Sonia Berrih-Aknin

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.

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.

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.

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. 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). 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. ClinicalTrials.gov, NCT02066519 . Registered on 13 January 2014.

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.

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 (HT) and Graves disease (GD). They are frequently associated with other organ or non-organ specific autoimmune diseases, 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.