659 results
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2. Immune modulation via T regulatory cell enhancement: disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases - An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)
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Antonios G.A. Kolios, Ian M. Adcock, Betty C.A.M. van Esch, Onur Boyman, Zuzana Diamant, Cristina Benito-Villalvilla, Francesca Levi-Schaffer, Frank A. Redegeld, Giuseppe Nocentini, Kian Fan Chung, Leif Bjermer, Luigi Cari, Rodolfo Bianchini, Gaetano Caramori, Ibon Eguiluz-Gracia, Oscar Palomares, Cristiana Stellato, Edward F. Knol, Franziska Roth-Walter, Afd Pharmacology, Pharmacology, University of Zurich, and Stellato, Cristiana
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Adoptive cell transfer ,Disease ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,FOOD ALLERGY ,adoptive cell therapies ,Autoimmunity ,CONFERS PROTECTION ,0302 clinical medicine ,allergy ,autoimmunity ,CAR-Treg cells ,immunoregulation ,Immunology and Allergy ,LYMPHOCYTE-ACTIVATION ,EXPERIMENTAL COLITIS ,10177 Dermatology Clinic ,MOUSE MODEL ,CAR‐ ,medicine.anatomical_structure ,1107 Immunology ,2723 Immunology and Allergy ,Allergen immunotherapy ,T cell ,Immunology ,DNA METHYLTRANSFERASE ,610 Medicine & health ,Autoimmune Diseases ,03 medical and health sciences ,Immune system ,medicine ,Hypersensitivity ,Humans ,ADOPTIVE TRANSFER ,2403 Immunology ,TRANSCRIPTION FACTOR FOXP3 ,business.industry ,Immunopharmacology ,Asthma ,Transplantation ,ATTENUATES AIRWAY INFLAMMATION ,ORAL TOLERANCE ,030228 respiratory system ,10033 Clinic for Immunology ,business ,Treg cells ,030215 immunology - Abstract
Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.
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- 2021
3. Cytokine Storm in COVID-19—Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper
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Sonu Bhaskar, Akansha Sinha, Maciej Banach, Shikha Mittoo, Robert Weissert, Joseph S. Kass, Santhosh Rajagopal, Anupama R. Pai, and Shelby Kutty
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CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,animal diseases ,CD8-Positive T-Lymphocytes ,Pathogenesis ,0302 clinical medicine ,Adrenal Cortex Hormones ,Hypothesis and Theory ,Case fatality rate ,Immunology and Allergy ,guidelines ,biology ,Anti-Inflammatory Agents, Non-Steroidal ,autoimmunity ,Acute kidney injury ,cytokine storm ,Cytokines ,Female ,Angiotensin-Converting Enzyme 2 ,Coronavirus Infections ,Vasculitis ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Critical Care ,immunological mechanisms ,Critical Illness ,Clinical Decision-Making ,Pneumonia, Viral ,Immunology ,CD4-CD8 Ratio ,Peptidyl-Dipeptidase A ,neuroimmunology ,Sepsis ,Betacoronavirus ,Immunocompromised Host ,03 medical and health sciences ,Sex Factors ,medicine ,Humans ,Janus Kinase Inhibitors ,Intensive care medicine ,Interleukin 6 ,Pandemics ,Interleukin-6 ,SARS-CoV-2 ,business.industry ,Endothelial Cells ,COVID-19 ,Thrombosis ,immunotherapies ,medicine.disease ,030104 developmental biology ,Neuroimmunology ,biology.protein ,lcsh:RC581-607 ,business ,Cytokine storm ,030215 immunology - Abstract
Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.
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- 2020
4. Identification of novel therapeutic targets for blocking acantholysis in pemphigus
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Nick Feldmann, Christoph M. Hammers, Shirin Emtenani, Enno Schmidt, Imke A. K. Burmester, Sarah Flaswinkel, Khalaf Kridin, Nina van Beek, Mayumi Kamaguchi, Clara-Sophie Thies, Valéria Bumiller-Bini, Ralf Ludwig, Detlef Zillikens, Jennifer E. Hundt, and Anika Kasprick
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Keratinocytes ,0301 basic medicine ,skin ,Human skin ,Desmoglein ,03 medical and health sciences ,0302 clinical medicine ,cell signaling ,Humans ,Medicine ,Autoantibodies ,Pharmacology ,Desmoglein 3 ,integumentary system ,business.industry ,Acantholysis ,autoimmunity ,Pemphigus vulgaris ,Autoantibody ,pemphigus ,medicine.disease ,Research Papers ,Pemphigus ,HaCaT ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,business ,Keratinocyte ,model system ,030217 neurology & neurosurgery ,Research Paper - Abstract
Background and purpose Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3 and/or non-Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent, and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half-life. However, topical modulation of PV autoantibody-induced blistering is an attractive target because it could promptly relieve symptoms. Experimental approach To address this issue, we performed an unbiased screen in a complex biological system using 141 small molecule inhibitors from a chemical library. Specifically, we evaluated PV IgG-induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model. Key results Overall, this approach led to the identification of 4 molecules involved in PV IgG-induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2. Conclusion and implications This unbiased screen revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life-threatening skin disease.
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- 2020
5. Long-term outcomes in systemic lupus erythematosus: trends over time and major contributors
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Laurent Arnaud and Maria G Tektonidou
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medicine.medical_specialty ,SLE ,Lupus nephritis ,Ethnic group ,Comorbidity ,Disease ,comorbidities ,treatment adherence ,medicine.disease_cause ,smoking ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,Rheumatology ,medicine ,Long term outcomes ,Humans ,Lupus Erythematosus, Systemic ,Pharmacology (medical) ,030212 general & internal medicine ,Intensive care medicine ,AcademicSubjects/MED00360 ,lupus nephritis ,030203 arthritis & rheumatology ,glucocorticoids ,business.industry ,Remission Induction ,medicine.disease ,mortality ,Health equity ,Treatment Outcome ,Supplement Papers ,socio-economic factors ,business ,damage ,long-term outcomes - Abstract
SLE is a chronic autoimmune rheumatic disorder of high heterogeneity in clinical presentation, treatment response and prognosis. Long-term outcomes in SLE have been dramatically improved over the past decades, however, increased morbidity and mortality, especially among young individuals, still exists. Unmet needs include residual disease activity and frequent flares, glucocorticoid treatment dependency and toxicity, comorbidity burden, reduced health-related quality of life, health disparities and damage. The main determinants of long-term outcomes in SLE are age, sex, race/ethnicity, genetic profile, environmental factors including smoking, disease activity, major organ involvement such as lupus nephritis and CNS involvement, comorbidities including cardiovascular disease and serious infections, coexistence with APS, treatment adherence, socio-economic factors and access to care. In this review we discuss trends in long-term outcomes in SLE over the years and major contributors such as genetic, disease-related, treatment, comorbidity, socio-economic and other factors.
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- 2020
6. Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood–brain barrier
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Florian C. Kurschus, Tobias Bopp, Ingo Bechman, Ari Waisman, Harald Binder, Silvia Cardoso, Subhashini Bolisetty, Lisa Johann, Judith Hauptmann, Federico Marini, Elisa Colombo, Ilgiz A. Mufazalov, Markus Schwaninger, Miguel P. Soares, Judith Strauß, Sonja Moos, Anupam Agarwal, Fred Lühder, Matthias Klein, Maja Kitic, Florian Wanke, Khalad Karram, Martin Krueger, and Tommy Regen
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0301 basic medicine ,Encephalomyelitis, Autoimmune, Experimental ,Experimental autoimmune encephalomyelitis (EAE) ,Autoimmunity ,Blood–brain barrier ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Chemokine receptor ,0302 clinical medicine ,medicine ,Animals ,Neuroinflammation ,Inflammation ,Original Paper ,Microglia ,Chemistry ,Experimental autoimmune encephalomyelitis ,Endothelial Cells ,Interleukin ,medicine.disease ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Heme oxygenase ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Blood-Brain Barrier ,Heme oxygenase-1 (HO-1) ,Neurology (clinical) ,Heme Oxygenase-1 ,030217 neurology & neurosurgery ,Interleukin-1 ,Signal Transduction - Abstract
The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood–brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation. Electronic supplementary material The online version of this article (10.1007/s00401-020-02187-x) contains supplementary material, which is available to authorized users.
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- 2020
7. Pathogenesis of psoriasis in the 'omic' era. Part I. Epidemiology, clinical manifestation, immunological and neuroendocrine disturbances
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Leszek Kalinowski, Magdalena Górecka-Sokołowska, Agata Płoska, Justyna Szczęch, Andrzej Slominski, Adrianna Radulska, Joanna Bartosińska, Marta Sobalska-Kwapis, Iwona T. Dobrucki, Dorota Krasowska, Roman Nowicki, Agnieszka Owczarczyk-Saczonek, Adam Reich, Radomir M. Slominski, Lawrence W. Dobrucki, Rafał Czajkowski, Anna Janaszak-Jasienicka, Dominik Samotij, Aneta Szczerkowska-Dobosz, Dorota Purzycka-Bohdan, Michał A. Żmijewski, Marta Macieja-Stawczyk, Edyta Reszka, Dominik Strapagiel, Anna Siekierzycka, Bogusław Nedoszytko, and Aleksandra Batycka-Baran
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neoangiogenesis ,T cell ,Population ,Inflammation ,Dermatology ,Disease ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Psoriasis ,medicine ,Immunology and Allergy ,education ,Internal medicine ,education.field_of_study ,Review Paper ,neurogenic inflammation ,business.industry ,autoimmunity ,psoriasis ,medicine.disease ,RC31-1245 ,medicine.anatomical_structure ,interleukins ,RL1-803 ,Immunology ,medicine.symptom ,business - Abstract
Psoriasis is a common, chronic, inflammatory, immune-mediated skin disease affecting about 2% of the world’s population. According to current knowledge, psoriasis is a complex disease that involves various genes and environmental factors, such as stress, injuries, infections and certain medications. The chronic inflammation of psoriasis lesions develops upon epidermal infiltration, activation, and expansion of type 1 and type 17 Th cells. Despite the enormous progress in understanding the mechanisms that cause psoriasis, the target cells and antigens that drive pathogenic T cell responses in psoriatic lesions are still unproven and the autoimmune basis of psoriasis still remains hypothetical. However, since the identification of the Th17 cell subset, the IL-23/Th17 immune axis has been considered a key driver of psoriatic inflammation, which has led to the development of biologic agents that target crucial elements of this pathway. Here we present the current understanding of various aspects in psoriasis pathogenesis.
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- 2020
8. Comparison of tyrosinase antibody, tyrosinase-related protein-1 and -2 antibodies, melanin-concentrating hormone receptor antibody levels with autologous serum skin test and autologous plasma skin test results in patients with vitiligo
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Necmettin Akdeniz, Abdullah Ünal, Hatice Uce Özkol, and Yasemin Bayram
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vitiligo ,Tyrosinase ,Vitiligo ,Dermatology ,medicine.disease_cause ,Autoimmunity ,In vivo ,medicine ,Immunology and Allergy ,Outpatient clinic ,antibodies ,TYRP1 ,skin and connective tissue diseases ,Internal medicine ,Original Paper ,integumentary system ,biology ,business.industry ,autoimmunity ,medicine.disease ,RC31-1245 ,Hormone receptor ,RL1-803 ,Immunology ,biology.protein ,autologous serum skin test ,Antibody ,business - Abstract
Introduction Although the exact etiopathogenesis of vitiligo is unknown, the autoimmunity hypothesis is much in evidence. The autologous serum skin test (ASST) and autologous plasma skin test (APST) are in vivo methods used in the diagnosis of some autoimmune diseases, which are easy and inexpensive to perform. Aim In this study, we investigated whether or not ASST and APST could determine autoimmunity in patients with vitiligo. Material and methods In this study, 30 vitiligo patients presenting to the dermatology outpatient clinic and 30 healthy volunteers without any known autoimmune diseases were included. Antibodies such as tyrosinase, tyrosinase-related protein-1 (TYRP1), tyrosinase-related protein-2 (TYRP2) and melanin-concentrating hormone receptor 1 (MCHR1) antibodies determined to be associated with vitiligo were examined. In addition, the association of these antibodies with the positivity of ASST and APST, which were suggested to be associated with autoimmunity, were examined. Results In our study, tyrosinase antibody was found to be significantly higher in vitiligo patients. ASST was positive in 12 (40%) patients with vitiligo and 8 (26.6%) control subjects. APST was positive in 8 (26.6%) of the patients with vitiligo and in 2 (6.6%) of the controls, and there was a significant difference between the groups in terms of APST positivity (p = 0.032). In addition, in our study, a significant correlation was found between TYRP1 antibody positivity and APST positivity in the patient group (p = 0.005). Conclusions These findings suggest that we may use APST to investigate the autoimmune etiopathogenesis of vitiligo.
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- 2020
9. The Association of Subclinical Insulin Resistance with Thyroid Autoimmunity in Euthyroid Individuals
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Vesna Vucelić, Jelena Marinković, Milan Vrkljan, Krešimir Rotim, Domagoj Gajski, Kristina Blaslov, Petar Gaćina, and Gorana Mirošević
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Adult ,Hashimoto thyroiditis ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,lcsh:Medicine ,Autoimmunity ,Hashimoto Disease ,Logistic regression ,Insulin resistance ,Internal medicine ,Humans ,Medicine ,Euthyroid ,Original Scientific Papers ,Subclinical infection ,biology ,business.industry ,lcsh:R ,5-hour oral glucose tolerance test ,General Medicine ,medicine.disease ,Anti-thyroid autoantibodies ,Endocrinology ,Homeostatic model assessment ,biology.protein ,Antibody ,business ,Follow-Up Studies - Abstract
SUMMARY Hashimoto thyroiditis is characterized by anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies that gradually lead to thyroid cell destruction. As hypothyroidism has been associated with insulin resistance (IR), we aimed to investigate whether IR is associated with thyroid antibody presence and whether the degree of IR correlates with their concentration in euthyroid individuals. A total of 164 non-diabetic, euthyroid individuals, average age 34 years, were included in the study, divided into two groups according to Hashimoto thyroiditis and underwent 5-hour oral glucose tolerance test. The degree of IR was evaluated by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). The Hashimoto thyroiditis group had higher HOMA-IR (p=0.003) and lower glucose levels (p=0.04). HOMA-IR correlated positively with anti-TPO (p
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- 2020
10. Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8+ T-cell memory in wild-type and humanized mice
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Chuanjian Lu, Run-Yue Huang, Chun-Ling Liang, Ling Han, Huazhen Liu, Yuhong Yan, Feifei Qiu, Qunfang Zhang, Yuchao Chen, and Zhenhua Dai
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Male ,0301 basic medicine ,Drug Evaluation, Preclinical ,Medicine (miscellaneous) ,Inflammation ,Human skin ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Memory T cells ,Autoimmunity ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Psoriasis ,Secondary Prevention ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Relapse ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Skin ,Interleukin-15 ,Transplantation Chimera ,Imiquimod ,business.industry ,Interleukin-17 ,Skin Transplantation ,medicine.disease ,Artemisinins ,Disease Models, Animal ,Dihydroartemisinin ,Methotrexate ,030104 developmental biology ,Cancer research ,medicine.symptom ,business ,Immunologic Memory ,Immunosuppression ,CD8 ,Research Paper ,030215 immunology ,medicine.drug - Abstract
Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms. Methods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed. Results: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8+ central memory T (TCM) and CD8+ resident memory T (TRM) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8+, but not CD4+, subset of CD44highCD62Lhigh TCM in psoriatic mice, whereas methotrexate (MTX) lowered CD4+, but not CD8+, TCM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8+ T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8+CLA+, CD8+CD69+ or CD8+CD103+ TRM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8+, but not CD4+, TCM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8+ TCM and CD103+ TRM cells in humanized mice. Conclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8+ T-cells.
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- 2020
11. Comment on: Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series
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Adi Kibari, Devy Zisman, Yael Paran, Victoria Furer, Ori Elkayam, and Doron Rimar
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reactivation ,Herpesvirus 3, Human ,Concise Report ,Disease ,medicine.disease_cause ,Letter to the Editor (Matters arising from published papers) ,COVID-19 BNT162b2 mRNA vaccine ,Autoimmunity ,0302 clinical medicine ,Medicine ,Pharmacology (medical) ,030212 general & internal medicine ,AcademicSubjects/MED00360 ,Leukemia ,Vaccination ,Middle Aged ,Rheumatoid arthritis ,Female ,Rheumatic Fever ,Adult ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,Herpes Zoster ,Autoimmune Diseases ,03 medical and health sciences ,rheumatic diseases/AIIRD ,Rheumatology ,Internal medicine ,Rheumatic Diseases ,Humans ,In patient ,RNA, Messenger ,Adverse effect ,BNT162 Vaccine ,030203 arthritis & rheumatology ,Messenger RNA ,Tofacitinib ,business.industry ,Postherpetic neuralgia ,SARS-CoV-2 ,COVID-19 ,medicine.disease ,Immunology ,Virus Activation ,Immunization ,business - Abstract
Objectives As global vaccination campaigns against COVID-19 disease commence, vaccine safety needs to be closely assessed. The safety profile of mRNA-based vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is unknown. The objective of this report is to raise awareness of reactivation of herpes zoster (HZ) following the BNT162b2 mRNA vaccination in patients with AIIRD. Methods The safety of the BNT162b2 mRNA vaccination was assessed in an observational study monitoring post-vaccination adverse effects in patients with AIIRD (n = 491) and controls (n = 99), conducted in two rheumatology departments in Israel. Results The prevalence of HZ was 1.2% (n = 6) in patients with AIIRD compared with none in controls. Six female patients aged 49 ± 11 years with stable AIIRD: RA (n = 4), Sjogren’s syndrome (n = 1), and undifferentiated connective disease (n = 1), developed the first in a lifetime event of HZ within a short time after the first vaccine dose in five cases and after the second vaccine dose in one case. In the majority of cases, HZ infection was mild, except a case of HZ ophthalmicus, without corneal involvement, in an RA patient treated with tofacitinib. There were no cases of disseminated HZ disease or postherpetic neuralgia. All but one patient received antiviral treatment with a resolution of HZ-related symptoms up to 6 weeks. Five patients completed the second vaccine dose without other adverse effects. Conclusion Epidemiologic studies on the safety of the mRNA-based COVID-19 vaccines in patients with AIIRD are needed to clarify the association between the BNT162b2 mRNA vaccination and reactivation of zoster.
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- 2021
12. Citrullination of a phage-displayed human peptidome library reveals the fine specificities of rheumatoid arthritis-associated autoantibodies
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Gabriel D. Román-Meléndez, Rachel S. Quizon, Janelle M. Montagne, Daniel R. Monaco, H. Benjamin Larman, Maximilian F. Konig, Erika Darrah, and Mekbib Astatke
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Medicine (General) ,Phage display ,Proteome ,Arthritis ,Computational biology ,Disease ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Autoimmunity ,Arthritis, Rheumatoid ,Epitopes ,R5-920 ,Peptide Library ,medicine ,Human proteome project ,Humans ,Phage ImmunoPrecipitation Sequencing ,Rheumatoid arthritis ,Autoantibodies ,Peptidylarginine deiminase ,Autoantibody ,Citrullination ,General Medicine ,medicine.disease ,Medicine ,Research Paper - Abstract
Background Post-translational modifications (PTMs) on proteins can be targeted by antibodies associated with autoimmunity. Despite a growing appreciation for their intrinsic role in disease, there is a lack of highly multiplexed serological assays to characterize the fine specificities of PTM-directed autoantibodies. Methods In this study, we used the programmable phage display technology, Phage ImmunoPrecipitation Sequencing (PhIP-Seq), to profile rheumatoid arthritis (RA) associated anti-citrullinated protein antibody (ACPA) reactivities. Findings Using both unmodified and peptidylarginine deiminase (PAD)-modified phage display libraries consisting of ~250,000 overlapping 90 amino acid peptide tiles spanning the human proteome, PTM PhIP-Seq robustly identified antibodies to citrulline-dependent epitopes. Interpretation PTM PhIP-Seq was used to quantify key differences among RA patients, including PAD isoform specific ACPA profiles, and thus represents a powerful tool for proteome-scale antibody-binding analyses. Funding This research is based upon work supported in part by the Office of the Director of National Intelligence (ODNI), Intelligence Advanced Research Projects Activity (IARPA). The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of ODNI, IARPA, or the US Government. The US Government is authorized to reproduce and distribute reprints for governmental purposes notwithstanding any copyright annotation therein. This study was made possible by a National Institute of General Medical Sciences (NIGMS) grant R01 GM136724 (HBL). MFK was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant T32AR048522. ED was supported by the Rheumatology Research Foundation.
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- 2021
13. An Insulin‐Inspired Supramolecular Hydrogel for Prevention of Type 1 Diabetes
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Zhongyan Wang, Yuna Shang, Mohan Liu, Dandan Feng, Chen Li, Jianfeng Liu, Zhimou Yang, and Xinxin Li
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type 1 diabetes ,General Chemical Engineering ,medicine.medical_treatment ,General Physics and Astronomy ,Medicine (miscellaneous) ,02 engineering and technology ,Nod ,Autoantigens ,T-Lymphocytes, Regulatory ,01 natural sciences ,Immune tolerance ,Mice ,Mice, Inbred NOD ,Insulin ,General Materials Science ,NOD mice ,self‐assembled peptides ,education.field_of_study ,Full Paper ,autoimmunity ,General Engineering ,Hydrogels ,Full Papers ,021001 nanoscience & nanotechnology ,Female ,0210 nano-technology ,Adjuvant ,immunoregulation ,Science ,Population ,010402 general chemistry ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Islets of Langerhans ,Antigen ,medicine ,Animals ,Hypoglycemic Agents ,education ,Type 1 diabetes ,business.industry ,medicine.disease ,Peptide Fragments ,0104 chemical sciences ,Disease Models, Animal ,Diabetes Mellitus, Type 1 ,Immunology ,supramolecular hydrogels ,business - Abstract
Supramolecular peptide hydrogel has shown promising potential in vaccine development largely because of its ability to function both as antigen depot and immune adjuvant. Nap‐GdFdFdY, a tetrapeptide hydrogel that has been previously reported to exhibit adjuvant effect, is inadvertently found to contain conserved peptide sequence for insulin, proinsulin, and glutamic acid decarboxylase, 3 major autoantigens for the autoimmune type 1 diabetes (T1D). At present, despite being managed clinically with insulin replacement therapy, T1D remains a major health threat with rapidly increasing incidences, especially in children and young adults, and antigen‐specific immune tolerance induction has been proposed as a feasible approach to prevent or delay T1D progression at an early stage. Here, it is reported that innoculation of Nap‐GdFdFdY leads to complete protection of nonobese diabetic (NOD) mice from T1D development till the age of 36 weeks. Better maintenance of pancreatic islet morphology with minimal immune cell infiltration is also observed from mice exposed to Nap‐GdFdFdY. This beneficial impact is mainly due to its facilitative role on enhancing peripheral T regulatory cell (Treg) population, shown as increased splenic Treg percentage, and function, demonstrated by maintenance of circulating TGF‐β1 level. Serum cytokine microarray data further implicate a “buffering” role of Nap‐GdFdFdY on systemic inflammatory tone in NOD mice. Thus, with its versatility, applicability, and excellent potency, Nap‐GdFdFdY is posited as a novel therapeutic intervention for T1D., A hydrogel of Nap‐GdFdFdY containing conserved sequence of autoantigens including insulin, proinsulin, and glutamic acid decarboxylase as a novel therapeutic intervention for the autoimmune type 1 diabetes. Better pancreatic islet morphology with minimal immune cell infiltration is observed from mice with hydrogel because of enhancing peripheral T regulatory cell population and maintenance of circulating TGF‐β1 level.
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- 2021
14. Point of view on the vaccination against COVID-19 in patients with autoimmune inflammatory rheumatic diseases
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Sander van Assen, Ulf Mueller-Ladner, Victoria Furer, Marc Bijl, Christien Rondaan, Karen Schreiber, Nancy Agmon-Levin, Klaus Warnatz, Nico M Wulffraat, Annette de Thurah, Daphna Paran, Meliha C Kapetanovic, and Ori Elkayam
- Subjects
Adult ,medicine.medical_specialty ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Adolescent ,CLINICAL-COURSE ,Immunology ,Population ,Arthritis ,Autoimmunity ,Patient safety ,Young Adult ,Rheumatology ,Rheumatic Diseases ,Pandemic ,Immunology and Allergy ,Medicine ,Humans ,autoimmune diseases ,Young adult ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,Intensive care medicine ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,Clinical Trials as Topic ,OUTCOMES ,business.industry ,SARS-CoV-2 ,COVID-19 ,Middle Aged ,medicine.disease ,SERIES ,vaccination ,METHOTREXATE ,Vaccination ,Practice Guidelines as Topic ,Position paper ,Patient Safety ,ARTHRITIS ,business - Abstract
In view of the COVID-19 pandemic, there is an unmet clinical need for the guidelines on vaccination of patients with autoimmune inflammatory rheumatic diseases (AIIRD). This position paper summarises the current data on COVID-19 infection in patients with AIIRD and development of vaccines against COVID-19, discusses the aspects of efficacy and safety of vaccination, and proposes preliminary considerations on vaccination against COVID-19 in patients with AIIRD, mainly based on the expert opinion and knowledge on the use of other vaccines in this population of patients.
- Published
- 2021
15. Immunodeficiency and autoimmunity during biological disease-modifying antirheumatic drug therapy
- Author
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Anna Czekalska, Mariusz Puszczewicz, and Dominik Majewski
- Subjects
biologic agents ,medicine.medical_treatment ,Immunology ,Population ,lcsh:Medicine ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Rheumatology ,medicine ,Immunology and Allergy ,Disease-modifying antirheumatic drug ,education ,Adverse effect ,Immunodeficiency ,030203 arthritis & rheumatology ,Review Paper ,education.field_of_study ,business.industry ,biological disease-modifying antirheumatic drugs ,lcsh:R ,medicine.disease ,Comorbidity ,adverse effects ,business - Abstract
Biological disease-modifying antirheumatic drugs target specific components of the immune response related to pathogenesis of autoimmune and inflammatory diseases. Introduction of biologic therapies has enabled better disease control than conventional drugs and thus a reduction in comorbidity and mortality. However, there is concern about adverse effects of these drugs including infections, cancers and drug-induced autoimmune diseases. Patients undergoing biologic treatment are at small but significant risk of serious infections. The overall risk of malignancies in patients on biologics compared with the general population is not increased, but there is evidence of a higher risk of individual cancers. Surprisingly, biological treatment may induce autoantibody production and, rarely, development of autoimmune diseases. A growing body of literature has evaluated the risk of adverse effects during biologic therapies. This paper outlines adverse effects of biological disease-modifying antirheumatic drugs related to immune system disorders, both immunodeficiency and autoimmunity.
- Published
- 2019
16. The 3p21.31 genetic locus promotes progression to type 1 diabetes through the CCR2/CCL2 pathway
- Author
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Jin-Xiong She, Fran Dong, Marian Rewers, Diane Hopkins, Kathleen Waugh, Eileen Kim, Stephen S. Rich, Sharad Purohit, Khaled Bin Satter, Suna Onengut-Gumuscu, and Paul Minh Huy Tran
- Subjects
CCR2 ,Research paper ,Fine mapping ,endocrine system diseases ,Immunology ,Single-nucleotide polymorphism ,Quantitative trait locus ,Biology ,medicine.disease_cause ,Autoimmunity ,Diabetes mellitus ,medicine ,Immunology and Allergy ,Family history ,Type 1 diabetes ,DAISY ,Autoantibody ,RC581-607 ,medicine.disease ,MCP1 ,Expression quantitative trait loci ,T1D ,Immunologic diseases. Allergy ,CCL2 ,Autoimmune - Abstract
Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2, were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway., Highlights • Serum CCL-2 levels are lower in individuals with islet autoantibodies and type 1 diabetes compared to controls. • Serum CCL-2 levels are associated with the 3p21.31 genetic locus. • The 3p21.31 genetic locus is associated with type 1 diabetes. • The 3p21.31 genetic locus is associated with gene expression of the CCL-2 receptor, CCR2.
- Published
- 2021
17. Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature
- Author
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Nicole Puertas Jurado, Edoardo Galli, David Bamert, Federica Sallusto, Sinduya Krishnarajah, Florian Ingelfinger, Hans H. Jung, Pascale Zwicky, Nicolás Gonzalo Núñez, Ayse Akarca, Sarah Mundt, Isabelle Opitz, Luca Piccoli, Donatella De Feo, Sebastian G. Utz, Didier Schneiter, Teresa Marafioti, Mirjam Lutz, Antonio Lanzavecchia, Michael Kramer, Burkhard Becher, Can Ulutekin, Bettina Schreiner, Corinne C Widmer, University of Zurich, Schreiner, Bettina, and Becher, Burkhard
- Subjects
0301 basic medicine ,Male ,10255 Clinic for Thoracic Surgery ,T-Lymphocytes ,2804 Cellular and Molecular Neuroscience ,Autoimmunity ,Tissue-resident T cells ,Biomarker ,Mass cytometry ,Immunophenotyping ,Thymus ,Myasthenia gravis ,Cytokines ,medicine.disease_cause ,Machine Learning ,0302 clinical medicine ,Receptors, Cholinergic ,Aged, 80 and over ,B-Lymphocytes ,Middle Aged ,Thymectomy ,3. Good health ,medicine.anatomical_structure ,2728 Neurology (clinical) ,Female ,Single-Cell Analysis ,Adult ,T cell ,610 Medicine & health ,Thymus Gland ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,Myasthenia Gravis ,medicine ,Humans ,Aged ,Autoantibodies ,Autoimmune disease ,Original Paper ,Autoantibody ,Correction ,Immune dysregulation ,medicine.disease ,10040 Clinic for Neurology ,2734 Pathology and Forensic Medicine ,030104 developmental biology ,Immunology ,10032 Clinic for Oncology and Hematology ,Neurology (clinical) ,Biomarkers ,030215 immunology - Abstract
Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02299-y.
- Published
- 2021
18. Just not himself these days: an invitation to submit papers on the topic of inflammation and immunity in organ systems physiology and pathophysiology
- Author
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David G. Harrison
- Subjects
Inflammation ,Publishing ,Phrase ,Physiology ,Interpretation (philosophy) ,media_common.quotation_subject ,Immunity ,Autoimmunity ,Adaptive Immunity ,Immunity, Innate ,Reflexive pronoun ,Autoimmune Diseases ,Disease Models, Animal ,Physiology (medical) ,Distraction ,Personality ,Animals ,Humans ,Psychology ,Organ system ,media_common - Abstract
when someone is acting oddly, it is often said that she or he is “not herself” or “not himself.” This generally refers to a change is personality, either due to distraction, stress, or some other emotional alteration. During the past decade, a new interpretation of this phrase has arisen.
- Published
- 2011
19. Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: A prospective cohort study
- Author
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Andreas Schulte-Mecklenbeck, Heinz Wiendl, Catharina C. Gross, Sven G. Meuth, Christoph Kleinschnitz, Michael Heming, Tobias Ruck, Steffen Pfeuffer, Susanne Windhagen, and Luisa Klotz
- Subjects
0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Research paper ,Medizin ,Thyroid Gland ,Autoimmunity ,General Biochemistry, Genetics and Molecular Biology ,Multiple sclerosis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Prospective Studies ,Prospective cohort study ,Alemtuzumab ,Secondary autoimmune disorders ,Thyroid autoimmunity ,Autoantibodies ,biology ,business.industry ,Thyroid ,Hazard ratio ,Autoantibody ,General Medicine ,medicine.disease ,Risk estimation ,Anti-thyroid autoantibodies ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,business ,Biomarkers ,medicine.drug - Abstract
Background Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions. Methods We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti–thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months. Findings Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73–31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity. Interpretation Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation. Fund German Ministry of Education, Science, Research and Technology and the German Research foundation.
- Published
- 2019
20. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients
- Author
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Marie L. Feser, William H. Robinson, Kevin D. Deane, Richard M. Keating, Rebecka L. Bourn, Hua Chen, James R. O'Dell, Patrick M. Gaffney, Michael H. Weisman, M. Kristen Demoruelle, Jennifer Seifert, Jill M. Norris, David A. Hafler, John B. Harley, Carl D. Langefeld, Jane H. Buckner, Elizabeth A. Bemis, Judith A. James, Kevin C. O’Connor, V. Michael Holers, Jennifer A. Kelly, Joel M. Guthridge, and Kendra A. Young
- Subjects
Adult ,Male ,0301 basic medicine ,Research paper ,Autoimmunity ,Disease ,Environment ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Nuclear Family ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,immune system diseases ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,First-degree relatives ,skin and connective tissue diseases ,Alleles ,Aged ,Autoantibodies ,Autoimmune disease ,Type 1 diabetes ,Systemic lupus erythematosus ,business.industry ,Autoantibody ,General Medicine ,Middle Aged ,medicine.disease ,3. Good health ,030104 developmental biology ,Organ Specificity ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Immunology ,Female ,business - Abstract
Background Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. Methods Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. Findings Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.
- Published
- 2019
21. Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management
- Author
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Adam Cuker, Christopher LaGanke, Congor Nadj, Alexandre Guerreiro, Sven G. Meuth, Brian Steingo, Bart Van Wijmeersch, Karthinathan Thangavelu, Mark A Agius, Krzysztof Selmaj, Timothy Thoits, Claudio E Rodriguez, David Margolin, Ann Jannsens, Tjalf Ziemssen, Darren P Baker, and Ann D Bass
- Subjects
Male ,AUTOIMMUNITY ,CHILDREN ,030204 cardiovascular system & hematology ,DISEASE ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Alemtuzumab ,Incidence ,Incidence (epidemiology) ,Middle Aged ,disease-modifying therapy ,immune thrombocytopenia ,Neurology ,Female ,5-YEAR FOLLOW-UP ,DEPLETION ,Life Sciences & Biomedicine ,Interferon beta-1a ,medicine.drug ,Adult ,safety ,PURPURA ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Neurology ,relapsing-remitting multiple sclerosis ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,Humans ,Immunologic Factors ,Purpura, Thrombocytopenic, Idiopathic ,Science & Technology ,business.industry ,Multiple sclerosis ,Neurosciences ,STANDARDIZATION ,medicine.disease ,Immune thrombocytopenia ,REMITTING MULTIPLE-SCLEROSIS ,Immunology ,Neurosciences & Neurology ,Neurology (clinical) ,business ,Original Research Papers ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.
- Published
- 2019
22. Sex and autoimmune disease: Four mechanisms pointing at women
- Author
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Angela Ceribelli, Maria De Santis, and Carlo Selmi
- Subjects
Review Paper ,Modern medicine ,lcsh:Diseases of the musculoskeletal system ,business.industry ,autoimmunity ,microbiome ,twins ,Public relations ,Affect (psychology) ,Single patient ,Patient management ,Rheumatology ,estradiol ,Gender medicine ,Microbiome ,Personalized medicine ,sex chromosome ,lcsh:RC925-935 ,business ,Psychology ,autoantibody - Abstract
The ultimate goal of modern medicine is a personalized approach being tailored on the single patient, ie, tailored, based on a finely tuned definition of the immunogenetics, epigenetics, microbiome, and biomarkers, to maximize results and minimize risks particularly of new targeted treatments. Among individual factors around which to tailor the patient management are sex and age, with gender-medicine finally becoming central to the research agenda. Of note, we are not convinced that a whole personalized medicine approach in its current form will necessarily include gender medicine and thus this should remain central to the research agenda. To tackle this crucial issue, however, we should first be able to answer a question of paramount importance, that is, why does autoimmunity affect women more than men? The growing number of experimental works in this area militate against an easy answer to this question, but we will herein briefly discuss four major candidates (sex hormones, sex chromosomes, environmental factors, and the microbiome) to which some unsuspected others may be ancillary.
- Published
- 2019
23. The role of pentraxin 3 in pemphigus vulgaris
- Author
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Ibrahim Halil Yavuz and Göknur Özaydın Yavuz
- Subjects
Dermatology ,medicine.disease_cause ,Autoimmunity ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,pentraxin 3 ,Internal medicine ,Original Paper ,integumentary system ,biology ,Pentraxins ,Cell adhesion molecule ,business.industry ,Pemphigus vulgaris ,pemphigus ,autoimmune ,PTX3 ,medicine.disease ,RC31-1245 ,Pemphigus ,Desmoglein 1 ,RL1-803 ,Immunology ,biology.protein ,Antibody ,business - Abstract
Introduction Pemphigus is a group of autoimmune bullous diseases caused by antibodies directed against the desmosomal adhesion molecules desmoglein 1 and 3, which are required for intercellular adhesion of keratinocytes. Pentraxins are a group of proteins that function as pattern recognition molecules and also play a role in humoral innate immunity. Pentraxin 3 (PTX3) is the prototype of the long pentraxins and has been shown to be increased in numerous autoimmune diseases. Aim To investigate whether PTX3 can be used as a marker of PV caused by autoimmunity and resulting in tissue injury. Material and methods The study included 30 patients who presented to the University Medical School Dermatology Department and were diagnosed with PV based on clinical, histological, and immunological findings. The control group included 30 healthy individuals. Human PTX3 concentration was measured with a commercially available ELISA kit, using a double antibody sandwich enzyme-linked immunosorbent assay. Results The 60 participants comprised 31 (52%) men and 29 (48%) women. The most common site of onset was mucosa + skin (n = 22; 73.3%) and a psychological pathology was present in 7 (23.3%) patients. Median PTX3 level was significantly higher in the PV group compared to the control group (p = 0.008). The ROC curve analysis indicated a significant area under curve (AUC) value for serum PTX3 level in the prediction of PV. Conclusions PTX3 was found to be increased in PV and PTX3 could be a useful indicator of disease activity in PV.
- Published
- 2019
24. Autoantibodies in Myositis. How to Achieve a Comprehensive Strategy for Serological Testing
- Author
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Miriam Mende, Wolfgang Schlumberger, Viola Borchardt-Lohölter, Thomas Scheper, and Wolfgang Meyer
- Subjects
medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,dermatomyositis ,autoantibodies ,Arthritis ,serology ,medicine.disease_cause ,Polymyositis ,Autoimmunity ,polymyositis ,Rheumatology ,Medicine ,Myositis ,Review Paper ,business.industry ,autoimmunity ,Autoantibody ,Interstitial lung disease ,inclusion body myositis ,Dermatomyositis ,medicine.disease ,Dermatology ,Inclusion body myositis ,lcsh:RC925-935 ,business ,myositis - Abstract
Myopathies are a rare type of acquired, chronic autoimmune diseases of the skeletal muscles and affect both children and adults. The hallmark symptoms of idiopathic inflammatory myopathies (IIM) are muscle inflammation, proximal muscle weakness and disability, arthritis, cutaneous rashes, calcinosis, ulceration, malignancy and interstitial lung disease (ILD). Subforms of IIM include polymyositis, dermatomyositis, cancer-related myositis and sporadic inclusion body myositis. Autoantibodies function as biomarkers for diagnosis of IIM and can be used to delimit clinically distinguishable IIM subforms. To maximise the diagnostic information it is essential to perform comprehensive multiparametric serological testing including both screening and confirmation tests.
- Published
- 2019
25. The immunological implication of the new vitamin D metabolism
- Author
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Luisa Agnello, Giulia Bivona, Marcello Ciaccio, Bivona, Giulia, Agnello, Luisa, and Ciaccio, Marcello
- Subjects
0301 basic medicine ,Calcitriol ,Immunology ,lcsh:Medicine ,vitamin D ,medicine.disease_cause ,immunomodulation ,Calcitriol receptor ,Autoimmunity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,CYPs ,CYP ,Vitamin D and neurology ,Immunology and Allergy ,Medicine ,VDR ,Calcium metabolism ,Review Paper ,Innate immune system ,business.industry ,autoimmunity ,lcsh:R ,030104 developmental biology ,chemistry ,business ,Cholecalciferol ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Vitamin D is a neuro-hormone regulating calcium-phosphate homeostasis, cell proliferation, and immunomodulation. exogenous and endogenous Vitamin D is inactive, and two hydroxylations are required to produce the active hormone. The first hydroxylation is unique to the liver, while the second step occurs in kidney, brain, lung, prostate, placenta, and immune cells. Kidney-derived calcitriol regulates calcium homeostasis. active hormone produced by brain and immune cells mediates immune system response; lung calcitriol is involved in fighting respiratory tract infections; finally, prostate and placenta Vitamin D regulates cells growth and proliferation within such tissues. immune modulation by Vitamin D includes enhancing innate immune response, attenuating and stimulating Th1 and Th2 cell proliferation, respectively, and promoting self-tolerance. Hypovitaminosis D is a common finding in several autoimmune diseases. it is unclear whether hypovitaminosis D could be a consequence or a cause of autoimmune diseases and whether Vitamin D supplementation has an impact on these patients. Moreover, there is no consensus on oral cholecalciferol dosage for supplementation. More interventional studies are required to better define how Vitamin D could represent both a causation agent in autoimmunity and a target for therapeutic strategies in autoimmune patients.
- Published
- 2018
26. Premature ovarian insufficiency – aetiopathology, epidemiology, and diagnostic evaluation
- Author
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Klaudia Klicka, Monika Grymowicz, Roman Smolarczyk, Jagoda Kruszewska, Joanna Kowalczyk, Wojciech Pięta, Jolanta Skórska, and Ewa Rudnicka
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,premature ovarian insufficiency ,Endocrinology, Diabetes and Metabolism ,Turner syndrome ,Population ,Hypoestrogenism ,lcsh:Medicine ,Disease ,Premature ovarian insufficiency ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Epidemiology ,medicine ,education ,Review Paper ,education.field_of_study ,Pregnancy ,030219 obstetrics & reproductive medicine ,business.industry ,autoimmunity ,lcsh:R ,Obstetrics and Gynecology ,medicine.disease ,030104 developmental biology ,business - Abstract
Premature ovarian insufficiency (POI) is defined as a cessation of ovarian function before the age of 40 years. It is associated with hypoestrogenism and loss of residual follicles, both of which lead to menstrual abnormalities, pregnancy failures, and decreased health-related quality of life. The prevalence of POI is estimated at 1% in the general population. Current European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria include: amenorrhoea or oligomenorrhoea for at least four months and increased follicle-stimulating hormone (FSH) levels > 25 IU/l measured twice (with a four-week interval). The aetiopathogenesis of the disease in most cases remains unexplained. Nevertheless, in some patients with POI, genetic abnormalities, metabolic disorders, autoimmunity, iatrogenic procedures, infections, or environmental factors have been established as underlying causes of the syndrome.
- Published
- 2018
27. The FOXP3 rs3761547 Gene Polymorphism in Multiple Sclerosis as a Male-Specific Risk Factor
- Author
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Adam Kretowski, Agata Zajkowska, Olga Zajkowska, Monika Chorąży, Joanna Tarasiuk, Natalia Wawrusiewicz-Kurylonek, Jan Kochanowicz, Renata Posmyk, and Alina Kułakowska
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Autoimmunity ,Multiple sclerosis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Multiple Sclerosis, Relapsing-Remitting ,Sex Factors ,Risk Factors ,Autoimmune disease ,medicine ,Humans ,Genetic Predisposition to Disease ,IL-2 receptor ,Allele ,Polymorphism ,Genotyping ,Original Paper ,business.industry ,Gene Expression Profiling ,FOXP3 ,Forkhead Transcription Factors ,medicine.disease ,FOXP3 gene ,030104 developmental biology ,Neurology ,Haplotypes ,Immunology ,Molecular Medicine ,Female ,Gene polymorphism ,business ,Treg cells ,030215 immunology - Abstract
The FOXP3 gene encodes a transcription factor and is predominantly expressed in the CD4+CD25+ regulatory T cells which plays a pivotal role in the maintenance of immune homeostasis. The defect of FOXP3 gene may provide a critical link between autoimmunity and immune deficiency. The purpose of our study was to evaluate the association of chosen polymorphisms of FOXP3 gene (rs3761549, rs3761548, rs3761547) with different clinical multiple sclerosis (MS) data of our relapsing-remitting groups of patients and in control group. The study was performed on a group consisting of 174 relapsing-remitting MS patients, diagnosed under 40 years of life, and 174 healthy volunteers. Genotyping was performed using a real-time PCR-based method by TaqMan Assays. Significant differences in distribution of allele C rs3761547 were found in male MS patients in comparison to the male healthy group (p = 0.046, OR 1.95, CI 95%). No association between MS and the other two polymorphisms was observed in males and females of both studied groups. Our data may suggest that FOXP3 rs3761547 gene polymorphism are related notably with the increased risk of MS development in males patients. To our knowledge this is the first study which indicates gender-specific relation between rs3761547 FOXP3 gene polymorphism and multiple sclerosis.
- Published
- 2018
28. Autoantibodies to Annexin A2 and cerebral thrombosis: Insights from a mouse model
- Author
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Joab Chapman, Itai Benhar, Valery Golderman, Tali Drori, Ekaterina Mindel, Ronen Weiss, Yael Diesendruck, Shay Anat Aharoni, David Orion, Doron Bushi, Efrat Shavit-Stein, Ofir Zmira, Orna Gera, Nancy Agmon-Levin, Almog Bitton, and Oren Kashi
- Subjects
Adult ,Injections, Subcutaneous ,Autoimmunity ,Annexin ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Severity of Illness Index ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Rheumatology ,Antiphospholipid syndrome ,Risk Factors ,Medicine ,Animals ,Humans ,MCAo ,Stroke ,Annexin A2 ,thrombosis ,Autoantibodies ,030203 arthritis & rheumatology ,Mice, Inbred BALB C ,business.industry ,Fibrinolysis ,Autoantibody ,Infarction, Middle Cerebral Artery ,Middle Aged ,medicine.disease ,Antiphospholipid Syndrome ,Thrombosis ,stroke ,Cerebral thrombosis ,Disease Models, Animal ,Ischemic Attack, Transient ,beta 2-Glycoprotein I ,Immunology ,Papers ,Antibodies, Antiphospholipid ,Female ,Intracranial Thrombosis ,business - Abstract
Introduction Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is β2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. Materials and Methods Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. Results Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). Conclusions This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.
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- 2021
29. DNA methylation profile of genes involved in inflammation and autoimmunity correlates with vascular function in morbidly obese adults
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Francesco Bianco, Mohamed M. Ali, Maryam Qureshi, Chandra Hassan, Antonio Gangemi, Giulianotti P Cristoforo, Patrice Frederick, Dina Naquiallah, Mario Masrur, Mohammed Imaduddin Mirza, Shane A. Phillips, and Abeer M. Mahmoud
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0301 basic medicine ,Adult ,Cancer Research ,Brachial Artery ,Inflammation ,Autoimmunity ,Disease ,Biology ,medicine.disease_cause ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Epigenetics ,Risk factor ,Molecular Biology ,Gene ,RNA-Binding Proteins ,DNA Methylation ,medicine.disease ,Obesity ,Obesity, Morbid ,030104 developmental biology ,030220 oncology & carcinogenesis ,DNA methylation ,medicine.symptom ,Research Paper - Abstract
Obesity is a major risk factor for cardiovascular disease. Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers. Therefore, we investigated DNA methylation of genes involved in inflammation in peripheral blood of obese subjects and lean controls and their correlation with cardiometabolic measurements. We obtained blood and adipose tissue (AT) samples from bariatric patients (n = 24) and control adults (n = 24). AT-isolated arterioles were tested for flow-induced dilation (FID) and production of nitric oxide (NO) and reactive oxygen species (ROS). Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity were analysed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. 77 genes had ahigher methylated fraction in the controls compare obese subjects and 28 proinflammatory genes were significantly hypomethylated in the obese individuals; on top of these genes are CXCL1, CXCL12, CXCL6, IGF2BP2, HDAC4, IL12A, and IL17RA. Fifteen of these genes had significantly higher mRNA in obese subjects compared to controls; on top of these genes are CXCL6, TLR5, IL6ST, EGR1, IL15RA, and HDAC4. Methylation % inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and C-reactive protein, arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Our results suggest that vascular dysfunction in obese adults may be attributed to asystemic hypomethylation and over expression of the immune-related genes.
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- 2021
30. Quality of life in patients with primary biliary cholangitis: A cross-geographical comparison
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Marco Carbone, Daphne D’Amato, L. Jopson, Luca Vecchio, Sesé Pilar, Massimo Miglioretti, Lorenzo Montali, Martina Lucà, S. E. O'Donnell, A Gerussi, Clara Mancuso, Pietro Invernizzi, Andrea Gragnano, Albert Parés, Dave Jones, Anna Reig, Alessandra Frigerio, Minami Yagi, George F. Mells, Vincenzo Ronca, Atsushi Tanaka, Laura Cristoferi, Montali, L, Gragnano, A, Miglioretti, M, Frigerio, A, Vecchio, L, Gerussi, A, Cristoferi, L, Ronca, V, D’Amato, D, O’Donnell, S, Mancuso, C, Lucà, M, Yagi, M, Reig, A, Jopson, L, Pilar, S, Jones, D, Pares, A, Mells, G, Tanaka, A, Carbone, M, and Invernizzi, P
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Factorial invariance ,Research paper ,Cholestasis ,business.industry ,Cognitive domain ,Immunology ,Mean age ,Cognition ,Autoimmunity ,RC581-607 ,Quality of life ,Liver ,Cholestasi ,Immunology and Allergy ,Medicine ,In patient ,Sun exposure ,Immunologic diseases. Allergy ,business ,Emotional dysfunction ,Fatigue ,Demography - Abstract
Background & aims Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p , Graphical abstract Image 1, Highlights • Primary Biliary Cholangitis (PBC) is a rare liver disease characterised by several symptoms that impair quality of life; • This study includes data from questionnaires provided to individuals with PBC in Italy, Japan, Spain and United Kingdom; • It shows a clear geographical pattern of distribution of PBC-related symptoms, with a significant difference based on latitude.
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- 2021
31. Treatment concerns for bullous pemphigoid in the COVID-19 pandemic era
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Dedee F. Murrell, Alireza Firooz, Seyyede Zeinab Azimi, and Maryam Daneshpazhooh
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Autoimmunity ,Dermatology ,medicine.disease_cause ,Risk Assessment ,Short Papers ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Immunocompromised Host ,0302 clinical medicine ,Risk Factors ,COVID‐19 ,Pandemic ,Pemphigoid, Bullous ,medicine ,Humans ,Short Paper ,skin and connective tissue diseases ,dermatologic therapy ,Coronavirus ,integumentary system ,business.industry ,SARS-CoV-2 ,Outbreak ,COVID-19 ,General Medicine ,medicine.disease ,Virology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,autoimmune bullous disease ,Bullous pemphigoid ,business ,Immunosuppressive Agents ,Blistering disease - Abstract
Bullous pemphigoid (BP) is the most common autoimmune blistering disease with subepidermal involvement, typically affecting the elderly. It has spontaneous remissions and exacerbations with significant morbidity. A novel coronavirus called severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) is responsible for the new universal coronavirus disease 2019 (COVID‐19) pandemic. The pandemic made concerns, especially about immunosuppressive therapy. In this article, we reviewed the management of BP in the COVID‐19 pandemic era. The data about the best management of autoimmune bullous diseases like BP, during the outbreak of COVID‐19, is evolving and updated every day. This article is protected by copyright. All rights reserved.
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- 2020
32. HSP70i
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Dinesh, Jaishankar, Cormac, Cosgrove, Prathyaya, Ramesh, James, Mahon, Rohan, Shivde, Emilia R, Dellacecca, Shiayin F, Yang, Jeffrey, Mosenson, José A, Guevara-Patiño, and I Caroline, Le Poole
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Male ,Original Paper ,Skin Neoplasms ,Autoimmunity ,DNA, Neoplasm ,Models, Biological ,Antibodies ,Cell Degranulation ,Killer Cells, Natural ,Mice, Inbred C57BL ,Cell Line, Tumor ,Mutation ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,Melanoma - Abstract
Developing immunosuppressive therapies for autoimmune diseases comes with a caveat that immunosuppression may promote the risk of developing other conditions or diseases. We have previously shown that biolistic delivery of an expression construct encoding inducible HSP70 (HSP70i) with one amino acid modification in the dendritic cell (DC) activating moiety 435–445 (HSP70i(Q435A)) to mouse skin resulted in significant immunosuppressive activity of autoimmune vitiligo, associated with fewer tissue infiltrating T cells. To prepare HSP70i(Q435A) as a potential therapeutic for autoimmune vitiligo, in this study we evaluated whether and how biolistic delivery of HSP70i(Q435A) in mice affects anti-tumor responses. We found that HSP70i(Q435A) in fact supports anti-tumor responses in melanoma-challenged C57BL/6 mice. Biolistic delivery of the HSP70i(Q435A)-encoding construct to mice elicited significant anti-HSP70 titers, and anti-HSP70 IgG and IgM antibodies recognize surface-expressed and cytoplasmic HSP70i in human and mouse melanoma cells. A peptide scan revealed that the anti-HSP70 antibodies recognize a specific C-terminal motif within the HSP70i protein. The antibodies elicited surface CD107A expression among mouse NK cells, representative of antibody-mediated cellular cytotoxicity (ADCC), supporting the concept, that HSP70i(Q435A)-encoding DNA elicits a humoral response to the stress protein expressed selectively on the surface of melanoma cells. Thus, besides limiting autoimmunity and inflammation, HSP70i(Q435A) elicits humoral responses that limit tumor growth and may be used in conjunction with immune checkpoint inhibitors to not only control tumor but to also limit adverse events following tumor immunotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12192-021-01229-x.
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- 2020
33. Establishment of a Cre-rat resource for creating conditional and physiological relevant models of human diseases
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Huimin Zhang, Ruby Yanru Chen-Tsai, and Qi Zheng
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0301 basic medicine ,Aging ,Transgene ,Autoimmunity ,Computational biology ,Genome ,Communicable Diseases ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Genetics ,CRISPR ,Animals ,Humans ,TARGATT ,CRISPR/Cas9 ,Inflammation ,Transplantation ,Original Paper ,biology ,Integrases ,Cas9 ,Genetic Diseases, Inborn ,Cre ,Integrase ,Genetically modified organism ,Laboratory rat ,Rats ,Transgenic rat ,Disease Models, Animal ,030104 developmental biology ,Cardiovascular Diseases ,biology.protein ,Animal Science and Zoology ,CRISPR-Cas Systems ,Agronomy and Crop Science ,030217 neurology & neurosurgery ,Biotechnology - Abstract
The goal of this study is to establish a Cre/loxP rat resource for conditional and physiologically predictive rat models of human diseases. The laboratory rat (R. norvegicus) is a central experimental animal in several fields of biomedical research, such as cardiovascular diseases, aging, infectious diseases, autoimmunity, cancer models, transplantation biology, inflammation, cancer risk assessment, industrial toxicology, pharmacology, behavioral and addiction studies, and neurobiology. Up till recently, the ability of creating genetically modified rats has been limited compared to that in the mouse mainly due to lack of genetic manipulation tools and technologies in the rat. Recent advances in nucleases, such as CRISPR/Cas9 (clustered regularly-interspaced short palindromic repeats/CRISPR associated protein 9), as well as TARGATT™ integrase system enables fast, efficient and site-specific introduction of exogenous genetic elements into the rat genome. Here, we report the generation of a collection of tissue-specific, inducible transgenic Cre rats as tool models using TARGATT™, CRISPR/Cas9 and random transgenic approach. More specifically, we generated Cre driver rat models that allow controlled gene expression or knockout (conditional models) both temporally and spatially through the Cre-ERT2/loxP system. A total of 10 Cre rat lines and one Cre reporter/test line were generated, including eight (8) Cre lines for neural specific and two (2) lines for cardiovascular specific Cre expression. All of these lines have been deposited with the Rat Resource and Research Center and provide a much-needed resource for the bio-medical community who employ rat models for their studies of human diseases.
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- 2020
34. Negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen in the human thymus
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Megan Sykes, Nichole M. Danzl, Chiara Borsotti, Maki Nakayama, Mohsen Khosravi Maharlooei, Grace Nauman, Hao Wei Li, Rachel Madley, Bart O. Roep, Estefania Chavez, and Remi J. Creusot
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lcsh:Immunologic diseases. Allergy ,Research paper ,T cell ,Immunology ,T-cell receptor ,T cell selection ,Autoimmunity ,Human leukocyte antigen ,Biology ,HLA ,Negative selection ,medicine.anatomical_structure ,Type 1 diabetes ,Antigen ,PD-1 ,medicine ,Immunology and Allergy ,Clone (B-cell biology) ,Antigen-presenting cell ,lcsh:RC581-607 ,Tolerance - Abstract
During T cell development in mice, thymic negative selection deletes cells with the potential to recognize and react to self-antigens. In human T cell-dependent autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, T cells reactive to autoantigens are thought to escape negative selection, traffic to the periphery and attack self-tissues. However, physiological thymic negative selection of autoreactive human T cells has not been previously studied. We now describe a human T-cell receptor-transgenic humanized mouse model that permits the study of autoreactive T-cell development in a human thymus. Our studies demonstrate that thymocytes expressing the autoreactive Clone 5 TCR, which recognizes insulin B:9–23 presented by HLA-DQ8, are efficiently negatively selected at the double and single positive stage in human immune systems derived from HLA-DQ8+ HSCs. In the absence of hematopoietic expression of the HLA restriction element, negative selection of Clone 5 is less efficient and restricted to the single positive stage. To our knowledge, these data provide the first demonstration of negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen. Intrathymic antigen presenting cells are required to delete less mature thymocytes, while presentation by medullary thymic epithelial cells may be sufficient to delete more mature single positive cells. These observations set the stage for investigation of putative defects in negative selection in human autoimmune diseases., Highlights • In the presence of the HLA-restriction element on hematopoietic stem cells (HSCs) and thymus.•Thymocytes bearing insulin peptide-reactive TCRs express markers of thymic negative selection.•Insulin peptide-reactive T cells are efficiently negatively selected in the human thymus.•The few transgenic T cells that escape negative selection largely express endogenous TCRs. • HLA-restriction element on HSCs is required for efficient negative selection.
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- 2020
35. Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells
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Julie M. Clarke, Hiroshi Takayanagi, Yuma Kabumoto, Yuichi Maeda, Atsuo Nakamura, Yuto Yanagisawa, Mizuki Ueda, Yohsuke Harada, Ryohtaroh Matsumoto, Takahiro G. Yamada, Yumiko Fujimura, Eiji Umemoto, Kisara Muroi, Koji Hase, Daisuke Takahashi, Noriko Komatsu, Hanako Asaoka, Naomi Hoshina, Kiyoshi Takeda, Aiko Saeki, Junya Isobe, Michio Tomura, Takaharu Okada, Akari Suzuki, and Hiyori Tanabe
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0301 basic medicine ,Adoptive cell transfer ,Research paper ,Intestinal microbiota ,Lymphoid Tissue ,Cellular differentiation ,lcsh:Medicine ,Arthritis ,Autoimmunity ,Butyrate ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,General Biochemistry, Genetics and Molecular Biology ,Histone Deacetylases ,Arthritis, Rheumatoid ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Humans ,Rheumatoid arthritis ,Cells, Cultured ,Aged ,lcsh:R5-920 ,Bacteria ,business.industry ,lcsh:R ,Autoantibody ,FOXP3 ,Follicular regulatory T cells ,Acetylation ,Cell Differentiation ,General Medicine ,Middle Aged ,medicine.disease ,Adoptive Transfer ,Arthritis, Experimental ,Gastrointestinal Microbiome ,Histone Deacetylase Inhibitors ,Butyrates ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Histone deacetylase ,lcsh:Medicine (General) ,business - Abstract
Background Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (TFR) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating TFR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling TFR cell differentiation remains unknown. Methods We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5+Bcl-6+Foxp3+ TFR (iTFR) cell culture system and examined whether butyrate promotes the differentiation of iTFR cells. Findings Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting TFR cell differentiation. Butyrate directly induced the differentiation of functional TFR cells in vitro by enhancing histone acetylation in TFR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the TFR-cell marker genes. The adoptive transfer of the butyrate-treated iTFR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. Funding This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).
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- 2020
36. CD8
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I S, Brorson, A M, Eriksson, I S, Leikfoss, V, Vitelli, E G, Celius, T, Lüders, T, Berge, H F, Harbo, H, Nilsen, and S D, Bos
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Original Research Paper ,Multiple sclerosis ,T-Lymphocytes ,neurology ,autoimmunity ,gene expression ,RNA - Abstract
Background Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. Methods RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.
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- 2020
37. Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease
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Zi Ye, Liping Du, Nan Qin, Ni Zhang, Chunjiang Zhou, Qingfeng Wang, Xiao Xiong, Jihong Tang, Qian Xu, Xinyue Huang, Aize Kijlstra, Peizeng Yang, Chunyan Wu, Qingfeng Cao, Fuzhen Li, RS: MHeNs - R3 - Neuroscience, and MUMC+: MA UECM Oogartsen MUMC (9)
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0301 basic medicine ,Male ,Genotyping Techniques ,AUTOIMMUNITY ,PROTEIN ,Disease ,fecal microbiota transplant ,Pathogenesis ,ACTIVATION ,Feces ,Mice ,0302 clinical medicine ,Adrenal Cortex Hormones ,WIDE ASSOCIATION ,Vogt-Koyanagi-Harada (VKH) disease ,Panuveitis ,Gastroenterology ,Biodiversity ,MULTIPLE-SCLEROSIS ,Fecal Microbiota Transplantation ,Prognosis ,Butyrates ,Infectious Diseases ,uveitis ,030211 gastroenterology & hepatology ,Female ,Uveitis ,Immunosuppressive Agents ,Microbiology (medical) ,Vogt–Koyanagi–Harada disease ,Adult ,DNA, Bacterial ,BIFIDOBACTERIUM ,Biology ,IMMUNITY ,Microbiology ,03 medical and health sciences ,medicine ,Animals ,Humans ,In patient ,Genetic Predisposition to Disease ,Lactic Acid ,lcsh:RC799-869 ,Gut microbiome ,Whole Genome Sequencing ,Fecal bacteriotherapy ,medicine.disease ,eye diseases ,Gastrointestinal Microbiome ,Disease Models, Animal ,030104 developmental biology ,Immunology ,Research Paper/Report ,Dysbiosis ,lcsh:Diseases of the digestive system. Gastroenterology ,Uveomeningoencephalitic Syndrome ,Metagenomic sequencing ,Genome-Wide Association Study - Abstract
Background: Vogt-Koyanagi-Harada (VKH) disease is a multisystemic autoimmune disorder characterized by granulomatous panuveitis. Gut microbiome has been considered to play a role in the pathogenesis of this disease but whether the alternation of gut microbiome was involved is unclear. This study was set up to identify abnormalities of gut microbiome composition in VKH disease. Results: Depleted butyrate-producing bacteria, lactate-producing bacteria and methanogens as well as enriched Gram-negative bacteria were identified in the active VKH patients, as well as in VKH patients of Mix enterotype and Bacteroides enterotype. Changes of gut microbiome in the VKH patients were partially restored after an immunosuppressive treatment. The disease susceptibility genotype HLA-DRA was associated with Bacteroides sp.2.1.33B, Paraprevotella clara, Alistipes finegoldii and Eubacterium eligens. A microbial marker profile including 40 disease-associated species was established to differentiate patients from controls. Another microbial marker profile including 37 species was found to be associated with the response to treatment. An animal experiment showed that transfer of gut microbiome from VKH patients could significantly exacerbate disease activity clinically and pathologically in the recipient mice. Conclusion: Our results revealed a distinct gut microbiome signature in VKH patients and showed an exacerbating effect of this gut microbiome on experimental autoimmune uveitis (EAU). We also developed two microbial marker profiles in differentiating VKH patients from healthy controls as well as predicting the effectiveness of treatment.
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- 2020
38. Ultra-efficient sequencing of T Cell receptor repertoires reveals shared responses in muscle from patients with Myositis
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H. Benjamin Larman, Lisa Christopher-Stine, Xuwen Alice Zheng, Janelle Montagne, Thomas E. Lloyd, Andrew L. Mammen, José C. Milisenda, and Iago Pinal-Fernandez
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0301 basic medicine ,T cell ,Biopsy ,T-Lymphocytes ,Amino Acid Motifs ,Receptors, Antigen, T-Cell ,lcsh:Medicine ,Autoimmunity ,Computational biology ,Complementarity determining region ,Biology ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Humans ,Amino Acid Sequence ,Framework region ,Muscle, Skeletal ,Myositis ,lcsh:R5-920 ,Idiopathic Inflammatory myopathy ,T-cell receptor ,lcsh:R ,Computational Biology ,High-Throughput Nucleotide Sequencing ,General Medicine ,Sequence Analysis, DNA ,Amplicon ,medicine.disease ,TCR repertoire ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Disease Susceptibility ,Primer (molecular biology) ,lcsh:Medicine (General) ,Biomarkers ,Research Paper - Abstract
Background Myositis, or idiopathic inflammatory myopathy (IIM), is a group disorders of unknown etiology characterized by the inflammation of skeletal muscle. The role of T cells and their antigenic targets in IIM initiation and progression is poorly understood. T cell receptor (TCR) repertoire sequencing is a powerful approach for characterizing complex T cell responses. However, current TCR sequencing methodologies are complex, expensive, or both, greatly limiting the scale of feasible studies. Methods Here we present Framework Region 3 AmplifiKation sequencing (“FR3AK-seq”), a simplified multiplex PCR-based approach for the ultra-efficient and quantitative analysis of TCR complementarity determining region 3 (CDR3) repertoires. By using minimal primer sets targeting a conserved region immediately upstream of CDR3, undistorted amplicons are analyzed via short read, single-end sequencing. We also introduce the novel algorithm Inferring Sequences via Efficiency Projection and Primer Incorporation (“ISEPPI”) for linking CDR3s to their associated variable genes. Findings We find that FR3AK-seq is sensitive and quantitative, performing comparably to two different industry standards. FR3AK-seq and ISEPPI were used to efficiently and inexpensively characterize the T cell infiltrates of surgical muscle biopsies obtained from 145 patients with IIM and controls. A cluster of closely related TCRs was identified in samples from patients with sporadic inclusion body myositis (IBM). Interpretation The ease and minimal cost of FR3AK-seq removes critical barriers to routine, large-scale TCR CDR3 repertoire analyses, thereby democratizing the quantitative assessment of human TCR repertoires in disease-relevant target tissues. Importantly, discovery of closely related TCRs in muscle from patients with IBM provides evidence for a shared antigen-driven T cell response in this disease of unknown pathogenesis. Funding This work was supported by NIH grant U24AI118633 and a Prostate Cancer Foundation Young Investigator Award.
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- 2020
39. Autoantibodies as biomarkers for interstitial lung disease in idiopathic inflammatory myositis and systemic sclerosis: The case of anti-eIF2B antibodies
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Carlo Selmi, Minoru Satoh, Maria De Santis, Natasa Isailovic, Angela Ceribelli, and Carolina Gorlino
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lcsh:Immunologic diseases. Allergy ,Pathology ,medicine.medical_specialty ,Research paper ,AUTOIMMUNITY ,Immunology ,Autoimmunity ,Interstitial lung disease ,DERMATOMYOSITIS ,Immunofluorescence ,medicine.disease_cause ,Polymyositis ,Scleroderma ,Dermatomyositis ,SCLERODERMA ,purl.org/becyt/ford/3.2 [https] ,medicine ,Immunology and Allergy ,skin and connective tissue diseases ,INTERSTITIAL LUNG DISEASE ,biology ,medicine.diagnostic_test ,business.industry ,Autoantibody ,medicine.disease ,POLYMYOSITIS ,biology.protein ,purl.org/becyt/ford/3 [https] ,Antibody ,lcsh:RC581-607 ,business - Abstract
Objectives Serum autoantibodies are pivotal for the early detection of systemic autoimmune rheumatic diseases such as Systemic Sclerosis (SSc) and Poly/Dermatomyositis (PM/DM), and in some cases are associated with organ complications such as interstitial lung disease (ILD). A paradigmatic example is provided by the autoantibody against the Eukaryotic Initiation Factor 2B (eIF2B) that has been recently detected in SSc. Methods Sera from 118 patients with SSc, 8 Poly/Dermatomyositis, 2 overlap SSc/Polymyositis, 4 undifferentiated connective tissue disease-UCTD and 3 healthy controls were tested first by indirect immunofluorescence for anti-nuclear antibodies-ANA pattern. Further, we employed prot ein-radioimmunoprecipitation (IP) and IP- Western Blot for the detection and confirmation of anti-eIF2B antibodies. Serum findings were further correlated with the clinical features of patients. Results We identified 3 SSc cases (2.5%) positive for anti-eIF2B antibodies while this autoantibody was not detected in control sera. Using protein-IP all three patients manifested the 38kD protein which is the antigenic target of anti-eIF2B antibodies, and this was associated with a cytoplasmic pattern at indirect immunofluorescence. The presence of anti-eIF2B was associated with ILD and a diffuse SSc variant, in one case in association with anti-Scl70/topoI. Conclusions Our data confirm that a small subgroup (2.5%) of patients with SSc have detectable anti-eIF2B with cytoplasmic-positive staining at immunofluorescence and this reactivity is associated with ILD., Highlights • A new and rare autoantibody called anti-eIF2B is detected in 2.5% of SSc sera. • Anti-eIF2B antibodies are associated to diffuse SSc and ILD. • Specific autoantibodies confer a diagnostic and prognostic value for ILD in SSc and PM/DM patients.
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- 2020
40. Helicobacter pylori seropositivity is associated with antinuclear antibodies in US adults, NHANES 1999–2000
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Gregg E. Dinse, Helen C.S. Meier, Frederick W. Miller, C C Cho, Clarice R. Weinberg, and Christine G. Parks
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medicine.medical_specialty ,Anti-nuclear antibody ,National Health and Nutrition Examination Survey ,Population ,03 medical and health sciences ,0302 clinical medicine ,Epidemiology ,medicine ,Seroprevalence ,030212 general & internal medicine ,education ,2. Zero hunger ,education.field_of_study ,Original Paper ,biology ,business.industry ,autoimmunity ,Odds ratio ,Helicobacter pylori ,biology.organism_classification ,3. Good health ,Antinuclear antibodies ,Infectious Diseases ,Immunology ,030211 gastroenterology & hepatology ,epidemiology ,business ,Body mass index ,H. pylori - Abstract
Infectious diseases, such as Helicobacter pylori, which produce systemic inflammation may be one key factor in the onset of autoimmunity. The association between H. pylori and antinuclear antibodies (ANA), a marker of autoimmunity, has been understudied. Data from the 1999–2000 National Health and Nutrition Examination Survey were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged ≥20 years. ANA was measured in a 1:80 dilution of sera by indirect immunofluorescence using HEp-2 cells (positive ⩾3). H. pylori immunoglobulin G enzyme-linked immunosorbent assays were used to categorise individuals as seropositive or seronegative. H. pylori seropositivity and ANA positivity were common in the adult US population, with estimated prevalences of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA (prevalence odds ratio = 1.89, 95% confidence interval = 1.08–3.33), adjusted for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction.
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- 2020
41. BCG: a vaccine with multiple faces
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Luisa Berenise Gámez-González, Ricardo U. Sorensen, Napoleón González-Saldaña, Alberto Unzueta, and Marco Antonio Yamazaki-Nakashimada
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Tuberculosis ,medicine.medical_treatment ,030231 tropical medicine ,Immunology ,Autoimmunity ,Disease ,medicine.disease_cause ,complex mixtures ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Adjuvants, Immunologic ,law ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Pharmacology ,business.industry ,Immunologic Deficiency Syndromes ,medicine.disease ,Meningeal Tuberculosis ,BCG Vaccine ,Leprosy ,business ,Adjuvant ,BCG vaccine ,Research Paper - Abstract
BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.
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- 2020
42. Successful aging: Insights from proteome analyses of healthy centenarians
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José L. Zugaza, Pedro L. Valenzuela, Beatriz G. Gálvez, Juan Antonio López, Alejandro Santos-Lozano, Helios Pareja-Galeano, Pedro Carrera-Bastos, Francisco Llavero, Enzo Emanuele, Simone Lista, Alejandro Lucia, Jesús Vázquez, Harald Hampel, University of Alcalá (España), Ministerio de Ciencia, Innovación y Universidades (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación La Marató TV3, Fundación La Caixa, Fundación ProCNIC, Fundación AXA, and Fundación de la Universidad Europea de Madrid
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Male ,Proteomics ,Senescence ,Aging ,senescence ,Proteome ,Health Status ,Calidad de vida ,Anciano ,Walking ,Disease ,Genética humana ,medicine.disease_cause ,elderly ,Autoimmunity ,Healthy Aging ,proteomics ,Immune system ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Inflammation ,Successful aging ,business.industry ,Cell Biology ,immune system ,healthy aging ,Immunology ,Life expectancy ,Female ,business ,Ancianos ,Research Paper - Abstract
Healthy aging depends on a complex gene-environment network that is ultimately reflected in the expression of different proteins. We aimed to perform a comparative analysis of the plasma proteome of healthy centenarians (n=9, 5 women, age range 100-103 years) with a notably preserved ambulatory capacity (as a paradigm of 'successful' aging), and control individuals who died from a major age-related disease before the expected life expectancy (n=9, 5 women, age range: 67-81 years), and while having impaired ambulatory capacity (as a paradigm of 'unsuccessful' aging). We found that the expression of 49 proteins and 86 pathways differed between the two groups. Overall, healthy centenarians presented with distinct expression of proteins/pathways that reflect a healthy immune function, including a lower pro-inflammatory status (less 'inflammaging' and autoimmunity) and a preserved humoral immune response (increased B cell-mediated immune response). Compared with controls, healthy centenarians also presented with a higher expression of proteins involved in angiogenesis and related to enhanced intercellular junctions, as well as a lower expression of proteins involved in cardiovascular abnormalities. The identification of these proteins/pathways might provide new insights into the biological mechanisms underlying the paradigm of healthy aging. The work of PLV is supported by University of Alcalá (FPI2016). AL and JLZ are supported by grants from the Spanish Ministry of Science, Innovation and Universities and Fondos FEDER (Fondo de Investigaciones Sanitarias [FIS], grants number PI15/00558, PI18/00139, and PI18/00207). JV and JAL are supported by grants from MINECO (BIO2015-67580-P), the Fundació Marató TV3 (122/C/2015) and “la Caixa” Banking Foundation (project code HR17-00247). The CNIC is supported by the Spanish Ministry of Economy and Science, Innovation and Universities and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). HH is an employee of Eisai Inc. During his previous work (until April 2019) he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer”, Paris, France. HP is suppoted by grant from Universidad Europea de Madrid (#2017/UEM05). Sí
- Published
- 2020
43. Treponema pallidum-specific immune responses and autoimmunity in patients who remain serofast after treatment of syphilis
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Agnieszka Kotnis-Gąska, Anna Wojas-Pelc, Bernadetta Jakubowicz, and Maciej Pastuszczak
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0301 basic medicine ,Anti-nuclear antibody ,030106 microbiology ,syphilis ,Dermatology ,medicine.disease_cause ,immune response ,Autoimmunity ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Immunology and Allergy ,Clinical significance ,030212 general & internal medicine ,Original Paper ,Treponema ,biology ,business.industry ,autoimmunity ,medicine.disease ,biology.organism_classification ,Immunology ,serofast ,biology.protein ,Syphilis ,Antibody ,business - Abstract
Introduction Approximately 15% of appropriately treated patients with early syphilis remain serofast. The pathogenesis and clinical significance of this phenomenon are unclear. Aim To determine the significance of Treponema pallidum-specific immune responses and autoimmunity in the treatment outcome of syphilis (serofast or proper serological response). Material and methods Forty-eight patients with secondary and early latent syphilis (ELS) were enrolled in this study. Reactivity of IgM/IgG antibodies to the treponemal antigens TpN47, TpN17, TpN15 and TmpA was evaluated before and 12 months after intramuscular penicillin therapy for syphilis. Additionally, the presence of antinuclear antibodies (ANA) was determined 12 months after treatment. Results After 1 year, patients were stratified into two groups based on their serological response: (1) serofast (n = 10) and (2) serologically-cured (n = 38) patients. The serological cure rate was 79.2% at 12 months after treatment. Weak pre- and post-treatment antibody reactivity to TpN47 antigen was found to be significantly associated with a higher risk of the serofast state (OR = 64; 95% CI: 5.01-817; p < 0.005). Patients who remained serofast had a significantly higher ANA prevalence and mean titer when compared to those with proper serological responses (100% vs. 5.3%, respectively, p < 0.005; 1 : 640 vs. 1 : 160, respectively, p < 0.005). Conclusions We demonstrate that baseline antigen-specific immune response to Treponema pallidum may be an important predictor of the treatment outcome. Further studies are warranted to identify the role of autoimmunity in the pathomechanism of the serofast state.
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- 2018
44. The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis
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Sulagna Ghosh, Jin Yuan Wang, Jackson Sandoe, Joanie Mok, Maura Charlton, Steven A. Carr, Namrata D. Udeshi, Aaron Burberry, Yingying Zhang, Quan Zhen Li, Kevin Eggan, Daniel A. Mordes, and Tanya Svinkina
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0301 basic medicine ,Gene isoform ,Mutant ,Autoimmunity ,Biology ,Proteomics ,Exocytosis ,Mice ,03 medical and health sciences ,Lysosomal-Associated Membrane Protein 1 ,C9orf72 ,Lysosome ,Genetics ,medicine ,Animals ,Humans ,Protein Isoforms ,Secretion ,Mice, Knockout ,C9orf72 Protein ,LAMP1 ,Protein Stability ,Macrophages ,Amyotrophic Lateral Sclerosis ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Membrane protein ,Mutation ,Splenomegaly ,Lymph Nodes ,Carrier Proteins ,Lysosomes ,Research Paper ,Developmental Biology - Abstract
While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components—phenotypes that we subsequently observed in C9orf72 loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis—processes of potential importance to ALS.
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- 2018
45. The effect of history of abnormal pap smear or preceding HPV infection on the humoral immune response to Quadrivalent Human Papilloma virus (qHPV) vaccine in women with systemic lupus erythematosus
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J. Patricia Dhar, Lynnette Essenmacher, Robert J. Sokol, Ardella Magee, Joel W. Ager, and Renee Dhar
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Adult ,HPV ,Adolescent ,cervical cancer ,Immunology ,SLE ,Uterine Cervical Neoplasms ,Antibodies, Viral ,medicine.disease_cause ,Autoimmunity ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Abnormal PAP Smear ,Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 ,immune system diseases ,vaccine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Human papillomavirus ,skin and connective tissue diseases ,Immunoassay ,030203 arthritis & rheumatology ,Pharmacology ,Human papilloma virus ,Cervical cancer ,business.industry ,Papillomavirus Infections ,autoimmunity ,HPV infection ,virus diseases ,Middle Aged ,medicine.disease ,Antibodies, Neutralizing ,female genital diseases and pregnancy complications ,Immunity, Humoral ,Uterine Neoplasms ,Female ,Anamnestic response ,business ,Immunologic Memory ,Papanicolaou Test ,Research Paper - Abstract
Objective : To determine if natural human papillomavirus (HPV) infection would induce an anamnestic response to quadrivalent (qHPV) vaccine in women with Systemic Lupus Erythematosus (SLE). Methods: Thirty four women (19-50 years) with mild to moderate and minimally active or inactive SLE received standard qHPV vaccine. Neutralizing antibody titers to HPV 6, 11, 16 and18 were evaluated pre- and post- vaccine using HPV competitive Luminex Immunoassay. For each HPV type, logistic regressions were performed to explore the relationship between a positive titer at baseline with their final geometric mean titer and with the rise in titer. Fisher's Exact Test was used to assess the association of at least one positive HPV antibody test at baseline and history of abnormal pap. Results: History of abnormal pap smear/cervical neoplasia occurred in 52.9%. Baseline anti HPV antibody titers: 21% = negative for all 4 HPV types, 79% = positive for ≥1 of the HPV types. Statistical analysis showed: those with a history of abnormal pap smear/cervical neoplasia were likely to have a positive anti-HPV antibody result pre-vaccine to ≥ 1 of the 4 types, p = 0.035 Fisher's Exact Test. In general, HPV exposed women showed higher post vaccine GMTs than HPV unexposed women with higher point estimates. However, when examining the rise in titers using logistic regression, there was no evidence of an anamnestic response. Conclusion: Prior HPV infection and cervical neoplasia in SLE are linked with no anamnestic response to HPV vaccine. This supports not checking HPV-antibodies pre-vaccine. Women with SLE should be vaccinated for HPV.
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- 2018
46. Immunological memory cells
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Paulina Niedźwiedzka-Rystwej, Weronika Ratajczak, Beata Tokarz-Deptuła, and Wiesław Deptuła
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0301 basic medicine ,Review Paper ,Effector ,Immunology ,Immunological memory ,Biology ,medicine.disease_cause ,Vaccine therapy ,Autoimmunity ,immunological memory ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,memory NK cells ,Antigen ,Immunity ,memory T cells ,medicine ,memory B cells ,Immunology and Allergy ,Hapten ,Effective response ,030215 immunology - Abstract
This article reviews immunological memory cells, currently represented by T and B lymphocytes and natural killer (NK) cells, which determine a rapid and effective response against a second encounter with the same antigen. Among T lymphocytes, functions of memory cells are provided by their subsets: central memory, effector memory, tissue-resident memory, regulatory memory and stem memory T cells. Memory T and B lymphocytes have an essential role in the immunity against microbial pathogens but are also involved in autoimmunity and maternal-fetal tolerance. Furthermore, the evidence of immunological memory has been established for NK cells. NK cells can respond to haptens or viruses, which results in generation of antigen-specific memory cells. T, B and NK cells, which have a role in immunological memory, have been characterized phenotypically and functionally. During the secondary immune response, these cells are involved in the reaction against foreign antigens, including pathogens, and take part in autoimmune diseases, but also are crucial to immunological tolerance and vaccine therapy.
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- 2018
47. NOX2 mediates quiescent handling of dead cell remnants in phagocytes
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Madelaine Hahn, Malin Hultqvist, Julia Stoof, Markus H. Hoffmann, Thomas Harrer, Andriy Mokhir, Jonas Hahn, Emelie Kilgus, Rikard Holmdahl, Peter Olofsson, Jasmin Knopf, Maximilien Euler, Deborah Kienhöfer, Martin Herrmann, Georg Schett, and Luis E. Muñoz
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0301 basic medicine ,Medicine (General) ,Phagocyte ,Neutrophils ,Clinical Biochemistry ,medicine.disease_cause ,Biochemistry ,Monocytes ,Autoimmunity ,SLE, systemic lupus erythematosus ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Chronic granulomatous disease ,Phagosomes ,Biology (General) ,NOX2, NADPH oxidase complex 2 ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,Phagocytes ,lcsh:R5-920 ,NADPH oxidase ,Systemic lupus erythematosus ,biology ,Superoxide ,Hydrogen-Ion Concentration ,3. Good health ,medicine.anatomical_structure ,Ncf1, neutrophil cytosol factor 1 ,NADPH Oxidase 2 ,Cytokines ,medicine.symptom ,Inflammation Mediators ,lcsh:Medicine (General) ,Research Paper ,QH301-705.5 ,Inflammation ,03 medical and health sciences ,Necrosis ,R5-920 ,ROS, reactive oxygen species ,Phagocytosis ,NHD, normal healthy donors ,medicine ,WT, wildtype ,Animals ,Autoantibodies ,Reactive oxygen species ,Organic Chemistry ,SNEC, secondary necrotic cells ,Receptors, IgG ,CGD, chronic granulomatous disease ,medicine.disease ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,Immunology ,biology.protein ,Reactive Oxygen Species ,030217 neurology & neurosurgery - Abstract
The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE., Graphical abstract Image 1 Graphical abstract: Inflammatory rerouting of SNECs occurs in individuals with a dysfunctional NOX2 complex.
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- 2019
48. X-linked TLR7 gene polymorphisms are associated with diverse immunological conditions but not with discoid lupus erythematosus in Polish patients
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Rafał Czajkowski, Sebastian Kaszewski, Tomasz Grzybowski, Jan Styczyński, Ewa Robak, Anna Krenska, Mariusz Wysocki, Katarzyna Skonieczna, Mariusz Gawrych, and Anna Woźniacka
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0301 basic medicine ,Discoid lupus erythematosus ,Single-nucleotide polymorphism ,Dermatology ,medicine.disease_cause ,Autoimmunity ,polymorphism ,03 medical and health sciences ,0302 clinical medicine ,systemic lupus erythematosus ,Genotype ,discoid lupus erythematosus ,medicine ,Immunology and Allergy ,aspergillosis ,Allele ,030203 arthritis & rheumatology ,Original Paper ,030102 biochemistry & molecular biology ,business.industry ,allele ,virus diseases ,TLR7 ,single-nucleotide polymorphism ,medicine.disease ,Genotype frequency ,Immunology ,business ,Anti-SSA/Ro autoantibodies - Abstract
Introduction Toll-like receptor 7 (TLR7) is an important molecule involved in the development of autoimmunity and the response to different pathogens. Several polymorphisms within the TLR7 gene were previously found to be associated with systemic lupus erythematosus (SLE). However, none of those studies investigated the TLR7 promoter flanking variants rs1634318 and rs1616583. TLR7 gene diversity has not been analyzed with respect to discoid lupus erythematosus (DLE) development, while its role in the human immunological response to fungal infection is not fully known. Aim To clarify the potential involvement of two novel single-nucleotide polymorphisms (SNPs) located in the TLR7 gene (rs1634318 and rs1616583) in a variety of immune-related conditions, we studied the variability of these loci in patients from a Polish population with SLE and DLE, as well as in immunocompromised patients who were affected by invasive aspergillosis (IA) and those who were not affected. Material and methods Real-time polymerase chain reaction was used to genotype SNPs. Statistically significant differences between case and control groups for both allele and genotype frequencies were assessed using the χ2 test with Yates' correction or two-tailed Fisher's exact test. The results were Bonferroni-corrected for multiple comparisons and odds ratios were calculated. Results Two polymorphisms located in TLR7 might be associated with the development of SLE but not DLE within the Polish population. Moreover, variation of the two investigated SNPs was found to be associated with IA in immunocompromised Polish patients. Conclusions In Polish patients, TLR7 promoter flanking gene polymorphisms might be associated with IA and SLE but not DLE.
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- 2018
49. Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling
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Toomas Neuman, Anri Kivil, Priit Adler, Dan Lindholm, Helle Sadam, Olli Vapalahti, Susan Pihelgas, Antti Vaheri, Markku Partinen, Jaak Vilo, Mariliis Jaago, Kaia Palm, Arno Pihlak, HUSLAB, Veterinary Microbiology and Epidemiology, Veterinary Biosciences, Olli Pekka Vapalahti / Principal Investigator, Viral Zoonosis Research Unit, Department of Virology, Medicum, Clinicum, University of Helsinki, Department of Biochemistry and Developmental Biology, and HUS Neurocenter
- Subjects
Male ,0301 basic medicine ,Narcolepsy type 1 ,Prostaglandin ,Receptors, Prostaglandin ,lcsh:Medicine ,Autoimmunity ,Antibodies, Viral ,Autoantigens ,Epitope ,Epitopes ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Pandemrix ,DP1 ,Child ,Antigens, Viral ,Neurons ,Vaccines ,lcsh:R5-920 ,biology ,Mimotope ,H1N1 ,General Medicine ,Prognosis ,3. Good health ,Influenza Vaccines ,Female ,Antibody ,lcsh:Medicine (General) ,Research Paper ,Adult ,Adolescent ,Non-rapid eye movement sleep ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Immune system ,Antigen ,Influenza, Human ,medicine ,Humans ,Amino Acid Sequence ,Autoantibodies ,Narcolepsy ,business.industry ,lcsh:R ,medicine.disease ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Immunology ,biology.protein ,Peptides ,business ,Biomarkers ,Epitope Mapping ,030217 neurology & neurosurgery - Abstract
Highlights • Using large-scale antibody profiling, differences between narcolepsy type 1 (NT1) and healthy controls became evident. • Prostaglandin D2 receptor DP1 was delineated as a novel autoantigenic target in NT1. • Utility of a 3-biomarker ELISPOT assay to assess exposure to H1N1 influenza virus and susceptibility to NT1 was demonstrated. This study reports on the diagnostic value of novel clinical biomarkers for detecting spontaneous and Pandemrix vaccine-associated NT1 and for stratification of A/H1N1 flu-specific response. Large-scale antibody profiling approach revealed the broad scope and high heterogeneity of NT1-associated immune response. We found a strong autoimmune-like response to prostaglandin D2 receptor DP1 suggesting a firm link between DP1/PDG2 and histamine pathways and the molecular basis of NT1. Together our results warrant further investigation of autoimmune ("self-") response in particular to PDG2 biosynthesis pathway as antibodies to the latter may modify the function of pharmaceutical compounds aimed at treating NT1., Background Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.
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- 2018
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50. Rheumatic Disease Autoantibodies in Patients with Autoimmune Thyroid Diseases
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Gisah Amaral de Carvalho, Shirley Ramos da Rosa Utiyama, Thelma L. Skare, Yasmine Gorczevski Pigosso, Nathalia Prado, and Renato Nisihara
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Adult ,Male ,medicine.medical_specialty ,Anti-nuclear antibody ,Extractable nuclear antigens ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Gastroenterology ,Thyroiditis ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,Antithyroid Agents ,Rheumatoid Factor ,Rheumatic Diseases ,Surveys and Questionnaires ,Internal medicine ,Prevalence ,medicine ,Humans ,Rheumatoid factor ,Aged ,Autoantibodies ,030203 arthritis & rheumatology ,Original Paper ,business.industry ,Thyroid ,Thyroiditis, Autoimmune ,Autoantibody ,General Medicine ,Middle Aged ,medicine.disease ,Graves Disease ,Latex fixation test ,Thyroxine ,medicine.anatomical_structure ,Antibodies, Antinuclear ,Female ,business ,Follow-Up Studies ,030215 immunology - Abstract
Background: Patients with autoimmune thyroid diseases (ATD) such as Graves’ disease (GD) and Hashimoto thyroiditis (HT) may have non-organ specific autoantibodies such as antinuclear antibodies (ANA) and rheumatoid factor (RF). Aim: To study the prevalence of rheumatic autoantibodies in a group of ATD patients without known rheumatic diseases and to evaluate its association with the patients’ epidemiological and treatment profiles. To follow positive non-organ specific autoantibody-positive ATD individuals to investigate whether they will develop a rheumatic disorder. Methods: A sample of 154 ATD patients (70 HT and 84 GD; mean age 45.3 ± 14.2) had determination of ANA by immunofluorescence, using hep-2 cells as substrate, extractable nuclear antigen profile by ELISA kits and RF by latex agglutination. Epidemiological and treatment profiles were obtained through chart review. These patients were followed for the mean period of 5 years, between 2010 and 2015. Results: Positive ANA was found in 17.5% (27/154) of the patients: anti-Ro/SS-A in 4/154 (2.5%); anti-RNP in 4/154 (2.5%), and anti-La/SS-B in 3/154 (1.9%). None had anti-Sm antibodies. RF was detected in 12/154 (7.7%) of ATD patients and was more common in older individuals (p = 0.007). There was a positive association between the presence of RF and ANA (p = 0.03; OR 3.89; 95% CI 1.1–13.3). None of the patients with positive autoantibodies developed clinical rheumatic diseases during the period of observation. Conclusion: We found rheumatic autoantibodies in 17.5% of ATD patients without rheumatic diseases. None of them were associated with the appearance of clinical rheumatic disorder during the period of 5 years.
- Published
- 2018
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