Autoimmune Thyroid Disease: Further Developments in Our Understanding*

Abstract

The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

“…H-2S and H-2q have been reported to be high-responder strains in terms of their levels of anti-TSHR antibodies when immunized with soluble human TSHR (5). This possibility would be consistent with the prevalence of certain HLA haplotypes (B35) in GD but not Hashimoto thyroiditis (31 (19)(20)(21), its biological significance has never been systematically examined and shown to be a primary causative factor, rather than a factor secondary to cytokine production by invading immune cells (22). A recent report by Sopedra et al (33), which showed the hyperinducibility of HLA class II expression in thyroid follicular cells from patients with GD, supports a possible role for class II molecules in the development of GD; our present data directly implicate aberrant class II expression as a potential causal factor in the development of stimulating TSHRAbs.…”

“…Thus, several studies have implicated class I as an important component in the development of autoimmune thyroid disease and in the action of methimazole, a drug used to treat GD (14)(15)(16)(17)(18). In addition, aberrant class II expression, as well as abnormal expression of class I molecules, is evident on thyrocytes in autoimmune thyroid diseases (19)(20)(21), although the cause and role of aberrant class II in disease expression remains controversial (22). The sum of these observations raised the possibility that immunization with full-length TSHR, in a functional conformation but in the context of abnormal MHC class I or class II expression, might lead to the development of GD.…”

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

“…However, despite their contrasting clinical presentations, GD and HT share many features in common, mainly, infiltration of the thyroid by T cells and production of antithyroid autoantibodies [antithyroglobulin and anti-thyroid peroxidase (TPO) antibodies] (3)(4)(5). AITDs are complex diseases, which are caused by an interaction between susceptibility genes (6)(7)(8) and nongenetic factors, such as infection (9)(10)(11)(12). This paradigm is based on solid epidemiologic evidence demonstrating a genetic predisposition to AITDs, including: (i) familial clustering (13); (ii) a sibling risk ratio ( s ) of Ͼ10 (7,14); (iii) a high concordance rate in monozygotic twins when compared with dizygotic twins (15)(16)(17)(18); and (iv) the presence of thyroid autoantibodies, which are markers of subclinical AITD, in up to 50% of siblings of patients with AITD (19,20).…”

Association studies of interleukin-8 gene in Graves’ disease and Graves’ ophthalmopathy

“…Many studies have shown that IL-8 participates in many diseases such as bronchial asthma, multiple sclerosis, systemic sclerosis, and psoriasis. GD, with the thyroid as a major target for autoimmunity, is characterized by reactivity to self-thyroid antigens and by lymphocyte infiltration of the gland [27][28][29][30]. Although the etiology of GD remains unclear, it is believed to be caused by a complex interaction between genetic and environmental factors.…”