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Acquired myasthenia gravis (MG), a neurological autoimmune disease, is caused by autoantibodies against components of the neuromuscular junction that lead to disabling muscle fatigability. The thymus is clearly involved in the pathogenesis of early-onset MG with anti-acetylcholine receptor antibodies, and thymic hyperplasia of lympho-proliferative origin is a hallmark of the disease. In this review, we describe the structural and cellular changes associated with thymic hyperplasia, its main characteristics being the development of ectopic germinal centers (GCs) associated with active neoangiogenic processes, such as development of high endothelial venules and lymphangiogenesis. What triggers such thymic abnormalities in MG is not yet clear. A thymic transcriptome analysis has demonstrated a strong inflammatory signature in MG that could orchestrate the development of thymic hyperplasia. In this context, thymic epithelial cells (TECs) seem to play a central role, either by contributing or responding to the inflammatory environment and up-regulating the autoimmune response. In particular, MG TECs clearly overexpress various cytokines, among which chemokines play a crucial role in the recruitment of peripheral lymphocytes to the thymus via the newly expanded vessel network, thereby leading to the development of ectopic GCs. Clearly, a better understanding of major events that lead to thymic hyperplasia will help optimize strategies toward more specific therapy for MG. [ABSTRACT FROM AUTHOR]

The thymus is frequently hyperplastic in young female myasthenia gravis (MG) patients presenting with anti-acetylcholine receptor (AChR) antibodies. This thymic pathology is characterized by the presence of ectopic germinal centers (GCs) containing B cells involved at least partially in the production of pathogenic anti-AChR antibodies. Our recent studies have furthered our understanding of the mechanisms leading to GC formation in the hyperplastic thymus. First, we showed that CXCL13 and CCL21, chemokines involved in GC formation, are overexpressed in MG thymus. Second, we demonstrated an increase in pro-inflammatory activity in the thymus from MG patients and its partial normalization by glucocorticoids, as evidenced by gene expression profile. Third, we found that pro-inflammatory cytokines are able to upregulate the expression of AChR subunits in thymic epithelial and myoid cells. Fourth, we showed that the function of T regulatory (Treg) cells, whose role is to downregulate the immune response, is severely impaired in the thymus of MG patients; such a defect could explain the chronic immune activation observed consistently in MG thymic hyperplasia. Altogether, these new data suggest that CXCL13 and CCL21, which are produced in excess in MG thymus, attract peripheral B cells and activated T cells, which are maintained chronically activated in the inflammatory thymic environment because of the defect in suppressive activity of Treg cells. Presence of AChR in the thymus and upregulation of its expression by the pro-inflammatory environment contribute to the triggering and maintenance of the anti-AChR autoimmune response. [ABSTRACT FROM AUTHOR]

Abstract: Myasthenia gravis (MG), a neuromuscular disease mediated by autoantibodies against the anti-acetylcholine receptor, is often associated with thymic hyperplasia characterized by ectopic germinal centers that contain autoreactive T and B cells. The MG thymus is the site of active neoangiogenic processes including the abnormal development of high endothelial venules (HEVs). This study tested the hypothesis that thymic HEVs and associated chemokines participate in MG pathology by mediating peripheral cell recruitment to the MG thymus. We observed that the number of HEVs positively correlated with the degree of thymic hyperplasia. Testing various chemokines, we demonstrated that thymic HEVs selectively expressed SDF-1 mRNA and presented SDF-1 protein on the lumen side. Antigen presenting cells (APCs) such as monocytes/macrophages, dendritic cells (DCs) and B cells expressing SDF-1 receptor CXCR4 were detected inside and around thymic HEVs. In the periphery, CXCR4 expression was especially reduced on myeloid DCs (mDCs). In parallel, the number of mDCs was decreased suggesting a recruitment of these cells from the periphery to MG thymus. Corticosteroid treatment normalized the number of HEVs and may thus decrease the recruitment of peripheral cells. Indeed, it restored the level of CXCR4 on peripheral mDCs and the number of peripheral mDCs. Altogether, our results suggest that HEV development and engagement of SDF-1 contribute to MG pathology by recruitment of peripheral B cells and APCs to the MG thymus. [Copyright &y& Elsevier]

Abstract: This review is dedicated to John Newsom-Davis, who was an exceptional colleague and friend, always exchanging ideas with respect and consideration. We shall not forget his involvement and passion in search for the truth on the role of thymectomy in the management of Myasthenia Gravis (MG). In this short review, we shall summarize what we learnt from DNA microarrays applied to MG thymus. We shall focus on three main comparisons of the thymic transcriptomes: 1) highly hyperplastic MG patients versus non-MG adults; 2) corticosteroid-treated versus untreated seropositive MG patients; and 3) seronegative versus seropositive MG patients. [Copyright &y& Elsevier]