PATHOLOGY RESEARCH AND PRAcnCE © Urban & Fischer Verlag http://wwN.urbanfischer .deljournalslprp The Role of T-Cells in the Initiation of Autoantibody Responses in Thymoma Patients Angela Vincent and Nick Willcox Neurosciences Group, Department of Clinical Neurology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, U.K. Summary Thymomas are associated with several different neuro- logical disorders. Highly specific autoantibodies direct- ed 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 direct- ed against cell surface antigens, and are directly pathogenic, while others are specific for intracellular antigens which are probably not accessible to antibo- dies in vivo. Moreover, the intact antigens do not appear to be present in the tumour itself. A hypothesis to ex- plain the role of the thymoma in inducing the autoim- munity must also account for the fact that the autoim- mune disorders do not necessarily remit after thymo- mectomy, and that in some cases they only begin sever- al 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 re- sults in release of other antigens, both cytoplasmic and membranous, leading to uptake and presentation by class II positive antigen presenting cells, including anti- gen-specific B-cells. Only when antigen, class Il-re- stricted helper T-cells and the specific B-cells are pre- sent together, in local lymph nodes, will the characteris- tic high affinity autoantibodies result. Of these, only those against cell surface antigens will be pathogenic. Key words: Thymus - Thymoma - Paraneoplastic - Autoimmunity - Cytotoxic Pathol. Res. Pract. 195: 535-540 (1999) Paraneoplastic Autoimmune Disorders with Thymomas Thymomas are the tumours with the highest inci- dence of well-defined autoimmune disorders. About 5- 10% of all thymoma patients have bone marrow aplasias and/or hypogammaglobulinaemia, both of which apparently have an autoimmune basis [23}. An- other 30-50% have myasthenia gravis (MG), some have acquired neuromyotonia , and other conditions such as stiff-person syndrome, limbic encephalitis, and periph- eral neuropathies have also been reported [20}. In addi- tion, several of these conditions can coexist in the pres- ence of a thymoma and myasthenia (Fig la) . By con- trast, although small cell lung cancer and gynaecologi- cal tumours also associate with specific neurological disorders, these occur in less than 5% of the tumour pa- tients. These topics are reviewed in more detail else- where [20, 21}. Thymomas are particularly interesting, because they offer clues to the initiating mechanisms in the associat- ed conditions, and perhaps to paraneoplastic and idio- pathic autoimmunity in general. As discussed below, it seems likely that they are the site of autosensitisation and constitute a particularly autoimmunogenic mi- croenvironment [22}. That may be because these corti- cal epithelial tumours usually contain abundant imma- ture thymocytes and developing CD4+ and CD8+T- cells; these T-cells may be actively selected or immu- nised against self antigens. In theory, these tumours could fail to delete, or randomly generate and export, non-tolerant T-cells; however, the narrow spectrum of associated autoantibodies and disorders makes that seem unlikely. Address for correspondence: A. Vincent, Neurosciences Group, Department of Clinical Neurology, Institute of Molec- ular Medicine, John Radcliffe Hospital, Oxford, U.K. 0344-0338/99/195/8-535 $12.00/0