Cell-mediated immunity and immune complexes in thyroid disease

Abstract

As shown diagrammatically in Figure 12, one might postulate that in vivo several immune mechanisms may play separate or associated roles in the pathogenesis of autoimmune thyroid disease. Although relatively little is known concerning the triggering of an autoimmune response, for the sake of simplicity one might say that the initiating reaction is some sort of breakdown in the control mechanism resulting in the proliferation of autoreactive T and B lymphocytes, i.e., a breakdown in immunological tolerance to self. Specifically sensitised B lymphocytes are involved in the production of antibody. The role of thyroid specific autoantibodies has not been firmly established and much evidence argues against their being primarily responsible for the thyroid lesions with the exception of thyrotoxicosis. Transfusion of large quantities of Hashimoto serum to Rhesus monkeys produces no thyroid alteration (Roitt and Doniach, 1960), and although thyroglobulin antibodies in high titre can cross the placenta, thyroiditis is rarely observed in babies of affected mothers (Parker and Beierwaters, 1961). Complement fixing thyroid microsomal antibody has proved to be cytotoxic to trypsinised thyroid cells in culture suggesting that slight surface injury to these cells may allow access of cytotoxic antibody resulting in cell death (Pulvertaft, Doniach and Roitt, 1961; Irvine, 1962). In vivo cytotoxic antibodies may play a secondary role in the potentiation of the disease following an initial damage to the gland (Roitt, Jones and Doniach, 1962). Morphological and immunological observations suggest that cell-mediated immune mechanisms may be involved in the pathogenesis of autoimmune thyroid disease. In vitro tests for CMI such as the migration inhibition test and lymphocyte transformation test suggest that patients with autoimmune thyroid disease possess circulating lymphocytes capable of recognising and responding to thyroid antigens. In vivo, such sensitised lymphocytes could cause thyroid cell damage either through a direct cytolytic action or via the release of lymphokines. A third mechanism which could be of pathogenic significance in vivo is that involving K cells and antibody. The presence of thyroid specific antigen-antibody complexes on the surface of a thyroid epithelial cell renders it highly susceptible to lysis by K cells. Whether in fact such complexes are freely available on the surface can only be speculative, although there is one report in the literature describing distinct electron-dense deposits in the follicular basement membrane of some follicles in Hashimoto thyroid glands resembling the antigen-antibody deposits of immune complex nephropathies. Similarly, the presence of antigen-antibody complexes in antibody excess in the circulation could result in the recruitment of large numbers of K cells with the specificity to destroy antigen-labelled target cells in the thyroid gland. The extent to which K-cell-mediated cytotoxic mechanisms as opposed to T-cell-mediated phenomena are involved in the production of thyroiditis is again speculative although it is of interest that the level of circulating K cells in Hashimoto patients is elevated, whereas the number of T cells appears to be within the normal range. Studies on the cytotoxic activity of lymphoid cells isolated from an infiltrated Hashimoto gland would be of considerable interest. Recently, Evans and Alexander (1972) have described mechanisms of immunologically specific killing of tumour cells by macrophages. Specific killing of tumour cells can be achieved by (i) macrophages from the peritoneal cavity of tumour-immunised mice, (ii) normal macrophages ‘armed’ in vitro by exposure to spleen cells from tumour-immunised mice and by (iii) normal macrophages ‘armed’ in vitro by exposure to the cell-free supernatant obtained when spleen cells from immunised mice are cultured with specific antigen. The role of macrophages in autoallergic thyroid cell damage has not so far been investigated but studies in this area are well merited. In view of the complexity of the immune system, it would seem unlikely that any one immune mechanism is solely responsible for the production of autoimmune lesions. It is more likely that several mechanisms play associated roles in the pathogenesis, the severity of the disease possibly being dependent on the extent to which one of these mechanisms predominates and this in turn may be related to the underlying triggering reaction. Although it is obviously essential in the first instance to characterise the basic mechanisms involved in the production of autoallergic tissue damage, a clear insight into the pathogenesis of thyroiditis cannot really be achieved until there is a better understanding of the nature of the autoimmune response.