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Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR + MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty., (© 2024. The Author(s).)

Objectives: This study aims to explore the impact of myasthenia gravis (MG) - in terms of treatments, side effects, comorbidities, psychological health and work or study- in the real world from a patient perspective., Design and Participants: This is a prospective, observational, digital, longitudinal study. Adults diagnosed with MG residing in the USA, Japan, Germany, the UK, Italy, Spain or Canada were eligible to participate in the study. There were no other exclusion criteria. Participants used a bespoke smartphone application to confirm eligibility, provide consent and enter data about their MG into a profile, a tracker to record MG-related events and a series of patient-reported outcome instruments. 1693 participants completed at least 1 survey and were included in this analysis., Results: Results are presented as a percentage of respondents to each survey question. The study population was largely female (69% of 1586 respondents), with an average age of 49.9 years (SD 14.8). In the previous 12 months, 83.7% of 1412 respondents confirmed that they had received one or more routine treatments for MG, and 67.1% of 255 respondents confirmed that they had experienced a side effect in the previous month. Commonly experienced comorbidities reported by 966 respondents were thyroid problems, hypertension and anxiety, experienced by 37.5%, 31.4% and 28.0% of respondents, respectively.According to 889 respondents to the Hospital Anxiety and Depression Scale survey, 52.7% and 43.2% had a score indicative of at least mild anxiety and mild depression, respectively. Of 257 respondents, 33.0% reported experiencing a work or study impact in the past month., Conclusions: This analysis of baseline characteristics of the MyRealWorld MG study population indicates that, despite current treatments, patients experience notable burden. Further scheduled analyses will develop a longitudinal picture of MG burden., Trial Registration Number: NCT04176211., Competing Interests: Competing interests: The principal investigator, ML is CEO and owner of Vitaccess, which has been commissioned by argenx BV to carry out the study. FA and CQ are employees of Vitaccess. JB, GP, FDR, JR and SP are employees of argenx BV, the sponsor of the study. SB-A is a consultant and receives honoraria from argenx BV for this study. AM has received speaker honoraria, consulting fees or financial research support from Alexion, argenx BV, Grifols, Hormosan Pharma, Janssen, Octapharma and UCB. He serves as Chairman of the medical advisory board of the German Myasthenia Gravis Society. KGC has received advisory board honoraria, speaker fees and funding for research from Alnylam Pharmaceuticals, Biogen, CSL Behring and Sanofi-Genzyme, and travel reimbursement from Sanofi-Genzyme. KGC holds the Emil von Behring Chair in Neuromuscular and Neurodegenerative Disorders, sponsored by CSL Behring. FS has received public-speaking honoraria from Almirall, Biogen, Mylan, Novartis, Roche, Sanofi and Teva Pharmaceuticals, and served on advisory boards for Almirall, argenx BV, AveXis, Biogen, Forward Pharma, Lexeo Therapeutics, Merck, Novartis, Novatek Pharmaceuticals, Pomona, Roche, Sanofi and Takeda., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-β. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investigated the chronic thymic IFN-I signature., Methods: Serum levels of IFN-β and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in peripheral mononuclear blood cells (PBMCs) were analyzed. The contribution of endogenous nucleic acids in thymic expression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68 + and CD163 + macrophages were analyzed in AChR-MG. To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody., Results: No IFN-I signature was observed in the periphery emphasizing that the IFN-I signature is restricted to the MG thymus. Molecules mimicking endogenous dsDNA signalization (Poly(dA:dT) and 2'3'-cGAMP), or dexamethasone-induced necrotic thymocytes increased IFN-β and α-AChR expression by thymic epithelial cells, and in the mouse thymus. A significant decrease in thymic macrophages was demonstrated in AChR-MG. In mice, a decrease in thymic macrophages led to an increase of necrotic thymocytes associated with IFN-β and α-AChR expression., Interpretation: These results suggest that the decrease of thymic macrophages in AChR-MG impairs the elimination of apoptotic thymocytes favoring the release of endogenous nucleic acids from necrotic thymocytes. In this inflammatory context, thymic epithelial cells may overexpress IFN-β, which specifically induces α-AChR, resulting in self-sensitization and thymic changes leading to AChR-MG. ANN NEUROL 2023;93:643-654., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Myasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient., Design: Prospective, observational, digital, longitudinal real-world study., Setting: Adult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG., Outcome Measures: Data was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I-V)., Results: Baseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I-V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I-IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I-IV., Conclusions: MG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity., Competing Interests: Competing interests: SD is the principal investigator of the study, and MFJ has been commissioned by argenx BV and received honoraria to design the study, analyse and report the data. ML is CEO and owner of Vitaccess, who has been commissioned by argenx BV to carry out the data collection. CQ and LD are employees of Vitaccess. GP, SP, JB and SC are employees of argenx BV, the sponsor of the study. SD and MFJ are members of the EuroQol Group. KGC has received advisory board honoraria, speaker fees and funding for research from Alnylam, Biogen, CSL Behring and Sanofi-Genzyme; and travel reimbursement from Sanofi-Genzyme. KGC holds the Emil von Behring Chair in Neuromuscular and Neurodegenerative Disorders, sponsored by CSL Behring. HM has served as a paid consultant for argenx BV, Alexion Pharmaceuticals, Ra Pharmaceuticals and UCB Pharma and has received speaker honoraria from the Japan Blood Products Organisation and research support from the Ministry of Health, Labour and Welfare, Japan. RM has received speaking honoraria from BioMarin, Alexion and UCB, served on advisory boards for Alexion, argenx BV and UCB and received support for congress participation from Merck, Teva and Biogen. FS has received public speaking honoraria from Biogen, Mylan, Novartis, Roche, Sanofi and Teva; and served on advisory boards for Almirall, argenx BV, AveXis, Biogen, Forward Pharma, Merk, Novartis, Novatek, Pomona, Roche and Sanofi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Myasthenia Gravis (MG) is a neurological autoimmune disease characterized by disabling muscle weaknesses due to anti-acetylcholine receptor (AChR) autoantibodies. To gain insight into immune dysregulation underlying early-onset AChR + MG, we performed an in-depth analysis of peripheral mononuclear blood cells (PBMCs) using mass cytometry. PBMCs from 24 AChR + MG patients without thymoma and 16 controls were stained with a panel of 37 antibodies. Using both unsupervised and supervised approaches, we observed a decrease in monocytes, for all subpopulations: classical, intermediate, and non-classical monocytes. In contrast, an increase in innate lymphoid cells 2 (ILC2s) and CD27 - γδ T cells was observed. We further investigated the dysregulations affecting monocytes and γδ T cells in MG. We analyzed CD27 - γδ T cells in PBMCs and thymic cells from AChR + MG patients. We detected the increase in CD27 - γδ T cells in thymic cells of MG patients suggesting that the inflammatory thymic environment might affect γδ T cell differentiation. To better understand changes that might affect monocytes, we analyzed RNA sequencing data from CD14 + PBMCs and showed a global decrease activity of monocytes in MG patients. Next, by flow cytometry, we especially confirmed the decrease affecting non-classical monocytes. In MG, as for other B-cell mediated autoimmune diseases, dysregulations are well known for adaptive immune cells, such as B and T cells. Here, using single-cell mass cytometry, we unraveled unexpected dysregulations for innate immune cells. If these cells are known to be crucial for host defense, our results demonstrated that they could also be involved in autoimmunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verdier, Fayet, Hemery, Truffault, Pinzón, Demeret, Behin, Fadel, Guihaire, Corneau, Blanc, Berrih-Aknin and Le Panse.)

Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR + autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR + MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects., (© 2023. The Author(s).)

Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against components of the neuromuscular junction, particularly the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG patients. In early-onset AChR-MG and thymoma-associated MG, an interferon type I (IFN-I) signature is clearly detected in the thymus. The origin of this chronic IFN-I expression in the thymus is not yet defined. IFN-I subtypes are normally produced in response to viral infection. However, genetic diseases called interferonopathies are associated with an aberrant chronic production of IFN-I defined as sterile inflammation. Some systemic autoimmune diseases also share common features with interferonopathies. This review aims to analyze the pathogenic role of IFN-I in these diseases as compared to AChR-MG in order to determine if AChR-MG could be an acquired interferonopathy.

Predisposition to autoimmunity and inflammatory disorders is observed in patients with fragile X-associated syndromes. These patients have increased numbers of CGG triplets in the 5' UTR region of FMR1 (Fragile X Mental Retardation 1) gene, that affects its expression. FMR1 is decreased in the thymus of myasthenia gravis (MG) patients, a prototypical autoimmune disease. We thus analyzed the number of CGG triplets in FMR1 in MG, and explored the regulatory mechanisms affecting thymic FMR1 expression. We measured the number of CGGs using thymic DNA from MG and controls, but no abnormalities in CGGs were found in MG that could explain thymic decrease of FMR1. We next analyzed by RT-PCR the expression of FMR1 and its transcription factors in thymic samples, and in thymic epithelial cell cultures in response to inflammatory stimuli. In control thymuses, FMR1 expression was higher in males than females, and correlated with CTCF (CCCTC-binding factor) expression. In MG thymuses, decreased expression of FMR1 was correlated with both CTCF and MAX (Myc-associated factor X) expression. Changes in FMR1 expression were supported by western blot analyses for FMRP. In addition, we demonstrated that FMR1, CTCF and MAX expression in thymic epithelial cells was also sensitive to inflammatory signals. Our results suggest that FMR1 could play a central role in the thymus and autoimmunity. First, in relation with the higher susceptibility of females to autoimmune diseases. Second, due to the modulation of its expression by inflammatory signals that are known to be altered in MG thymuses., (© 2021. The Author(s).)

Introduction: Myasthenia gravis (MG) is a rare, chronic, autoimmune disease, mediated by immunoglobulin G antibodies, which causes debilitating muscle weakness. As with most rare diseases, there is little patient-reported data with which to understand and address patient needs. This study explores the impact of MG in the real world from the patient perspective., Methods and Analysis: This is a 2-year prospective, observational, digital, longitudinal study of adults with MG, resident in the following countries: the USA, Japan, Germany, France, the UK, Italy, Spain, Canada and Belgium. The planned sample size is 2000. Recruitment will be community based, via patient advocacy groups, social media and word of mouth. Participants will use a smartphone application (app) to check eligibility, provide consent and contribute data. Planned data entry is as follows: (1) personal profile on enrollment-covering demographics, MG characteristics and previous care; (2) monthly event tracker-current treatments, healthcare visits, treatment-related adverse events, productivity losses; (3) monthly selection of validated generic and disease-specific patient-reported outcomes instruments: EQ-5D-5L, Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Quality of Life 15-item revised scale, Hospital Anxiety and Depression Scale and Health Utilities Index III. Analyses are planned for when the study has been running in most countries for approximately 6, 12, 18 and 24 months., Ethics and Dissemination: The study protocol has been reviewed and granted ethics approval by Salus IRB for participants resident in the following countries: Germany, the UK and the US. Local ethics approval is being sought for the following study countries: Belgium, Canada, France, Italy, Japan and Spain. Study results will be communicated to the public and participants via conference presentations and journal publications, as well as regular email, social media and in-application communication., Trial Registration Number: NCT04176211., Competing Interests: Competing interests: The principal investigator, ML, is CEO and owner of Vitaccess, which has been commissioned by argenx BV, to carry out the study. EB and HK are or were employees of Vitaccess. JB, TL and SP are employees of argenx BV. MFJ is a member of the EuroQol Group. SD, MFJ and SB-A are consultants and received honoraria from argenx BV for this study. KGC has received advisory board honoraria, speaker fees and funding for research from Alnylam, Biogen, CSL Behring and Sanofi-Genzyme; and travel reimbursement from Sanofi-Genzyme. KGC holds the Emil von Behring Chair in Neuromuscular and Neurodegenerative Disorders, sponsored by CSL Behring. HM has served as a consultant for argenx BV, Alexion Pharmaceuticals, Ra Pharmaceuticals and UCB Pharma and has received speaker honoraria from the Japan Blood Products Organisation and research support from the Ministry of Health, Labour and Welfare, Japan. RM has received speaking honoraria from Biomarin, Alexion and UCB, served on advisory boards for Alexion, argenx BV and UCB and received support for congress participation from Merck, Teva and Biogen. FS has received public speaking honoraria from Biogen, Mylan, Novartis, Roche, Sanofi and Teva; and served on advisory boards for Almirall, argenx BV, Avexis, Biogen, Forward Pharma, Merk, Novartis, Novatek, Pomona, Roche and Sanofi., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Myasthenia gravis (MG) is a rare autoimmune disease mainly mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. The thymus is the effector organ, and its removal alleviates the symptoms of the disease. In the early-onset form of MG, the thymus displays functional and morphological abnormalities such as B cell infiltration leading to follicular hyperplasia, and the production of AChR antibodies. Type-I interferon (IFN-I), especially IFN-β, is the orchestrator of thymic changes observed in MG. As Dicer and miR-29 subtypes play a role in modulating the IFN-I signalization in mouse thymus, we investigated their expression in MG thymus., Methods: The expression of DICER and miR-29 subtypes were thoroughly investigated by RT-PCR in human control and MG thymuses, and in thymic epithelial cells (TECs). Using miR-29a/b-1-deficient mice, with lower miR-29a/b-1 expression, we investigated their susceptibility to experimental autoimmune MG (EAMG) as compared to wild-type mice., Results: DICER mRNA and all miR-29 subtypes were down-regulated in the thymus of MG patients and DICER expression was correlated with the lower expression of miR-29a-3p. A decreased expression of miR-29 subtypes was similarly observed in MG TECs; a decrease also induced in TECs upon IFN-β treatment. We demonstrated that miR-29a/b-1-deficient mice were more susceptible to EAMG without higher levels of anti-AChR IgG subtypes. In the thymus, if no B cell infiltration was observed, an increased expression of Ifn-β associated with Baff expression and the differentiation of Th17 cells associated with increased expression of Il-6, Il-17a and Il-21 and decreased Tgf-β1 mRNA were demonstrated in miR-29a/b-1-deficient EAMG mice., Conclusions: It is not clear if the decreased expression of miR-29 subtypes in human MG is a consequence or a causative factor of thymic inflammation. However, our results from the EAMG mouse model indicated that a reduction in miR-29a/b1 may contribute to the pathophysiological process involved in MG by favoring the increased expression of IFN-β and the emergence of pro-inflammatory Th17 cells.

The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation., (Copyright © 2020 Truffault, Nazzal, Verdier, Gradolatto, Fadel, Roussin, Eymard, Le Panse and Berrih-Aknin.)

In western countries, the slope of autoimmune disease (AD) incidence is increasing and affects 5-8% of the population. Mainly prevalent in women, these pathologies are due to thymic tolerance processes breakdown. The female sex hormone, estrogen, is involved in this AD female susceptibility. However, predisposition factors have to act in concert with unknown triggering environmental factors (virus, microbiota, pollution) to initiate AD. Individuals are exposed to various environmental compounds that display endocrine disruption abilities. The cellular effects of some of these molecules may be mediated through the aryl hydrocarbon receptor (AhR). Here, we review the effects of these molecules on the homeostasis of the thymic cells, the immune tolerance intrinsic factors (transcription factors, epigenetic marks) and on the immune tolerance extrinsic factors (microbiota, virus sensibility). This review highlights the contribution of estrogen and endocrine disruptors on the dysregulation of mechanisms sustaining AD development., Competing Interests: Declaration of Competing Interest The authors declare that they have no relevant conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Thymomas are associated with a very high risk of developing Myasthenia Gravis (MG). Our objectives were to identify histological and biological parameters to allow early diagnosis of thymoma patients susceptible to developing MG. We conducted a detailed retrospective analysis from a patient database, searching for differences between patients with thymoma-associated MG (MGT, n = 409) and thymoma without MG (TOMA, n = 111) in comparison with nonthymomatous MG patients (MG, n = 1246). We also performed multiplex and single molecule arrays to measure the serum levels of cytokines in these groups of patients and controls (n = 14-22). We identified a set of parameters associated with MG development in thymoma patients: 1) detection of anti-acetylcholine receptor (AChR) antibodies, 2) development of B1 or B2 thymoma subtypes, 3) presence of ectopic thymic germinal centers (GCs), 4) local invasiveness of thymoma, and 5) being a woman under 50 years old. Among these parameters, 58.8% of MGT patients displayed GCs with a positive correlation between the number of GCs and anti-AChR titers. By immunohistochemistry, we found thymic GCs in the adjacent tissues of thymomas encircled by high endothelial venules (HEVs) that could favor peripheral cell recruitment. We also clearly associated MG symptoms with higher IFN-γ, IL-1β and sCD40L serum levels, specifically in MGT patients compared to TOMA patients. Altogether, these analyses allowed the clear identification of histological, in particular the presence of GCs, and biological parameters that would facilitate the evaluation of the probability of the MG outcome postoperatively in thymoma patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Myasthenia gravis (MG) is a rare autoimmune disease mediated by pathogenic antibodies (Ab) directed against components of the neuromuscular junction (NMJ), mainly the acetylcholine receptor (AChR). The etiological mechanisms are not totally elucidated, but they include a combination of genetic predisposition, triggering event(s), and hormonal components. MG disease is associated with defective immune regulation, chronic cell activation, inflammation, and the thymus is frequently abnormal. MG is characterized by muscle fatigability that is very invalidating and can be life-threatening when respiratory muscles are affected. MG is not cured, and symptomatic treatments with acetylcholinesterase inhibitors and immunosuppressors are life-long medications associated with severe side effects (especially glucocorticoids). While the muscle is the ultimate target of the autoimmune attack, its place and role are not thoroughly described, and this mini-review will focus on the cascade of pathophysiologic mechanisms taking place at the NMJ and its consequences on the muscle biology, function, and regeneration in myasthenic patients, at the histological, cellular, and molecular levels. The fine structure of the synaptic cleft is damaged by the Ab binding that is coupled to focal complement-dependent lysis in the case of MG with anti-AChR antibodies. Cellular and molecular reactions taking place in the muscle involve several cell types as well as soluble factors. Finally, the regenerative capacities of the MG muscle tissue may be altered. Altogether, the studies reported in this review demonstrate that the muscle is not a passive target in MG, but interacts dynamically with its environment in several ways, activating mechanisms of compensation that limit the pathogenic mechanisms of the autoantibodies., (Copyright © 2019 Vilquin, Bayer, Le Panse and Berrih-Aknin.)

Autoimmune Myasthenia gravis (MG) is a chronic neuromuscular disease mainly due to antibodies against the acetylcholine receptor (AChR) at the neuromuscular junction that induce invalidating muscle weaknesses. In early-onset MG, the thymus is the effector organ and is often characterized by B-cell infiltrations leading to ectopic germinal center (GC) development. The microRNA miR-150-5p has been previously characterized as a biomarker in MG due to its increase in the serum of patients and its decrease after thymectomy, correlated with an improvement of symptoms. Here, we investigated the causes and consequences of the miR-150 increase in the serum of early-onset MG patients. We observed that miR-150 expression was upregulated in MG thymuses in correlation with the presence of thymic B cells and showed by in situ hybridization experiments, that miR-150 was mainly expressed by cells of the mantle zone of GCs. However, we did not observe any correlation between the degree of thymic hyperplasia and the serum levels in MG patients. In parallel, we also investigated the expression of miR-150 in peripheral blood mononuclear cells (PBMCs) from MG patients. We observed that miR-150 was down-regulated, especially in CD4 + T cells compared to controls. These results suggest that the increased serum levels of miR-150 could result from a release from activated peripheral CD4 + T cells. Next, we demonstrated that the in vitro treatment of PBMCs with miR-150 or antimiR-150 oligonucleotides, respectively, decreased or increased the expression of one of its major target gene: the proto-oncogene MYB , a well-known actor of hematopoiesis. These results revealed that increased serum levels of miR-150 in MG patients could have a functional effect on PBMCs. We also showed that antimiR-150 caused increased cellular death of CD4 + and CD8 + T cells, along with the overexpression of pro-apoptotic genes targeted by miR-150 suggesting that miR-150 controlled the survival of these cells. Altogether, these results showed that miR-150 could play a role in MG both at the thymic level and in periphery by modulating the expression of target genes and peripheral cell survival.

IL-23/Th17 pathway has been identified to sustain inflammatory condition in several autoimmune diseases and therefore being targeted in various therapeutic and effective approaches. Patients affected with autoimmune myasthenia gravis exhibit a disease effector tissue, the thymus, that harbors ectopic germinal centers that sustain production of auto-antibodies, targeting proteins located in the neuromuscular junction, cause of the organ-specific chronic autoimmune disease. The present study aims to investigate the IL-23/Th17 cell pathway in the thymic inflammatory and pathogenic events. We found that thymuses of MG patients displayed overexpression of Interleukin-17, signature cytokine of activated Th17 cells. This activation was sustained by a higher secretion of Interleukin-23 by TEC, in addition to the increased expression of cytokines involved in Th17 cell development. The overexpression of Interleukin-23 was due to a dysregulation of interferon type I pathway. Besides, Interleukin-17 secreted, and Th17 cells were localized around thymic ectopic germinal centers. These cells expressed podoplanin, a protein involved in B-cell maturation and antibody secretion. Finally, production of Interleukin-23 was also promoted by Interleukin-17 secreted itself by Th17 cells, highlighting a chronic loop of inflammation sustained by thymic cell interaction. Activation of the IL-23/Th17 pathway in the thymus of autoimmune myasthenia gravis patients creates an unstoppable loop of inflammation that may participate in ectopic germinal center maintenance. To alleviate the physio-pathological events in myasthenia gravis patients, this pathway may be considered as a new therapeutic target., (Copyright © 2018. Published by Elsevier Ltd.)

We analyzed the number and functionality of regulatory B (Breg) cells in well-defined myasthenia gravis patients. We first showed a decreased number of circulating CD19 + CD24 ++ CD38 ++ Breg cells and an altered functionality of Breg cells in untreated myasthenia gravis patients. Next, we demonstrated that the proportion of circulating Breg cells was restored in myasthenia gravis patients after thymectomy, probably as Breg cells could be sequestered in the myasthenia gravis thymus. In contrast, corticosteroid treatments did not restore and decreased even more the proportion of Breg cells in myasthenia gravis patients. These results clearly demonstrated that two distinct immunomodulatory therapies affect differentially Breg cells.

Thymic epithelial cells are one of the main components of the thymic microenvironment required for T-cell development. In this work, we describe an efficient method free of enzymatic and Facs-sorted methods to culture human medullary thymic epithelial cells without affecting the cell phenotypic, physiologic and functional features. Human medulla thymic epithelial cells (mTECs) are obtained by culturing thymic biopsies explants. After 7 days of primo-culture, mTECs keep their ability to express key molecules involved in immune tolerance processes such as autoimmune regulator, tissue-specific antigens, chemokines, and cytokines. In addition, the cells sensor their cultured environment and consequently adjust their gene expression network. Therefore, we describe and provide a human mTEC model that may be used to test the effect of various molecules on thymic epithelial cell homeostasis and physiology. This method should allow the investigations of the specificities and the knowledge of human mTECs in normal or pathological conditions and therefore discontinue the extrapolations done on the murine models.

In early-onset Myasthenia Gravis (MG) with anti-acetylcholine receptor antibodies, thymic abnormalities associated with ectopic germinal centers are frequent. miRNAs by acting as post-transcriptional regulators are involved in autoimmunity. To investigate the implication of miRNAs in thymic changes associated with early-onset MG, we performed a miRnome study and data were analyzed with different approaches. miRNAs of interest were further investigated by RT-PCR and transfection experiments for functional tests. First, analyzing specific dysregulated miRNAs, we focused our attention on miR-7-5p and miR-125a-5p, and confirmed by RT-PCR their respective down- and up-regulation in MG thymuses. miR-7 was the most down-regulated thymic miRNA in MG and we observed an inverse correlation between its expression and CCL21 mRNA expression. We next showed that miR-7 down-regulation was due to thymic epithelial cells and by transfecting these cells with miR-7, we demonstrated that it controlled CCL21 release. As CCL21 is essential for germinal center development, we suggested that miR-7 could be involved in thymic changes associated with MG. miR-125a was up-regulated in MG thymuses and is of great interest as it is known to regulate FoxP3 expression, and to modulate the different inflammatory signaling pathways. Thanks to this thymic miRnome study, we also showed the specific dysregulation of miRNA clusters. In particular, we observed that miRNAs localized at the extremity of the X chromosome were down-regulated. This effect seemed linked to their close localization to the fragile X mental retardation 1 gene (FMR1) and the DNA methylation status. Altogether, this miRnome analysis demonstrated that specific thymic miRNAs can be associated with MG and provides novel insights into the pathogenesis of MG., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Autoimmune diseases (AIDs) are chronic disorders characterized by inflammatory reactions against self-antigens that can be either systemic or organ specific. AIDs can differ in their epidemiologic features and clinical presentations, yet all share a remarkable complexity. AIDs result from an interplay of genetic and epigenetic factors with environmental components that are associated with imbalances in the immune system. Many of the pathogenic mechanisms of AIDs are also implicated in myasthenia gravis (MG), an AID in which inflammation of the thymus leads to a neuromuscular disorder. Our goal here is to highlight the similarities and differences between MG and other AIDs by reviewing the common transcriptome signatures and the development of germinal centers and by discussing some unresolved questions about autoimmune mechanisms. This review will propose hypotheses to explain the origin of regulatory T (T reg ) cell defects and the causes of chronicity and specificity of AIDs., (© 2018 New York Academy of Sciences.)

A chronic autoimmune disease, myasthenia gravis (MG) is characterized in 85% of patients by antibodies directed against the acetylcholine receptor (AChR) located at the neuromuscular junction. The functional and effective balance between regulatory T cells (T reg cells) and effector T cells (T eff cells) is lost in the hyperplastic thymus of MG patients with antibodies specific for the AChR (AChR + MG patients). The objective of this review is to describe how T reg cells and inflammatory T cells participate in this imbalance and contribute to induce a chronic inflammatory state in the MG thymus. We discuss the origins and characteristics of T reg cells and their reported dysfunctions in AChR + MG patients. We also review the inflammatory condition observed in MG thymus, including overexpression of interleukin (IL)-1β, IL-6, and IL-23, cytokines that promote the differentiation of T helper 17 (T H 17) cells and the expression of IL-17. We summarize the preclinical models used to determine the implication of expression of cytokines, such as IL-6, IL-12 (IL-23 subunit), IL-17, and interferon γ to the development of experimental autoimmune MG. Finally, we suggest that biological agents, such as humanized monoclonal antibodies that target the IL-23/T H 17 pathway, should be investigated in the context of MG, as they have proven efficiency in other autoimmune diseases., (© 2018 New York Academy of Sciences.)

Background: Research exploring the effects of physical exercise in auto-immune myasthenia gravis (MG) is scarce. The few existing studies present methodological shortcomings limiting the conclusions and generalisability of results. It is hypothesised that exercise could have positive physical, psychological as well as immunomodulatory effects and may be a beneficial addition to current pharmacological management of this chronic disease. The aim of this study is to evaluate the benefits on perceived quality of life (QOL) and physical fitness of a home-based physical exercise program compared to usual care, for patients with stabilised, generalised auto-immune MG., Methods: MGEX is a multi-centre, interventional, randomised, single-blind, two-arm parallel group, controlled trial. Forty-two patients will be recruited, aged 18-70 years. Following a three-month observation period, patients will be randomised into a control or experimental group. The experimental group will undertake a 40-min home-based physical exercise program using a rowing machine, three times a week for three months, as an add-on to usual care. The control group will receive usual care with no additional treatment. All patients will be followed up for a further three months. The primary outcome is the mean change in MGQOL-15-F score between three and six months (i.e. pre-intervention and immediately post-intervention periods). The MGQOL-15-F is an MG-specific patient-reported QOL questionnaire. Secondary outcomes include the evaluation of deficits and functional limitations via MG-specific clinical scores (Myasthenia Muscle Score and MG-Activities of Daily Living scale), muscle force and fatigue, respiratory function, free-living physical activity as well as evaluations of anxiety, depression, self-esteem and overall QOL with the WHO-QOL BREF questionnaire. Exercise workload will be assessed as well as multiple safety measures (ECG, biological markers, medication type and dosage and any disease exacerbation or crisis)., Discussion: This is the largest randomised controlled trial to date evaluating the benefits and tolerance of physical exercise in this patient population. The comprehensive evaluations using standardised outcome measures should provide much awaited information for both patients and the scientific community. This study is ongoing., Trial Registration: ClinicalTrials.gov, NCT02066519 . Registered on 13 January 2014.

It has long been established that the thymus plays a central role in autoimmune myasthenia gravis (MG) because of either thymoma or thymic hyperplasia of lymphoproliferative origin. In this review, we discuss thymic changes associated with thymic hyperplasia and their implications in the development of an autoimmune response against the acetylcholine receptor (AChR).The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development. As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells. How the thymus turns into a TLO is not known, but local inflammation seems mandatory. Interferon (IFN)-β is overexpressed in MG thymus and could orchestrate thymic changes associated with MG. Knowledge about how IFN-β is induced in MG thymus and why its expression is sustained even long after disease onset would be of interest in the future to better understand the etiological and physiopathological mechanisms involved in autoimmune MG., (© 2017 New York Academy of Sciences.)

Women are more susceptible to autoimmune diseases than men. Autoimmunity results from tolerance breakdown toward self-components. Recently, three transcription modulators were identified in medullary thymic epithelial cells that orchestrate immune central tolerance processes: the autoimmune regulator (AIRE), FEZ family zinc finger 2 (FEZF2 or FEZ1), and PR domain zinc finger protein 1 (PRDM1). Interestingly, these three transcription modulators regulate nonredundant tissue-specific antigen subsets and thus cover broad antigen diversity. Recent data from different groups demonstrated that sex hormones (estrogen and testosterone) are involved in the regulation of thymic AIRE expression in humans and mice through direct transcriptional modulation and epigenetic changes. As a consequence, AIRE displays gender-biased thymic expression, with females showing a lower expression compared with males, a finding that could explain the female susceptibility to autoimmune diseases. So far, FEZF2 has not been related to an increased gender bias in autoimmune disease. PRDM1 expression has not been shown to display gender-differential thymic expression, but its expression level and its gene polymorphisms are associated with female-dependent autoimmune disease risk. Altogether, various studies have demonstrated that increased female susceptibility to autoimmune diseases is in part a consequence of hormone-driven reduced thymic AIRE expression., (© 2017 New York Academy of Sciences.)

Myasthenia gravis (MG) is a neuromuscular disease caused in most cases by anti-acetyl-choline receptor (AChR) autoantibodies that impair neuromuscular signal transmission and affect skeletal muscle homeostasis. Myogenesis is carried out by muscle stem cells called satellite cells (SCs). However, myogenesis in MG had never been explored. The aim of this study was to characterise the functional properties of myasthenic SCs as well as their abilities in muscle regeneration. SCs were isolated from muscle biopsies of MG patients and age-matched controls. We first showed that the number of Pax7+ SCs was increased in muscle sections from MG and its experimental autoimmune myasthenia gravis (EAMG) mouse model. Myoblasts isolated from MG muscles proliferate and differentiate more actively than myoblasts from control muscles. MyoD and MyoG were expressed at a higher level in MG myoblasts as well as in MG muscle biopsies compared to controls. We found that treatment of control myoblasts with MG sera or monoclonal anti-AChR antibodies increased the differentiation and MyoG mRNA expression compared to control sera. To investigate the functional ability of SCs from MG muscle to regenerate, we induced muscle regeneration using acute cardiotoxin injury in the EAMG mouse model. We observed a delay in maturation evidenced by a decrease in fibre size and MyoG mRNA expression as well as an increase in fibre number and embryonic myosin heavy-chain mRNA expression. These findings demonstrate for the first time the altered function of SCs from MG compared to control muscles. These alterations could be due to the anti-AChR antibodies via the modulation of myogenic markers resulting in muscle regeneration impairment. In conclusion, the autoimmune attack in MG appears to have unsuspected pathogenic effects on SCs and muscle regeneration, with potential consequences on myogenic signalling pathways, and subsequently on clinical outcome, especially in the case of muscle stress.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. MG symptoms are characterized by muscle weaknesses. The thymus of MG patients is very often abnormal and possesses all the characteristics of tertiary lymphoid organs such as neoangiogenesis processes, overexpression of inflammatory cytokines and chemokines, and infiltration of B lymphocytes leading to ectopic germinal center (GC) development. We previously demonstrated that injections of mice with polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic double-stranded RNA mimicking viral infection, induce thymic changes and trigger MG symptoms. Upon Poly(I:C) injections, we observed increased thymic expressions of α-AChR, interferon-β and chemokines such as CXCL13 and CCL21 leading to B-cell recruitment. However, these changes were only transient. In order to develop an experimental MG model associated with thymic GCs, we used Poly(I:C) in the classical experimental autoimmune MG model induced by immunizations with purified AChR emulsified in complete Freund's adjuvant. We observed that Poly(I:C) strongly favored the development of MG as almost all mice displayed MG symptoms. Nevertheless, we did not observe any ectopic GC development. We next challenged mice with Poly(I:C) together with other toll-like receptor (TLR) agonists known to be involved in GC development and that are overexpressed in MG thymuses. Imiquimod and CpG oligodeoxynucleotides that activate TLR7 and TLR9, respectively, did not induce thymic changes. In contrast, lipopolysaccharide that activates TLR4 potentiated Poly(I:C) effects and induced a significant expression of CXCL13 mRNA in the thymus associated with a higher recruitment of B cells that induced over time thymic B-lymphoid structures. Altogether, these data suggest that tertiary lymphoid genesis in MG thymus could result from a combined activation of TLR signaling pathways.

The early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and α-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, α-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of α-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to.

Objective: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design., Methods: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples., Results: >100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity., Interpretation: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Autoimmune diseases (AIDs) are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as "self" are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD) is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto's thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG). In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed.

Myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro-preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell-related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.

Abnormal toll-like receptor (TLR) activation and uncontrolled resolution of inflammation are suspected to play a key role in the development of autoimmune diseases. Acquired myasthenia gravis (MG) is an invalidating neuromuscular disease leading to muscle weaknesses. MG is mainly mediated by anti-acetylcholine receptor (AChR) autoantibodies, and thymic hyperplasia characterized by ectopic germinal centers is a common feature in MG. An abnormal expression of certain TLRs is observed in the thymus of MG patients associated with the overexpression of interferon (IFN)-β, the orchestrator of thymic changes in MG. Experimental models have been developed for numerous autoimmune diseases. These models are induced by animal immunization with a purified antigen solubilized in complete Freund's adjuvant (CFA) containing heat-inactivated mycobacterium tuberculosis (MTB). Sensitization against the antigen is mainly due to the activation of TLR signaling pathways by the pathogen motifs displayed by MTB, and attempts have been made to substitute the use of CFA by TLR agonists. AChR emulsified in CFA is used to induce the classical experimental autoimmune MG model (EAMG). However, the TLR4 activator lipopolysaccharide (LPS) has proved to be efficient to replace MTB and induce a sensitization against purified AChR. Poly(I:C), the well-known TLR3 agonist, is also able by itself to induce MG symptoms in mice associated with early thymic changes as observed in human MG. In this review, we discuss the abnormal expression of TLRs in MG patients and we describe the use of TLR agonists to induce EAMG in comparison with other autoimmune experimental models.

Autoimmune diseases are a group of about 80 different diseases affecting 5-8% of the population. They are due to a deregulation of the immune system that attacks specific molecules and/or cells in the body. The thymus is the school of T cells that must be able to react to foreign molecules penetrating into the body. This education process is mediated by interactions between T cells and thymic epithelial cells (TEC) that express specific proteins of the peripheral tissues (TSA, "tissue-specific antigen"). This complex mechanism is called central tolerance. Most of the autoimmune diseases display a common feature : women are more susceptible to these diseases than men. Since the thymus is the main organ of central tolerance, we conducted a comparative study of thymic transcriptome of women and men. Our data revealed sex-associated differences in the expression of TSAs that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. By studying human and murine cell models, we analyzed the relationship between gender, hormones and AIRE. Our work shows that AIRE is less expressed in women than in men after puberty. Furthermore, we show that estrogen induces decreased thymic AIRE expression by epigenetic modifications through increased number of methylation sites within the AIRE promoter. Consequently, these data suggest that from puberty, women have a reduced effectiveness of central tolerance process, leading to increased number of autoreactive lymphocytes, and as a result, increased susceptibility to autoimmune diseases. Together, these data may question the impact of exposure to "estrogen-like" molecules on the growing incidence of autoimmune diseases., (© 2017 médecine/sciences – Inserm.)

The most common form of Myasthenia gravis (MG) is due to anti-acetylcholine receptor (AChR) antibodies and is frequently associated with thymic pathology. In this review, we discuss the immunopathological characteristics and molecular mechanisms of thymic follicular hyperplasia, the effects of corticosteroids on this thymic pathology, and the role of thymic epithelial cells (TEC), a key player in the inflammatory thymic mechanisms. This review is based not only on the literature data but also on thymic transcriptome results and analyses of pathological and immunological correlations in a vast cohort of 1035 MG patients without thymoma. We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women. The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies. The degree of hyperplasia is not dependent upon the time from the onset, implying that either the antigen is chronically expressed and/or that the mechanisms of the resolution of the GC are not efficiently controlled. Glucocorticoids, a conventional therapy in MG, induce a significant reduction in the GC number, together with changes in the expression of chemokines and angiogenesis. These changes are likely related to the acetylation molecular process, overrepresented in corticosteroid-treated patients, and essential for gene regulation. Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients.

Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases.