metabolism, Male, Middle Aged, Models, Statistical, Phenotype, Sjogren's Syndrome classification, Sjogren's Syndrome immunology, Sjogren's Syndrome metabolism, Tumor Necrosis Factor Ligand Superfamily Member 14 genetics, Tumor Necrosis Factor Ligand Superfamily Member 14 immunology, Tumor Necrosis Factor Ligand Superfamily Member 14 metabolism, Gene Expression, Sjogren's Syndrome genetics
- Abstract
Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes., Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200., Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters., Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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18. Sjögren Syndrome without Focal Lymphocytic Infiltration of the Salivary Glands.
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Sharma R, Chaudhari KS, Kurien BT, Grundahl K, Radfar L, Lewis DM, Lessard CJ, Li H, Rasmussen A, Sivils KL, and Scofield RH
- Subjects
- Antibodies, Antinuclear blood, Autoantibodies blood, Autoantigens immunology, Biopsy, Gene Expression Regulation, Histological Techniques, Humans, Interferons genetics, Interferons metabolism, Keratoconjunctivitis Sicca blood, Keratoconjunctivitis Sicca pathology, Lymphocytes pathology, RNA, Small Cytoplasmic immunology, Rheumatoid Factor blood, Ribonucleoproteins immunology, Salivary Glands pathology, Sjogren's Syndrome blood, Sjogren's Syndrome pathology, SS-B Antigen, Cell Movement immunology, Keratoconjunctivitis Sicca immunology, Lymphocytes immunology, Salivary Glands immunology, Sjogren's Syndrome immunology
- Abstract
Objective: Primary Sjögren syndrome (SS) is characterized by a focal lymphocytic infiltrate in exocrine glands. We describe patients who lacked this key feature., Methods: We evaluated patients with sicca in a comprehensive clinic at which medical, dental, and ophthalmological examinations were performed. All subjects underwent a minor salivary gland biopsy with focus score calculation. Extraglandular manifestations were also determined. We categorized subjects as high, intermediate, or low in terms of expression of interferon (IFN)-regulated genes., Results: About 20% (51 of 229, 22%) of those classified as having primary SS had a focus score of zero. Compared to those with anti-Ro positivity and a focus score > 1.0, the patients with focus score of zero (who by classification criteria must be anti-Ro-positive) were statistically less likely to have anti-La (or SSB) and elevated immunoglobulin, as well as less severe corneal staining. The focus score zero patients were less likely to have elevated expression of IFN-regulated genes in peripheral blood mononuclear cells than anti-Ro-positive SS patients with a focal salivary infiltrate., Conclusion: There are only a few clinical differences between patients with primary SS with focus score zero and those with both anti-Ro and a focus score > 1.0. The small subset of focus score zero patients tested did not have elevated expression of IFN-regulated genes, but did have systemic disease. Thus, extraglandular manifestations are perhaps more related to the presence of anti-Ro than increased IFN. This may have relevance to pathogenesis of SS.
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- 2020
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19. Reproducibility of Ocular Surface Staining in the Assessment of Sjögren Syndrome-Related Keratoconjunctivitis Sicca: Implications on Disease Classification.
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Rasmussen A, Stone DU, Kaufman CE, Hefner KS, Fram NR, Siatkowski RL, Huang AJW, Chodosh J, Rasmussen PT, Fife DA, Pezant N, Grundahl K, Radfar L, Lewis DM, Weisman MH, Venuturupalli S, Wallace DJ, Rhodus NL, Brennan MT, Montgomery CG, Lessard CJ, Scofield RH, and Sivils KL
- Abstract
Objective: The objective of this study was to assess the performance and reproducibility of the two currently used ocular surface staining scores in the assessment of keratoconjunctivitis sicca in Sjögren syndrome (SS) research classification., Methods: In a multidisciplinary clinic for the evaluation of sicca, we performed all tests for the American European Consensus Group (AECG) and the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, including the van Bijsterveld score (vBS) and the Ocular Staining Score (OSS), in 994 participants with SS or with non-SS sicca. We analyzed the concordance between the scores, the diagnostic accuracy and correlation with clinical variables, and interrater and intrasubject reproducibility., Results: A total of 308 (31.1%) participants had a discordant vBS and OSS that was due to extra corneal staining points in the OSS. The presence of one or more of the additional points was highly predictive of SS classification (odds ratio = 3.66; P = 1.65 × 10e-20) and was associated with abnormal results of all measures of autoimmunity and glandular dysfunction. Receiver operating characteristic curves showed optimal cutoff values of four for the vBS (sensitivity = 0.62; specificity = 0.71; Youden's J = 0.33) and five for the OSS (sensitivity = 0.56; specificity = 0.75; Youden's J = 0.31). Notably, there was very poor consistency in interobserver mean scores and distributions ( P < 0.0001) and in intrasubject scores after a median of 5.5 years (35% changed status of the ocular criterion)., Conclusion: Ocular surface staining scores are useful for SS research classification; however, they are subject to significant interrater and intrasubject variability, which could result in changes in classification in 5%-10% of all subjects. These results highlight the need for objective and reproducible markers of disease that have thus far remained elusive for SS.
- Published
- 2019
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20. Genetics in Sjögren's syndrome: where we are and where we go.
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Harris VM, Scofield RH, and Sivils KL
- Subjects
- Arthritis, Rheumatoid, Autoimmune Diseases, Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, Sjogren's Syndrome genetics
- Abstract
Sjögren's syndrome is a complex autoimmune disease that involves dysregulation of immune responses that preferentially target exocrine glands. Systemic manifestations vary and may involve nearly every organ system. Genetic studies to date are in their infancy relative to other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, each with more than 100 genetic associations now established. However, recent work in SS has successfully established associations that shed light on pathophysiology and implicate aberrant innate and adaptive immune responses. In this review, we provide an overview of genetic approaches used to identify risk variants in SS, discuss major findings and their relevance to SS, and describe the future directions that are likely to lead to understanding fundamental causes of this disease and new opportunities for improving clinical care.
- Published
- 2019
21. Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans.
- Author
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Hanscombe KB, Morris DL, Noble JA, Dilthey AT, Tombleson P, Kaufman KM, Comeau M, Langefeld CD, Alarcon-Riquelme ME, Gaffney PM, Jacob CO, Sivils KL, Tsao BP, Alarcon GS, Brown EE, Croker J, Edberg J, Gilkeson G, James JA, Kamen DL, Kelly JA, McCune J, Merrill JT, Petri M, Ramsey-Goldman R, Reveille JD, Salmon JE, Scofield H, Utset T, Wallace DJ, Weisman MH, Kimberly RP, Harley JB, Lewis CM, Criswell LA, and Vyse TJ
- Subjects
- Black or African American genetics, Female, Genetic Association Studies, Haplotypes, Humans, Male, Models, Genetic, White People genetics, Genetic Predisposition to Disease, Lupus Erythematosus, Systemic genetics, Major Histocompatibility Complex genetics, Polymorphism, Single Nucleotide
- Abstract
Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.
- Published
- 2018
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22. Evidence of Alternative Modes of B Cell Activation Involving Acquired Fab Regions of N-Glycosylation in Antibody-Secreting Cells Infiltrating the Labial Salivary Glands of Patients With Sjögren's Syndrome.
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Koelsch KA, Cavett J, Smith K, Moore JS, Lehoux SD, Jia N, Mather T, Quadri SMS, Rasmussen A, Kaufman CE, Lewis DM, Radfar L, Scordino TA, Lessard CJ, Kurien BT, Cummings RD, James JA, Sivils KL, Farris AD, and Scofield RH
- Subjects
- Adult, Aged, Cell Proliferation genetics, Female, Glycosylation, Humans, Lymphocyte Activation physiology, Male, Middle Aged, Salivary Glands cytology, Sjogren's Syndrome genetics, Antibody-Producing Cells metabolism, B-Lymphocytes immunology, Salivary Glands immunology, Sjogren's Syndrome immunology, Somatic Hypermutation, Immunoglobulin immunology
- Abstract
Objective: To better understand the role of B cells, the potential mechanisms responsible for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjögren's syndrome (SS), this study explored patterns of selection pressure and sites of N-glycosylation acquired by somatic mutation (acN-glyc) in the IgG variable (V) regions of antibody-secreting cells (ASCs) isolated from the minor salivary glands of patients with SS and non-SS control patients with sicca symptoms., Methods: A novel method to produce and characterize recombinant monoclonal antibodies (mAb) from single cell-sorted ASC infiltrates was applied to concurrently probe expressed genes (all heavy- and light-chain isotypes as well as any other gene of interest not related to immunoglobulin) in the labial salivary glands of patients with SS and non-SS controls. V regions were amplified by reverse transcription-polymerase chain reaction, sequenced, and analyzed for the incidence of N-glycosylation and selection pressure. For specificity testing, the amplified regions were expressed as either the native mAb or mutant mAb lacking the acN-glyc motif. Protein modeling was used to demonstrate how even an acN-glyc site outside of the complementarity-determining region could participate in, or inhibit, antigen binding., Results: V-region sequence analyses revealed clonal expansions and evidence of secondary light-chain editing and allelic inclusion, of which neither of the latter two have previously been reported in patients with SS. Increased frequencies of acN-glyc were found in the sequences from patients with SS, and these acN-glyc regions were associated with an increased number of replacement mutations and lowered selection pressure. A clonal set of polyreactive mAb with differential framework region 1 acN-glyc motifs was also identified, and removal of the acN-glyc could nearly abolish binding to autoantigens., Conclusion: These findings support the notion of an alternative mechanism for the selection and proliferation of some autoreactive B cells, involving V-region N-glycosylation, in patients with SS., (© 2018, American College of Rheumatology.)
- Published
- 2018
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23. A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.
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Patel ZH, Lu X, Miller D, Forney CR, Lee J, Lynch A, Schroeder C, Parks L, Magnusen AF, Chen X, Pujato M, Maddox A, Zoller EE, Namjou B, Brunner HI, Henrickson M, Huggins JL, Williams AH, Ziegler JT, Comeau ME, Marion MC, Glenn SB, Adler A, Shen N, Nath SK, Stevens AM, Freedman BI, Pons-Estel BA, Tsao BP, Jacob CO, Kamen DL, Brown EE, Gilkeson GS, Alarcón GS, Martin J, Reveille JD, Anaya JM, James JA, Sivils KL, Criswell LA, Vilá LM, Petri M, Scofield RH, Kimberly RP, Edberg JC, Ramsey-Goldman R, Bang SY, Lee HS, Bae SC, Boackle SA, Cunninghame Graham D, Vyse TJ, Merrill JT, Niewold TB, Ainsworth HC, Silverman ED, Weisman MH, Wallace DJ, Raj P, Guthridge JM, Gaffney PM, Kelly JA, Alarcón-Riquelme ME, Langefeld CD, Wakeland EK, Kaufman KM, Weirauch MT, Harley JB, and Kottyan LC
- Subjects
- Female, Humans, Lupus Erythematosus, Systemic epidemiology, Male, Risk Factors, Alleles, Lupus Erythematosus, Systemic genetics, Polymorphism, Genetic, Quantitative Trait Loci, STAT1 Transcription Factor genetics, STAT4 Transcription Factor genetics
- Abstract
Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2018
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24. How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project).
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Brito-Zerón P, Acar-Denizli N, Ng WF, Zeher M, Rasmussen A, Mandl T, Seror R, Li X, Baldini C, Gottenberg JE, Danda D, Quartuccio L, Priori R, Hernandez-Molina G, Armagan B, Kruize AA, Kwok SK, Kvarnström M, Praprotnik S, Sène D, Bartoloni E, Solans R, Rischmueller M, Suzuki Y, Isenberg DA, Valim V, Wiland P, Nordmark G, Fraile G, Bootsma H, Nakamura T, Giacomelli R, Devauchelle-Pensec V, Knopf A, Bombardieri M, Trevisani VF, Hammenfors D, Pasoto SG, Retamozo S, Gheita TA, Atzeni F, Morel J, Vollenveider C, Horvath IF, Sivils KL, Olsson P, De Vita S, Sánchez-Guerrero J, Kilic L, Wahren-Herlenius M, Mariette X, and Ramos-Casals M
- Subjects
- Adult, Aged, Antibodies, Antinuclear blood, Biomarkers blood, Female, Humans, Male, Middle Aged, Phenotype, Prognosis, Registries, Rheumatoid Factor blood, Sjogren's Syndrome diagnosis, Sjogren's Syndrome epidemiology, Autoantibodies blood, Complement C3 analysis, Complement C4 analysis, Cryoglobulins analysis, Sjogren's Syndrome immunology
- Abstract
Objectives: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS)., Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays., Results: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESS- DAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains)., Conclusions: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.
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- 2018
25. Minor salivary gland fibrosis in Sjögren's syndrome is elevated, associated with focus score and not solely a consequence of aging.
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Leehan KM, Pezant NP, Rasmussen A, Grundahl K, Moore JS, Radfar L, Lewis DM, Stone DU, Lessard CJ, Rhodus NL, Segal BM, Scofield RH, Sivils KL, Montgomery C, and Farris AD
- Subjects
- Adult, Age Factors, Aged, Area Under Curve, Biopsy, Case-Control Studies, Female, Fibrosis, Humans, Linear Models, Logistic Models, Male, Middle Aged, Predictive Value of Tests, Prognosis, ROC Curve, Salivary Glands, Minor immunology, Severity of Illness Index, Sjogren's Syndrome immunology, Salivary Glands, Minor pathology, Sjogren's Syndrome pathology
- Abstract
Objectives: Evaluate the presence of minor salivary gland (SG) fibrosis in primary Sjögren's syndrome (pSS) as a function of disease pathology or a consequence of ageing., Methods: Subjects with sicca symptoms attending a Sjögren's research clinic were classified by American European Consensus Group (AECG) criteria as either pSS or non-SS (nSS). Discovery (n=34 pSS, n=28 nSS) and replication (n=35 pSS, n=31 nSS) datasets were evaluated. Minor SG cross-sections from haematoxylin and eosin stained slides were imaged, digitally reconstructed and analysed for percent area fibrosis. Relationships between SG fibrosis, age, and clinical measures were evaluated using Spearman correlations. Association with SS was assessed by: ROC curve, Variable Selection Using Random Forests (VSURF) and uni- and bi-variate regression analyses., Results: SS subjects had significantly more fibrotic tissue in their minor labial salivary glands (median 24.39%, range 5.12-51.67%) than nSS participants (median 16.7%, range 5.97-38.65%, p<0.0001); age did not differ between groups (average ± SD pSS 50.2 ±13.9 years, nSS 53.8±12.4 years). In both the discovery and replication data sets, multiple regression models showed that the area of minor salivary gland fibrosis predicted pSS significantly better than age alone. Age-corrected linear regression revealed that the area of minor salivary gland fibrosis positively associated with vanBijsterveld score (p=0.042) and biopsy focus score (p=0.002). ROC curve and VSURF analyses ranked fibrosis as a significantly more important variable for subject discrimination than age., Conclusions: SG fibrosis is an element of pSS pathology that is related to focus score and is not solely attributable to age.
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- 2018
26. Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus.
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Kheir JM, Guthridge CJ, Johnston JR, Adams LJ, Rasmussen A, Gross TF, Munroe ME, Bourn RL, Sivils KL, Guthridge JM, Weisman MH, Wallace DJ, Anaya JM, Rojas Villarraga A, Jarvis JN, Harley JB, and James JA
- Abstract
Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE., Methods: Patients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins)., Results: NA patients met SLE classification at a younger age (29.89±12.3 years) than European Americans (EA; 32.02±12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud's phenomenon, interstitial lung disease, Sjӧgren's syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (≥1:3240; P<0.0001) and had more SLE-associated autoantibodies. Autoantibodies with unknown specificities were more common in NAs (41%) compared with other racial/ethnic groups in this collection (AA: 24%, P=0.0006; EA: 17%, P<0.0001; HIS: 23%, P=0.0050). Fewer NA patients used hydroxychloroquine (68%) compared with others (AA: 74%, P=0.0308; EA: 79%, P=0.0001, HIS: 77%, P=0.0173); this was influenced by lower hydroxychloroquine use in NA patients from Latin America (32%). NA patients had higher rates of methotrexate use (28%) compared with AA (18%, P=0.0006) and HIS patients (14%, P=0.0003), higher azathioprine use (38%) compared with EA patients (30%, P=0.0105) and higher mycophenolate mofetil use (26%) compared with EA (17%, P=0.0012) and HIS patients (11%, P<0.0001)., Conclusions: NA patients are diagnosed with SLE earlier in life and present worse concurrent rheumatic disease symptoms than EA patients. NA patients also are more likely to have expanded autoantibody profiles and precipitins of unknown specificities., Competing Interests: Competing interests: AR reports personal fees from ThermoFisher for talks regarding diagnosis and classification of Sjögren’s syndrome and the different autoantibody testing platforms.
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- 2018
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27. Corrigendum to "Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome" [Clin. Immunol. 168 (2016) 25-29].
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Harris VM, Sharma R, Cavett J, Kurien BT, Liu K, Koelsch KA, Rasmussen A, Radfar L, Lewis D, Stone DU, Kaufman CE, Li S, Segal B, Wallace DJ, Weisman MH, Venuturupalli S, Kelly JA, Alarcon-Riquelme ME, Pons-Estel B, Jonsson R, Lu X, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Alevizos I, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Xie G, Siminovitch KA, Ng WF, Nordmark G, Bucher SM, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer M, Wahren-Herlenius M, Witte T, Mariette X, Lessard CJ, Harley JB, Sivils KL, and Scofield RH
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- 2018
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28. Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21 -/low B Cells From Patients With Sjögren's Syndrome.
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Glauzy S, Boccitto M, Bannock JM, Delmotte FR, Saadoun D, Cacoub P, Ice JA, Sivils KL, James JA, Wolin SL, and Meffre E
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- Adult, Aged, Autoantibodies genetics, Autoantibodies immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Fluorescent Antibody Technique, Indirect, Humans, Immunoprecipitation, Lymphoproliferative Disorders immunology, Middle Aged, Mutation, Polymerase Chain Reaction, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell metabolism, Receptors, Complement 3d immunology, Receptors, Complement 3d metabolism, Sjogren's Syndrome complications, B-Lymphocytes immunology, Lymphoproliferative Disorders etiology, Sjogren's Syndrome immunology
- Abstract
Objective: Patients with Sjögren's syndrome (SS) are prone to develop malignant lymphomas, and a correlation has been established between the lymphoproliferations occurring in these disorders and the presence in patients' blood of an unusual B cell population that down-regulates complement receptor 2/CD21. This study was undertaken to identify the B cell compartment from which these lymphoproliferations emerge and determine the mechanisms that promote clonal B cell expansion in patients with SS., Methods: The reactivity of antibodies expressed by CD19+CD10-CD27-IgM+CD21
-/low cells isolated from the blood of patients with SS was tested using a polymerase chain reaction-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells., Results: Clonal expansions were identified in CD21-/low B cells isolated from the peripheral blood of 3 patients with SS. These lymphoproliferations expressed B cell receptors (BCRs) that displayed somatic hypermutation lineage trees characteristic of a strong selection by antigens; one of these antigens was identified as a ribosomal self antigen. When the mutated BCR sequences expressed by the expanded CD21-/low B cell clones from patients with SS were reverted in vitro to their germline counterparts, one clone remained autoreactive., Conclusion: Clonal lymphoproliferations in patients with SS preferentially accumulate in the autoreactive CD21-/low B cell compartment often expanded in these subjects, and recognition of self antigens may drive the clonal B cell expansion while further refining BCR self-reactivity., (© 2017, American College of Rheumatology.)- Published
- 2018
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29. Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren's syndrome.
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Leehan KM, Pezant NP, Rasmussen A, Grundahl K, Moore JS, Radfar L, Lewis DM, Stone DU, Lessard CJ, Rhodus NL, Segal BM, Kaufman CE, Scofield RH, Sivils KL, Montgomery C, and Farris AD
- Subjects
- Adult, Aged, Autoantibodies immunology, Biomarkers, Biopsy, Female, Humans, Male, Middle Aged, Prognosis, Sjogren's Syndrome metabolism, Adipose Tissue pathology, Aging immunology, Aging pathology, Salivary Glands, Minor immunology, Salivary Glands, Minor pathology, Sjogren's Syndrome immunology, Sjogren's Syndrome pathology
- Abstract
Objective: Determine the presence and assess the extent of fatty infiltration of the minor salivary glands (SG) of primary SS patients (pSS) as compared to those with non-SS sicca (nSS)., Methods: Minor SG biopsy samples from 134 subjects with pSS (n = 72) or nSS (n = 62) were imaged. Total area and fatty replacement area for each glandular cross-section (n = 4-6 cross-sections per subject) were measured using Image J (National Institutes of Health, Bethesda, MD). The observer was blinded to subject classification status. The average area of fatty infiltration calculated per subject was evaluated by logistic regression and general linearized models (GLM) to assess relationships between fatty infiltration and clinical exam results, extent of fibrosis and age., Results: The average area of fatty infiltration for subjects with pSS (median% (range) 4.97 (0.05-30.2)) was not significantly different from that of those with nSS (3.75 (0.087-41.9). Infiltration severity varied widely, and subjects with fatty replacement greater than 6% were equivalently distributed between pSS and nSS participants (χ
2 p = .50). Age accounted for all apparent relationships between fatty infiltration and fibrosis or reduced saliva flow. The all-inclusive GLM for prediction of pSS versus non-SS classification including fibrosis, age, fatty replacement, and focus score was not significantly different from any desaturated model. In no iteration of the model did fatty replacement exert a significant effect on the capacity to predict pSS classification., Conclusions: Fatty infiltration is an age-associated phenomenon and not a selective feature of Sjögren's syndrome. Sicca patients who do not fulfil pSS criteria have similar rates of fatty infiltration of the minor SG.- Published
- 2017
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30. Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls.
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Aberle T, Bourn RL, Munroe ME, Chen H, Roberts VC, Guthridge JM, Bean K, Robertson JM, Sivils KL, Rasmussen A, Liles M, Merrill JT, Harley JB, Olsen NJ, Karp DR, and James JA
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- Adult, Aged, Aged, 80 and over, Antirheumatic Agents therapeutic use, Biomarkers blood, British Virgin Islands, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Ethnicity, Female, Fluorescent Antibody Technique, Indirect, Humans, Hydroxychloroquine therapeutic use, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic immunology, Male, Middle Aged, Predictive Value of Tests, Puerto Rico, Racial Groups, Registries, Severity of Illness Index, Surveys and Questionnaires, United States, United States Virgin Islands, Antibodies, Anticardiolipin blood, B-Cell Activating Factor immunology, Lupus Erythematosus, Systemic classification, Lupus Erythematosus, Systemic diagnosis, Serologic Tests, Terminology as Topic
- Abstract
Objective: Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients., Methods: Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays., Results: On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non-European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001)., Conclusion: Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE., (© 2017, American College of Rheumatology.)
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- 2017
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31. Characterization and classification of lupus patients based on plasma thermograms.
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Garbett NC, Brock GN, Chaires JB, Mekmaysy CS, DeLeeuw L, Sivils KL, Harley JB, Rovin BH, Kulasekera KB, and Jarjour WN
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- Adult, Aged, Aged, 80 and over, Calorimetry, Differential Scanning, Case-Control Studies, Female, Humans, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic classification, Male, Middle Aged, Sensitivity and Specificity, Lupus Erythematosus, Systemic diagnosis
- Abstract
Objective: Plasma thermograms (thermal stability profiles of blood plasma) are being utilized as a new diagnostic approach for clinical assessment. In this study, we investigated the ability of plasma thermograms to classify systemic lupus erythematosus (SLE) patients versus non SLE controls using a sample of 300 SLE and 300 control subjects from the Lupus Family Registry and Repository. Additionally, we evaluated the heterogeneity of thermograms along age, sex, ethnicity, concurrent health conditions and SLE diagnostic criteria., Methods: Thermograms were visualized graphically for important differences between covariates and summarized using various measures. A modified linear discriminant analysis was used to segregate SLE versus control subjects on the basis of the thermograms. Classification accuracy was measured based on multiple training/test splits of the data and compared to classification based on SLE serological markers., Results: Median sensitivity, specificity, and overall accuracy based on classification using plasma thermograms was 86%, 83%, and 84% compared to 78%, 95%, and 86% based on a combination of five antibody tests. Combining thermogram and serology information together improved sensitivity from 78% to 86% and overall accuracy from 86% to 89% relative to serology alone. Predictive accuracy of thermograms for distinguishing SLE and osteoarthritis / rheumatoid arthritis patients was comparable. Both gender and anemia significantly interacted with disease status for plasma thermograms (p<0.001), with greater separation between SLE and control thermograms for females relative to males and for patients with anemia relative to patients without anemia., Conclusion: Plasma thermograms constitute an additional biomarker which may help improve diagnosis of SLE patients, particularly when coupled with standard diagnostic testing. Differences in thermograms according to patient sex, ethnicity, clinical and environmental factors are important considerations for application of thermograms in a clinical setting.
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- 2017
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32. Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome.
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Sharma R, Harris VM, Cavett J, Kurien BT, Liu K, Koelsch KA, Fayaaz A, Chaudhari KS, Radfar L, Lewis D, Stone DU, Kaufman CE, Li S, Segal B, Wallace DJ, Weisman MH, Venuturupalli S, Kelly JA, Pons-Estel B, Jonsson R, Lu X, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Alevizos I, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Nordmark G, Bucher SM, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer M, Wahren-Herlenius M, Witte T, Alarcón-Riquelme M, Mariette X, Lessard CJ, Harley JB, Ng WF, Rasmussen A, Sivils KL, and Scofield RH
- Subjects
- Alleles, Bayes Theorem, Female, Gene Dosage, Humans, Karyotype, Lupus Erythematosus, Systemic epidemiology, Polymorphism, Single Nucleotide, Sex Chromosome Disorders of Sex Development epidemiology, Sex Chromosome Disorders of Sex Development genetics, Sjogren's Syndrome epidemiology, Trisomy genetics, Turner Syndrome epidemiology, Turner Syndrome genetics, Chromosomes, Human, X genetics, Lupus Erythematosus, Systemic genetics, Mosaicism statistics & numerical data, Sex Chromosome Aberrations statistics & numerical data, Sjogren's Syndrome genetics
- Abstract
Objective: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome., Methods: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients., Results: Among ~2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among ~2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000-50,000 live female births, while partial triplications are even rarer., Conclusion: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative., (© 2017, American College of Rheumatology.)
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- 2017
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33. Transancestral mapping and genetic load in systemic lupus erythematosus.
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Langefeld CD, Ainsworth HC, Cunninghame Graham DS, Kelly JA, Comeau ME, Marion MC, Howard TD, Ramos PS, Croker JA, Morris DL, Sandling JK, Almlöf JC, Acevedo-Vásquez EM, Alarcón GS, Babini AM, Baca V, Bengtsson AA, Berbotto GA, Bijl M, Brown EE, Brunner HI, Cardiel MH, Catoggio L, Cervera R, Cucho-Venegas JM, Dahlqvist SR, D'Alfonso S, Da Silva BM, de la Rúa Figueroa I, Doria A, Edberg JC, Endreffy E, Esquivel-Valerio JA, Fortin PR, Freedman BI, Frostegård J, García MA, de la Torre IG, Gilkeson GS, Gladman DD, Gunnarsson I, Guthridge JM, Huggins JL, James JA, Kallenberg CGM, Kamen DL, Karp DR, Kaufman KM, Kottyan LC, Kovács L, Laustrup H, Lauwerys BR, Li QZ, Maradiaga-Ceceña MA, Martín J, McCune JM, McWilliams DR, Merrill JT, Miranda P, Moctezuma JF, Nath SK, Niewold TB, Orozco L, Ortego-Centeno N, Petri M, Pineau CA, Pons-Estel BA, Pope J, Raj P, Ramsey-Goldman R, Reveille JD, Russell LP, Sabio JM, Aguilar-Salinas CA, Scherbarth HR, Scorza R, Seldin MF, Sjöwall C, Svenungsson E, Thompson SD, Toloza SMA, Truedsson L, Tusié-Luna T, Vasconcelos C, Vilá LM, Wallace DJ, Weisman MH, Wither JE, Bhangale T, Oksenberg JR, Rioux JD, Gregersen PK, Syvänen AC, Rönnblom L, Criswell LA, Jacob CO, Sivils KL, Tsao BP, Schanberg LE, Behrens TW, Silverman ED, Alarcón-Riquelme ME, Kimberly RP, Harley JB, Wakeland EK, Graham RR, Gaffney PM, and Vyse TJ
- Subjects
- Age of Onset, Case-Control Studies, Hispanic or Latino genetics, Humans, Logistic Models, Multifactorial Inheritance, Mutagenesis, Insertional, Polymorphism, Single Nucleotide, Sequence Deletion, American Indian or Alaska Native genetics, Black People genetics, Genetic Load, HLA Antigens genetics, Lupus Erythematosus, Systemic genetics, White People genetics
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10
-8 ), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.- Published
- 2017
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34. A new MHC-linked susceptibility locus for primary Sjögren's syndrome: MICA.
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Carapito R, Gottenberg JE, Kotova I, Untrau M, Michel S, Naegely L, Aouadi I, Kwemou M, Paul N, Pichot A, Locke J, Bowman SJ, Griffiths B, Sivils KL, Sibilia J, Inoko H, Micelli-Richard C, Nocturne G, Ota M, Ng WF, Mariette X, and Bahram S
- Subjects
- Adult, Alleles, Female, Gene Frequency genetics, Genetic Predisposition to Disease, HLA-B Antigens genetics, HLA-DRB1 Chains genetics, Haplotypes, Histocompatibility Antigens Class I metabolism, Humans, Linkage Disequilibrium, Major Histocompatibility Complex genetics, Male, Middle Aged, Polymorphism, Genetic, White People genetics, Histocompatibility Antigens Class I genetics, Sjogren's Syndrome genetics
- Abstract
The association of primary Sjögren's syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS' etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10-35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10-04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2017
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35. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
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Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, Wang S, He B, Grundahl KM, Glenn SB, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Gøransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Cunninghame Graham DS, Patel K, Adler AJ, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Hefner KS, Houston GD, Huang AJW, Hughes PJ, Lewis DM, Radfar L, Vista ES, Edgar CE, Rohrer MD, Stone DU, Vyse TJ, Harley JB, Gaffney PM, James JA, Turner S, Alevizos I, Anaya JM, Rhodus NL, Segal BM, Montgomery CG, Scofield RH, Kovats S, Mariette X, Rönnblom L, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng WF, Nordmark G, Lessard CJ, and Sivils KL
- Subjects
- 2',5'-Oligoadenylate Synthetase biosynthesis, Alleles, Alternative Splicing genetics, Female, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Interferon Type I metabolism, Male, Sjogren's Syndrome metabolism, Sjogren's Syndrome pathology, Virus Diseases genetics, Virus Diseases virology, 2',5'-Oligoadenylate Synthetase genetics, Interferon Type I genetics, Quantitative Trait Loci genetics, Sjogren's Syndrome genetics
- Abstract
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
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- 2017
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36. Anti-La positive, anti-Ro negative subset of primary Sjögren's syndrome: anti-La is a reality but is the disease?
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Danda D, Sharma R, Truong D, Koelsch KA, Kurien BT, Bagavant H, Deshmukh U, Kaufman CE, Lewis DM, Stone DU, Radfar L, Rasmussen A, Sivils KL, and Scofield RH
- Subjects
- Adult, Biomarkers blood, Enzyme-Linked Immunosorbent Assay, False Negative Reactions, Humans, Immunoprecipitation, Male, Middle Aged, Predictive Value of Tests, Reproducibility of Results, Serologic Tests, Sjogren's Syndrome diagnosis, Sjogren's Syndrome immunology, Antibodies, Antinuclear blood, Autoimmunity, Sjogren's Syndrome blood
- Abstract
Objectives: To characterise the serological and clinical findings in primary Sjögren's syndrome in which anti-La was found without anti-Ro. We hypothesised that a significant portion of these are falsely negative for anti-Ro60., Methods: Twenty-nine sera from primary Sjögren's syndrome patients were tested for antibodies directed against La and Ro. Anti-La was detected using bovine La treated with or without DNAase and RNAase to identify potential false positivity. Anti-Ro60 antibodies were detected using HEp-2000 substrate (in which cells are transfected with human Ro60) and HEp-2 substrate. Anti-Ro60 and Ro-52 were also tested by in vitro transcription/translation followed by immunoprecipitation assay., Results: All 29 sera bound La, even after treatment with DNAase and RNAase. Of the 29 sera, 25 were unequivocally negative on HEp-2000 (1:40 dilution). Four samples were anti-Ro60 positive with a speckled pattern, three of the four at 1:320 dilution. Thus, false negative anti-Ro60 exists in a small fraction (14%) of the Ro-negative/La-positive primary Sjögren's patients. However, all the samples were negative for Ro60 and Ro52 by in vitro immunoprecipitation assay. Clinically these patients tended not to have salivary gland pathology characteristic of Sjögren's syndrome., Conclusions: We found only a small fraction of Ro negative/La positive sera to show positive HEp-2000 pattern. These subjects did not have characteristic findings on pathological examination of minor salivary glands, suggesting these subjects have a process distinct from Sjögren's syndrome.
- Published
- 2017
37. Use of SLICC criteria in a large, diverse lupus registry enables SLE classification of a subset of ACR-designated subjects with incomplete lupus.
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Aberle T, Bourn RL, Chen H, Roberts VC, Guthridge JM, Bean K, Robertson JM, Sivils KL, Rasmussen A, Liles M, Merrill JT, Harley JB, Olsen NJ, Karp DR, and James JA
- Abstract
Objective: SLE is traditionally classified using the American College of Rheumatology (ACR) criteria. The Systemic Lupus International Collaborating Clinics (SLICC) recently validated an alternative system. This study examined large cohorts of subjects with SLE and incomplete lupus erythematosus (ILE) to compare the impact of ACR and SLICC criteria., Methods: Medical records of subjects in the Lupus Family Registry and Repository were reviewed for documentation of 1997 ACR classification criteria, SLICC classification criteria and medication usage. Autoantibodies were assessed by indirect immunofluorescence (ANA, antidouble-stranded DNA), precipitin (Sm) and ELISA (anticardiolipin). Other relevant autoantibodies were detected by precipitin and with a bead-based multiplex assay., Results: Of 3575 subjects classified with SLE under at least one system, 3312 (92.6%) were classified as SLE by both systems (SLE
both ), 85 only by ACR criteria (SLEACR-only ) and 178 only by SLICC criteria (SLESLICC-only ). Of 440 subjects meeting 3 ACR criteria, 33.9% (149/440) were SLESLICC-only , while 66.1% (n=291, designated ILE) did not meet the SLICC classification criteria. Under the SLICC system, the complement criterion and the individual autoantibody criteria enabled SLE classification of SLESLICC-only subjects, while SLEACR-only subjects failed to meet SLICC classification due to the combined acute/subacute cutaneous criterion. The SLICC criteria classified more African-American subjects by the leucopenia/lymphopenia criterion than did ACR criteria. Compared with SLEACR-only subjects, SLESLICC-only subjects exhibited similar numbers of affected organ systems, rates of major organ system involvement (∼30%: pulmonary, cardiovascular, renal, neurological) and medication history., Conclusions: The SLICC criteria classify more subjects with SLE than ACR criteria; however, individuals with incomplete lupus still exist under SLICC criteria. Subjects who gain SLE classification through SLICC criteria exhibit heterogeneous disease, including potential major organ involvement. These results provide supportive evidence that SLICC criteria may be more inclusive of SLE subjects for clinical studies., Competing Interests: Competing interests: None declared.- Published
- 2017
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38. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases.
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Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, Lee HS, Li QZ, Wakeland EK, Qiu R, Liu M, Guo J, Li Z, Tan W, Rasmussen A, Lessard CJ, Sivils KL, Hahn BH, Grossman JM, Kamen DL, Gilkeson GS, Bae SC, Gaffney PM, Shen N, and Tsao BP
- Subjects
- Black or African American genetics, Asian People genetics, Case-Control Studies, Female, Humans, Lupus Erythematosus, Systemic genetics, Male, Reactive Oxygen Species metabolism, Sjogren's Syndrome genetics, White People genetics, Autoimmune Diseases genetics, Genetic Predisposition to Disease genetics, NADPH Oxidases genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47
phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta = 3.1 × 10-104 ), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.- Published
- 2017
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39. Effect of Tobacco Smoking on The Clinical, Histopathological, and Serological Manifestations of Sjögren's Syndrome.
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Stone DU, Fife D, Brown M, Earley KE, Radfar L, Kaufman CE, Lewis DM, Rhodus NL, Segal BM, Wallace DJ, Weisman MH, Venuturupalli S, Brennan MT, Lessard CJ, Montgomery CG, Scofield RH, Sivils KL, and Rasmussen A
- Subjects
- Adult, Aged, Autoantibodies blood, Biomarkers, Biopsy, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, Sjogren's Syndrome diagnosis, Sjogren's Syndrome blood, Sjogren's Syndrome pathology, Smoking adverse effects
- Abstract
Objectives: To assess the association of smoking habits with the clinical, serological, and histopathological manifestations of Sjögren's syndrome (SS) and non-Sjögren's sicca (non-SS sicca)., Methods: Cross-sectional case-control study of 1288 patients with sicca symptoms (587 SS and 701 non-SS sicca) evaluated in a multi-disciplinary research clinic. Smoking patterns were obtained from questionnaire data and disease-related clinical and laboratory data were compared between current, past, ever, and never smokers., Results: Current smoking rates were 4.6% for SS patients compared to 14.1% in non-SS sicca (p = 5.17x10E-09), 18% in a local lupus cohort (p = 1.13x10E-14) and 16.8% in the community (p = 4.12x10E-15). Current smoking was protective against SS classification (OR 0.35, 95%CI 0.22-0.56, FDR q = 1.9E10-05), focal lymphocytic sialadenitis (OR 0.26, 95%CI 0.15-0.44, FDR q = 1.52x10E-06), focus score ≥1 (OR 0.22, 95%CI 0.13-0.39, FDR q = 1.43x10E-07), and anti-Ro/SSA(+) (OR 0.36, 95%CI 0.2-0.64, FDR q = 0.0009); ever smoking was protective against the same features and against anti-La/SSB(+) (OR 0.52, 95%CI 0.39-0.70, FDR q = 5.82x10E-05). Duration of smoking was inversely correlated with SS even after controlling for socioeconomic status, BMI, alcohol and caffeine consumption., Conclusions: Current tobacco smoking is negatively and independently associated with SS, protecting against disease-associated humoral and cellular autoimmunity. The overall smoking rate amongst SS patients is significantly lower than in matched populations and the effects of smoking are proportional to exposure duration. In spite of the protective effects of tobacco on SS manifestations, it is associated with other serious comorbidities such as lung disease, cardiovascular risk and malignancy, and should thus be strongly discouraged in patients with sicca., Competing Interests: The authors have declared that no competing interests exist.
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- 2017
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40. Genetics in Sjögren Syndrome.
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Reksten TR, Lessard CJ, and Sivils KL
- Subjects
- Antigen Presentation genetics, B-Lymphocytes, Cell Differentiation genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, HLA Antigens genetics, Humans, Interferon Regulatory Factors genetics, Interferons genetics, Interleukins genetics, Lymphocytes, NF-kappa B, Receptors, CXCR5 genetics, STAT4 Transcription Factor genetics, Signal Transduction genetics, Tumor Necrosis Factor alpha-Induced Protein 3 genetics, Vascular Cell Adhesion Molecule-1 genetics, src-Family Kinases genetics, Sjogren's Syndrome genetics
- Abstract
The genes associated with Sjögren syndrome (SS) can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation. The frequencies of risk variants show they are common with modest genetic effects. The strongest genetic association outside the human leukocyte antigen region is in IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation. Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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41. Previous diagnosis of Sjögren's Syndrome as rheumatoid arthritis or systemic lupus erythematosus.
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Rasmussen A, Radfar L, Lewis D, Grundahl K, Stone DU, Kaufman CE, Rhodus NL, Segal B, Wallace DJ, Weisman MH, Venuturupalli S, Kurien BT, Lessard CJ, Sivils KL, and Scofield RH
- Subjects
- Aged, Antibodies, Antinuclear blood, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Rheumatoid Factor blood, Sjogren's Syndrome blood, Arthritis, Rheumatoid diagnosis, Diagnostic Errors, Lupus Erythematosus, Systemic diagnosis, Sjogren's Syndrome diagnosis
- Abstract
Objective: The diagnosis of SS is often difficult and many patients are symptomatic for years with other diagnoses before confirmation of SS. Our aim was to determine whether overlapping clinical and serologic features with RA and SLE may in part drive the misdiagnoses., Methods: A total of 1175 sicca patients were evaluated in a multidisciplinary clinic and classified as having SS based on the American-European Consensus Group Criteria. They were interrogated for a past history of suspicion or diagnosis of RA, SLE or SSc. These diseases were confirmed or ruled out by applying the corresponding classification criteria if the patients responded affirmatively., Results: Of these, 524 (44.6%) subjects reported previous diagnosis or suspicion of RA, SLE or SSc, which was confirmed in 130 (24.8%) but excluded in 394 (75.2%) subjects. Of those previously diagnosed with another illness, 183 (34.9%) met the criteria for primary SS. RF was present in 70/191 patients with previous diagnosis of RA compared with 445/845 without a prior RA diagnosis (P = 3.38E-05), while 128/146 with a diagnosis of SLE had positive ANA compared with 622/881 without the diagnosis (P = 8.77E-06). Age also influenced former diagnoses: people with suspected RA were older than those without the diagnosis (P = 5.89E-06), while patients with SLE suspicion were younger (P = 0.0003). Interestingly, the previous diagnoses did not significantly delay a final classification of SS., Conclusion: Among subjects classified as SS, the presence of a positive ANA or RF was associated with a previous, apparently erroneous diagnosis of SLE or RA, respectively., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2016. This work is written by US Government employees and is in the public domain in the United States.)
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- 2016
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42. Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome.
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Harris VM, Sharma R, Cavett J, Kurien BT, Liu K, Koelsch KA, Rasmussen A, Radfar L, Lewis D, Stone DU, Kaufman CE, Li S, Segal B, Wallace DJ, Weisman MH, Venuturupalli S, Kelly JA, Alarcon-Riquelme ME, Pons-Estel B, Jonsson R, Lu X, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Alevizos I, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Xie G, Siminovitch KA, Ng WF, Nordmark G, Bucher SM, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer M, Wahren-Herlenius M, Witte T, Mariette X, Lessard CJ, Harley JB, Sivils KL, and Scofield RH
- Subjects
- Chromosomes, Human, X genetics, Chromosomes, Human, Y genetics, Female, Gene Frequency, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Arthritis, Rheumatoid genetics, Klinefelter Syndrome genetics, Lupus Erythematosus, Systemic genetics, Sjogren's Syndrome genetics
- Abstract
Primary Sjögren's syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelter's syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fisher's exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fisher's exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA., (Published by Elsevier Inc.)
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- 2016
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43. Single-cell analysis of glandular T cell receptors in Sjögren's syndrome.
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Joachims ML, Leehan KM, Lawrence C, Pelikan RC, Moore JS, Pan Z, Rasmussen A, Radfar L, Lewis DM, Grundahl KM, Kelly JA, Wiley GB, Shugay M, Chudakov DM, Lessard CJ, Stone DU, Scofield RH, Montgomery CG, Sivils KL, Thompson LF, and Farris AD
- Abstract
CD4
+ T cells predominate in salivary gland (SG) inflammatory lesions in Sjögren's syndrome (SS). However, their antigen specificity, degree of clonal expansion, and relationship to clinical disease features remain unknown. We used multiplex reverse-transcriptase PCR to amplify paired T cell receptor α (TCRα) and β transcripts of single CD4+ CD45RA- T cells from SG and peripheral blood (PB) of 10 individuals with primary SS, 9 of whom shared the HLA DR3/DQ2 risk haplotype. TCRα and β sequences were obtained from a median of 91 SG and 107 PB cells per subject. The degree of clonal expansion and frequency of cells expressing two productively rearranged α genes were increased in SG versus PB. Expanded clones from SG exhibited complementary-determining region 3 (CDR3) sequence similarity both within and among subjects, suggesting antigenic selection and shared antigen recognition. CDR3 similarities were shared among expanded clones from individuals discordant for canonical Ro and La autoantibodies, suggesting recognition of alternative SG antigen(s). The extent of SG clonal expansion correlated with reduced saliva production and increased SG fibrosis, linking expanded SG T cells with glandular dysfunction. Knowledge of paired TCRα and β sequences enables further work toward identification of target antigens and development of novel therapies.- Published
- 2016
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44. The anti-inflammatory CASPASE-12 gene does not influence SLE phenotype in African-Americans.
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Fuchs T, Kelly JA, Simon E, Sivils KL, and Hermel E
- Subjects
- Adult, Alleles, Antibodies, Antinuclear blood, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Interleukin-1beta blood, Male, Middle Aged, Polymorphism, Single Nucleotide, Black or African American, Caspase 12 genetics, Lupus Erythematosus, Systemic genetics, Mutation genetics, Sepsis genetics
- Abstract
In the vast majority of human populations, the gene encoding CASPASE-12 (CASP12) has a premature termination codon that precludes the production of protein. However, approximately 20% of persons of recent African descent have a single nucleotide polymorphism (#rs497116; A->G) that turns the stop codon into one encoding Arg. The subsequent functional allele is a risk factor for sepsis as it uniquely downregulates inflammatory cytokines in African-Americans (AA). To determine if CASP12 could be protective for systemic lupus erythematosus (SLE) in AA, we genotyped AA SLE patients and controls. There was a weak association between CASP12 genotype with the absence of anti-dsDNA autoantibodies in SLE patients. No effect was seen upon serum interleukin-1 beta levels, nor was any other protective effect noted for the CASP12 genotype, whether upon association with SLE, or any of the 11 American College of Rheumatology classification criteria. CASP12 genotype thus does not influence the phenotype of SLE in AA., (Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
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- 2016
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45. Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.
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Lessard CJ, Sajuthi S, Zhao J, Kim K, Ice JA, Li H, Ainsworth H, Rasmussen A, Kelly JA, Marion M, Bang SY, Joo YB, Choi J, Lee HS, Kang YM, Suh CH, Chung WT, Lee SK, Choe JY, Shim SC, Oh JH, Kim YJ, Han BG, Shen N, Howe HS, Wakeland EK, Li QZ, Song YW, Gaffney PM, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Vyse TJ, Harley JB, Sivils KL, Bae SC, Langefeld CD, and Tsao BP
- Subjects
- Case-Control Studies, Genetic Predisposition to Disease, Genotype, HLA-DQ beta-Chains genetics, HLA-DRB1 Chains genetics, Humans, OX40 Ligand genetics, Polymorphism, Single Nucleotide, Republic of Korea, Tumor Necrosis Factor alpha-Induced Protein 3 genetics, Asian People genetics, Autophagy-Related Proteins genetics, Carrier Proteins genetics, Lupus Erythematosus, Systemic genetics, Membrane Proteins genetics, Receptors, Purinergic P2Y2 genetics
- Abstract
Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population., Methods: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China., Results: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified., Conclusion: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2., (© 2016, American College of Rheumatology.)
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- 2016
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46. X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.
- Author
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Liu K, Kurien BT, Zimmerman SL, Kaufman KM, Taft DH, Kottyan LC, Lazaro S, Weaver CA, Ice JA, Adler AJ, Chodosh J, Radfar L, Rasmussen A, Stone DU, Lewis DM, Li S, Koelsch KA, Igoe A, Talsania M, Kumar J, Maier-Moore JS, Harris VM, Gopalakrishnan R, Jonsson R, Lessard JA, Lu X, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Illei GG, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Xie G, Ng WF, Nordmark G, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer M, Segal BM, Vyse TJ, Wahren-Herlenius M, Witte T, Pons-Estel B, Alarcon-Riquelme ME, Guthridge JM, James JA, Lessard CJ, Kelly JA, Thompson SD, Gaffney PM, Montgomery CG, Edberg JC, Kimberly RP, Alarcón GS, Langefeld CL, Gilkeson GS, Kamen DL, Tsao BP, McCune WJ, Salmon JE, Merrill JT, Weisman MH, Wallace DJ, Utset TO, Bottinger EP, Amos CI, Siminovitch KA, Mariette X, Sivils KL, Harley JB, and Scofield RH
- Subjects
- Autoimmune Diseases epidemiology, Case-Control Studies, Chromosomes, Human, X, Female, Gene Dosage, Humans, In Situ Hybridization, Fluorescence, Prevalence, Sarcoidosis epidemiology, Sex Chromosome Aberrations, Sex Distribution, Trisomy, Arthritis, Rheumatoid epidemiology, Liver Cirrhosis, Biliary epidemiology, Lupus Erythematosus, Systemic epidemiology, Sex Chromosome Disorders of Sex Development epidemiology, Sjogren's Syndrome epidemiology
- Abstract
Objective: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls., Methods: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction., Results: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients., Conclusion: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity., (© 2016, American College of Rheumatology.)
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- 2016
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47. Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma.
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Nocturne G, Tarn J, Boudaoud S, Locke J, Miceli-Richard C, Hachulla E, Dubost JJ, Bowman S, Gottenberg JE, Criswell LA, Lessard CJ, Sivils KL, Carapito R, Bahram S, Seror R, Ng WF, and Mariette X
- Subjects
- Case-Control Studies, Cohort Studies, France, Hodgkin Disease genetics, Humans, Logistic Models, Lymphoma complications, Lymphoma, B-Cell genetics, Multivariate Analysis, Mycosis Fungoides genetics, Polymorphism, Single Nucleotide, Sjogren's Syndrome complications, Skin Neoplasms genetics, Tumor Necrosis Factor alpha-Induced Protein 3, United Kingdom, White People genetics, DNA-Binding Proteins genetics, Germ-Line Mutation genetics, Intracellular Signaling Peptides and Proteins genetics, Lymphoma genetics, Nuclear Proteins genetics, Sjogren's Syndrome genetics
- Abstract
Background and Objective: A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association., Patients and Methods: The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts., Results: The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively)., Conclusions: This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
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- 2016
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48. Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
- Author
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Alarcón-Riquelme ME, Ziegler JT, Molineros J, Howard TD, Moreno-Estrada A, Sánchez-Rodríguez E, Ainsworth HC, Ortiz-Tello P, Comeau ME, Rasmussen A, Kelly JA, Adler A, Acevedo-Vázquez EM, Cucho-Venegas JM, García-De la Torre I, Cardiel MH, Miranda P, Catoggio LJ, Maradiaga-Ceceña M, Gaffney PM, Vyse TJ, Criswell LA, Tsao BP, Sivils KL, Bae SC, James JA, Kimberly RP, Kaufman KM, Harley JB, Esquivel-Valerio JA, Moctezuma JF, García MA, Berbotto GA, Babini AM, Scherbarth H, Toloza S, Baca V, Nath SK, Aguilar Salinas C, Orozco L, Tusié-Luna T, Zidovetzki R, Pons-Estel BA, Langefeld CD, and Jacob CO
- Subjects
- Argentina, CD11b Antigen genetics, Case-Control Studies, Chile, Chromosomes, Human, Pair 10 genetics, DNA-Binding Proteins genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ Antigens genetics, HLA-DQ beta-Chains genetics, Haplotypes, Humans, Interferon Regulatory Factors, Interleukin-1 Receptor-Associated Kinases genetics, Male, Mexico, Mitochondrial Proton-Translocating ATPases genetics, NADPH Oxidases genetics, Odds Ratio, Peru, Principal Component Analysis, STAT4 Transcription Factor genetics, United States, White People genetics, beta Karyopherins, American Indian or Alaska Native genetics, Lupus Erythematosus, Systemic genetics
- Abstract
Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage., Methods: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated., Results: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE., Conclusion: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases., (© 2016, American College of Rheumatology.)
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- 2016
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49. Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity.
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Wolska N, Rybakowska P, Rasmussen A, Brown M, Montgomery C, Klopocki A, Grundahl K, Scofield RH, Radfar L, Stone DU, Anaya JM, Ice JA, Lessard CJ, Lewis DM, Rhodus NL, Gopalakrishnan R, Huang AJ, Hughes PJ, Rohrer MD, Weisman MH, Venuturupalli S, Guthridge JM, James JA, Sivils KL, Bagavant H, and Deshmukh US
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- Female, Humans, Hypergammaglobulinemia immunology, Immunoprecipitation, Male, Methionine, Middle Aged, Rheumatoid Factor blood, Ribonucleoproteins immunology, Sjogren's Syndrome physiopathology, Sulfur Radioisotopes, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Autoantibodies blood, Carrier Proteins immunology, Severity of Illness Index, Sjogren's Syndrome immunology
- Abstract
Objective: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti-TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease., Methods: Serum samples from patients with primary SS (n = 235) and controls (n = 50) were analyzed for reactivity with in vitro-transcribed and -translated (35) S-methionine-labeled TRIM38 protein. The associations of anti-TRIM38 with various laboratory and clinical measures of primary SS were evaluated. Reactivity of anti-TRIM38 with different structural domains of TRIM38 was analyzed. Affinity-purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21., Results: TRIM38-reactive autoantibodies were detected in the sera of 24 of the 235 patients with primary SS and 2 of the 50 controls. Anti-TRIM38 positivity was significantly associated with the presence of anti-Ro60, anti-Ro52, anti-La, rheumatoid factor, and hypergammaglobulinemia. Clinically, anti-TRIM38 was associated with significantly higher ocular surface staining scores, lower Schirmer's test scores, and minor labial salivary gland biopsy focus scores of ≥3.0. Anti-TRIM38 antibodies mainly recognized the cortactin-binding protein 2 (CortBP-2; amino acids 128-238) and the B30.2/SPRY (amino acids 268-465) domains on TRIM38. Affinity-purified antibodies to TRIM38-CortBP-2 and TRIM38-B30.2/SPRY domains reacted with TRIM21., Conclusion: Our data demonstrate that anti-TRIM38 specificity arising in a subset of patients with primary SS is associated with increased severity of the disease., (© 2016, American College of Rheumatology.)
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- 2016
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50. Interaction between innate immunity and Ro52-induced antibody causes Sjögren's syndrome-like disorder in mice.
- Author
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Szczerba BM, Kaplonek P, Wolska N, Podsiadlowska A, Rybakowska PD, Dey P, Rasmussen A, Grundahl K, Hefner KS, Stone DU, Young S, Lewis DM, Radfar L, Scofield RH, Sivils KL, Bagavant H, and Deshmukh US
- Subjects
- Animals, Humans, Immunoglobulin G immunology, Sialadenitis pathology, Sjogren's Syndrome pathology, Submandibular Gland pathology, Autoantibodies immunology, Disease Models, Animal, Immunity, Innate immunology, Immunization, Passive, Mice, Ribonucleoproteins immunology, Sialadenitis immunology, Sjogren's Syndrome immunology, Submandibular Gland immunology
- Abstract
Objectives: Autoantibodies reactive with Ro52 are often found in sera of patients with Sjögren's syndrome (SS). This study was undertaken to investigate the role of Ro52-induced immune responses in pathogenesis of SS., Methods: New Zealand Mixed (NZM) 2758 mice were immunised with Ro52 in alum adjuvant. Control mice were immunised either with maltose-binding protein or injected with alum alone. Mice were monitored for anti-Ro52 antibody, sialoadenitis and pilocarpine-induced salivation. Antibody binding to salivary gland (SG) cells was analysed in vivo and in vitro by immunofluorescence. Sera from immunised mice were passively transferred into untreated or alum injected NZM2758 mice., Results: By day 30 post-immunisation, Ro52 immunised mice generated immunoprecipitating anti-Ro52 antibodies and they had the maximum drop in saliva production. Both Ro52 immunised and control mice showed evidence of mild sialoadenitis. However, only Ro52 immunised mice had antibody deposition in their SG. Passive transfer of Ro52-immune sera induced SG dysfunction in recipient mice, only if the recipients were primed with alum. In vitro, antibodies from Ro52-immune sera were internalised by a SG cell line and this uptake was inhibited by cytochalasin D treatment., Conclusions: Our data show for the first time that antibodies induced by Ro52 are capable of inducing SG dysfunction, and that this phenomenon is dependent on the activation of innate immunity. The mouse model described in this study implies that autoantibody deposition in the SG might be an important step in the induction of xerostomia and pathogenesis of SS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
- Full Text
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