The role of T-cells in the initiation of autoantibody responses in thymomapatients

Thymomas are associated with several different neurological disorders. High ly specific autoantibodies directed against central nervous system and musc le antigens are found in the sera of these patients. These antibodies usual ly have high affinity and specificity for the intact conformation of the an tigen. However, some are directed against cell surface antigens, and are di rectly pathogenic, while others are specific for intracellular antigens whi ch are probably not accessible to antibodies in vivo. Moreover, the intact antigens do not appear to be present in the tumour itself. A hypothesis to explain the role of the thymoma in inducing the autoimmunity must also acco unt for the fact that the autoimmune disorders do not necessarily remit aft er thymomectomy, and that in some cases they only begin several years after the operation. Thymomas often generate large numbers of T-cells that appear to be sensitis ed to self- epitopes in the thymoma. We hypothesise that both cytotoxic and helper T-cells are induced against specific peptides in thymoma, and then move to the periphery where they can persist. At some stage, the cytotoxic T-cells recognise epitopes presented by muscle or CNS tissue, perhaps follo wing minor tissue damage or inflammation with upregulation of class I and/o r accessory molecules. Cytotoxicity results in release of other antigens, b oth cytoplasmic and membranous, leading to uptake and presentation by class II positive antigen presenting cells, including antigen-specific B-cells. Only when antigen, class II-restricted helper T-cells and the specific B-ce lls are present together, in local lymph nodes, will the characteristic hig h affinity autoantibodies result. Of these, only those against cell surface antigens will be pathogenic.