Regulatory and Pathogenic Mechanisms in Human Autoimmune Myasthenia Gravis

• Published in: Annals of the New York Academy of Sciences Vol. 1132; no. 1; pp. 135 - 142
• Main Authors: Le Panse, Rozen, Cizeron-Clairac, Géraldine, Cuvelier, Mélinée, Truffault, Frédérique, Bismuth, Jacky, Nancy, Patrice, De Rosbo, Nicole Kerlero, Berrih-Aknin, Sonia
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.06.2008; Wiley
• Subjects: Adrenal Cortex Hormones - therapeutic use; Age Distribution; anti-AChR antibodies; B cells; chemokines; Chemokines - immunology; Chemokines - metabolism; fas Receptor - metabolism; Female; Gene Expression Regulation - drug effects; germinal center; Humans; Life Sciences; Male; Myasthenia Gravis - complications; Myasthenia Gravis - immunology; Myasthenia Gravis - metabolism; Myasthenia Gravis - pathology; Oligonucleotide Array Sequence Analysis; T cells; T-Lymphocytes, Regulatory - immunology; thymic hyperplasia; thymic remodeling; Thymus Hyperplasia - complications; Thymus Hyperplasia - epidemiology; Thymus Hyperplasia - pathology; Treg
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1405.019

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.