Scenarios for Autoimmunization of T and B Cells in Myasthenia Gravis

Abstract

We have studied responses in thymoma patients to interferon-alpha and to the acetylcholine receptor (AChR) in early-onset myasthenia gravis (EOMG), seeking clues to autoimmunizing mechanisms. Our new evidence implicates a two-step process: (step 1) professional antigen-presenting cells and thymic epithelial cells prime AChR-specific T cells; then (step 2) thymic myoid cells subsequently provoke germinal center formation in EOMG. Our unifying hypothesis proposes that AChR epitopes expressed by neoplastic or hyperplastic thymic epithelial cells aberrantly prime helper T cells, whether generated locally or infiltrating from the circulation. These helper T cells then induce antibody responses against linear epitopes that cross-react with whole AChR and attack myoid cells in the EOMG thymus. The resulting antigen-antibody complexes and the recruitment of professional antigen-presenting cells increase the exposure of thymic cells to the infiltrates and provoke local germinal center formation and determinant spreading. Both these and the consequently enhanced heterogeneity and pathogenicity of the autoantibodies should be minimized by early thymectomy.

Cellular and genetic mechanisms of self tolerance and autoimmunity

“…Each of the checkpoints described above deals with self-reactive receptors generated by V(D)J recombination in the primary lymphoid organs; however, self-reactive BCRs are also generated in a second wave of receptor-gene diversification through somatic hypermutation in germinal-centre follicles of peripheral lymphoid tissues 30,83,84 (Fig. 2).…”

“…A less-defined abnormality of medullary thymic epithelium appears to be responsible for myasthenia gravis, where hyperproliferative or neoplastic thymic epithelial cells that display subunits of the acetylcholine receptor activate T cells and precipitate the formation of circulating anti-acetylcholine receptor autoantibodies 30 . Surgical removal of the thymus in some cases cures the autoimmunity.…”

“…Germinal centres and hypermutated, autoantigenspecific BCRs form in ectopic sites immediately adjacent to sources of autoantigen in a range of human autoimmune diseases 30,87 , as well as arising in lymph nodes that drain organs affected by autoimmunity in experimental animals 88 .…”

“…Second, the follicular pathway of B-cell differentiation generates longlived plasma cells and memory cells, which can continue to produce antibody indefinitely 85 . Third, autologous DNA, an important selfantigen target in SLE, is presented by the numerous apoptotic cells 86 in germinal centres, and organ-specific self components are trapped and displayed as immune complexes on follicular dendritic cells in autoimmune disease 30,87 , where they represent a powerful potential stimulus for autoantibody production.…”

Effect of complement and its regulation on myasthenia gravis pathogenesis

“…The initial trigger of MG is not known, but extensive literature points towards the thymus as a site of disease initiation given its central role in immune tolerance [85,86] The mechanism for autosensitization of the helper T cells appears to fall to binding of antibody to the AChR expressed myoid and epithelial cells followed by complement-mediated lysis of the myoid cells with subsequent generation of germinal centers [87]. Early-onset MG patients demonstrate evidence of complement activation in thymus with C1q, C3b and C9 deposition.…”