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Résumé: La myasthénie se caractérise par une faiblesse musculaire et une fatigabilité anormale à l’effort. C’est une maladie auto-immune due à la présence d’anticorps dirigés contre des composants de la membrane musculaire localisés au niveau de la jonction neuromusculaire. Dans la majorité des cas, il s’agit d’auto-anticorps dirigés contre le récepteur de l’acétylcholine (RACh). Récemment d’autres cibles ont été décrites, telles que les protéines muscle-specific kinase (MuSK) ou lipoprotein related protein 4 (LRP4). L’origine de la réponse auto-immune n’est pas connue, mais les anomalies thymiques et les défauts de régulation du système immunitaire jouent certainement un rôle majeur chez les patients avec anticorps anti-RACh. Une prédisposition génétique influence très probablement la survenue de la maladie. Quant aux hormones sexuelles, elles jouent vraisemblablement un rôle dans la forme précoce de la maladie. La faiblesse musculaire est fluctuante et s’aggrave avec l’effort. La classification de la myasthénie peut être faite en fonction de la localisation des muscles atteints (oculaire versus généralisée), l’âge de début des symptômes, les anomalies thymiques et le profil des auto-anticorps. Ces critères permettent d’optimiser la prise en charge et le traitement des patients. Dans cette revue, nous analyserons les derniers concepts de la physiopathologie de la myasthénie en fonction des différents sous-groupes de la pathologie, en décrivant notamment le rôle des facteurs immunologiques, génétiques et environnementaux dans le développement de cette maladie. L’origine potentiellement virale de cette maladie sera évoquée. Enfin, nous discuterons de l’importance des tests biologiques disponibles pour confirmer le diagnostic. [Copyright &y& Elsevier]

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.)

Myasthenia Gravis (MG) is an autoimmune disease mediated by antibodies directed against the acetylcholine receptor (AChR). Treatment by IVIg is effective in acute forms of myasthenia gravis. In order to determine the in vivo effects of the various fractions of human immunoglobulins, we used an experimental model of myasthenia gravis in SCID mice. To this end, thymic cells from MG patients are transferred to these mice according to a well defined protocol. When establishing of the model, we noticed the appearance of anti-AChR antibodies and the loss of AChR expression at the muscle level. After treatment with IVIgG or IVIgM, the mice displayed a lower anti-AChR antibody titer compared to control mice (albumin treated) and the loss of the AChR number at the muscle was significantly reduced. These results obtained from one MG patient indicate that the human immunoglobulin preparations induce significant effects on pathogenic parameters in the SCID mouse model. Therefore this model is interesting to approach the mechanisms of action of human immunoglobulins and deserves further investigation.

Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on alveolar macrophages (AM) may be one of the the basic mechanisms by which AM regulate the course of inflammatory response during pulmonary allograft rejection and infectious processes by mediating macrophage-lymphocyte interactions. As a model for studying anti-inflammatory activity of drugs on AM, we have investigated the effect of fusafungine, a local antibiotic which displays also anti-inflammatory properties, on the regulation of ICAM-1 membrane expression induced in vitro by stimulating AM from lung-transplant recipients. We have studied ICAM-1 membrane expression by immunocytofluorometric analysis using the anti-CD54 monoclonal antibody. The ICAM-1 molecule was expressed on 10 to 47% of freshly isolated AM, depending on the clinical status of the patients. After 24 hr cultivation with 250 U/ml gamma-IFN, the percentage of ICAM-1+ AM s increased to more than 90%. When added with the stimulating agent, fusafungine could inhibit the induction of ICAM-1 membrane expression, up to 90% of inhibition at 8 microgram/ml. However, once ICAM-1 was induced after 24 hr cultivation upon stimulation, fusafungine could not afford any reversion. On going investigations on mRNA for ICAM-1 should indicate whether fusafungine acts at the transcriptional level. These results clearly demonstrate the capacity of fusafungine to down-regulate ICAM-1 expression on AM upon activation. This approach could represent a useful tool for in vitro study of drug efficacy upon inflammatory processes of the respiratory mucasa.

In myasthenia gravis (MG), the frequency of histologic abnormalities (hyperplasia in young patients, thymoma in older cases) and clinical improvement after thymectomy indicate involvement of the thymus in the pathophysiology of the disease. MG patient thymuses are characterized by the following features: increased amount of B cells (in hyperplasia) and functional abnormalities, mainly activation of B, T and epithelial cells. Moreover, thymic lymphocytes are sensitized to acetylcholine receptor (AChR): first, AChR specific T and B lines can be grown from MG thymus cultures, second, cultured thymic lymphocytes proliferate in the presence of AChR and produce anti-AChR antibodies. AChR molecules are expressed in thymic myoid cells and AChR-like molecules could be displayed at the surface of other cell types. Thus, autosensitization conditions are combined in MG thymus, and potential mechanisms are discussed. It could be a primary event, autosensitization of lymphocytes to AChR taking place initially in the thymus. Or it could be a secondary process, lymphocytes sensitized to AChR in the periphery could be trapped by myoid cells and restimulated in the thymus. In thymoma, autoimmunization occurs differently: the autoimmune process could be initiated by the tumor epithelial cells which express an AChR-like protein. The possible role of severe architectural disturbance in MG thymus (particularly in thymoma), altering thymic lymphocyte selection and maturation is also discussed.

Bronchiolitis obliterans (BO) remains the major complication in long-term survivors with lung transplants, occurring in up to 30% of them. As a non-invasive follow-up of lung recipients, we studied the phenotype of peripheral blood lymphocyte subsets. Using a flow cytometric analysis, we could define a specific pattern during BO. The most important findings were 1) disappearance of the CD19+ B cell population, despite normal or increased immunoglobulin blood levels; 2) marked decrease of the CD4+/CD8+ ratio; 3) dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+ (MHC Class I-restricted allocytotoxicity) and CD3+CD4-CD8- (MHC Class I-non restricted allocytotoxicity); 4) marked increase of the CD4+CD29+ (helper/inducer T cell) to CD4+CD45RA+ (suppressor/inducer T cell) ratio associated with the loss of phenotypic suppressor/inducer CD4+CD45RA+ T cells. Moreover, we have shown that the maintenance triple immunosuppressive regimen that consisted of cyclosporin, prednisolone and azathioprine, did not affect the relative distribution of lymphocyte subsets, except for the CD3+CD4-CD8- cytotoxic subset that was slightly decreased under therapy. Thus, using a selected combination of lymphocyte membrane antigens, sequential prospective testing should be useful in the non-invasive follow-up of lung-transplanted patients to predict and halt the progressive course towards BO.