A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes

• Published in: The Journal of clinical investigation 1998-05, Vol.101 (10), p.2268-2277
• Main Authors: Nagvekar, N, Moody, A M, Moss, P, Roxanis, I, Curnow, J, Beeson, D, Pantic, N, Newsom-Davis, J, Vincent, A, Willcox, N
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigen-Presenting Cells - immunology; Antigens, CD - immunology; Autoimmunity - immunology; Clone Cells - immunology; Epitope Mapping; Flow Cytometry; Histocompatibility Antigens Class II - immunology; Humans; Immunohistochemistry; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Molecular Sequence Data; Myasthenia Gravis - immunology; Receptors, Antigen, T-Cell - chemistry; Receptors, Cholinergic - chemistry; Receptors, Cholinergic - immunology; Sequence Analysis, DNA; T-Lymphocytes, Helper-Inducer - immunology; Thymoma - immunology; Thymoma - physiopathology
• ISSN: 0021-9738
• DOI: 10.1172/JCI2068

Myasthenia gravis (MG) is caused by helper T cell-dependent autoantibodies against the muscle acetylcholine receptor (AChR). Thymic epithelial tumors (thymomas) occur in 10% of MG patients, but their autoimmunizing potential is unclear. They express mRNAs encoding AChR alpha and epsilon subunits, and might aberrantly select or sensitize developing thymocytes or recirculating peripheral T cells against AChR epitopes. Alternatively, there could be defective self-tolerance induction in the abundant maturing thymocytes that they usually generate. For the first time, we have isolated and characterized AChR-specific T cell clones from two MG thymomas. They recognize extracellular epitopes (alpha75-90 and alpha149-158) which are processed very efficiently from muscle AChR. Both clones express CD4 and CD8alpha, and have a Th-0 cytokine profile, producing IL-4 as well as IFN-gamma. They are restricted to HLA-DP14 and DR52a; expression of these minority isotypes was strong on professional antigen-presenting cells in the donors' tumors, although it is generally weak in the periphery. The two clones' T cell receptor beta chains are different, but their alpha chain sequences are very similar. These resemblances, and the striking contrasts with T cells previously cloned from non-thymoma patients, show that thymomas generate and actively induce specific T cells rather than merely failing to tolerize them against self antigens.