The Role of T-Cells in the Initiation of Autoantibody Responses in Thymoma Patients

Abstract

Thymomas are associated with several different neurological disorders. Highly specific autoantibodies directed against central nervous system and muscle antigens are found in the sera of these patients. These antibodies usually have high affinity and specificity for the intact conformation of the antigen. However, some are directed against cell surface antigens, and are directly pathogenic, while others are specific for intracellular antigens which 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 account for the fact that the autoimmune disorders do not necessarily remit after 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 sensitised 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 following minor tissue damage or inflammation with upregulation of class I and/or accessory molecules. Cytotoxicity results in release of other antigens, both 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-cells are present together, in local lymph nodes, will the characteristic high affinity autoantibodies result. Of these, only those against cell surface antigens will be pathogenic.