Mechanisms of Thyroid Autoimmunity

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Predisposition

It is well established that a complex interplay of diverse environmental and genetic susceptibility factors interact in predisposing an individual to autoimmune thyroid disease (fig. 1). Moreover, the contribution that each factor makes varies from patient to patient, and as yet there are no clear genotype-phenotype correlations. We have shown that polymorphisms in the thyroid stimulating hormone receptor (TSH-R) are associated with Graves' disease but not autoimmune

Genetic factors HLA CTLA-4 PTPN 22 TSH-R

Others: ? CD40

Environmental factors

? vitamin

Genetic factors HLA CTLA-4 PTPN 22 TSH-R

Others: ? CD40

? vitamin

Iodine

Stress

Irradiation

Smoking

Drugs

Others: ? infection

Clinical autoimmune thyroid disease

Iodine

Stress

Irradiation

Smoking

Drugs

Others: ? infection

? toxins

Clinical autoimmune thyroid disease

Endogenous factors Female sex Age '

Pregnancy Others: ? birthweight

? fetal microchimerism ? response to stress

Fig. 1. Interaction of factors predisposing to autoimmune thyroid disease.

hypothyroidism [2]. The other known genetic loci associated with thyroid autoimmunity, namely HLA, CTLA-4 and PTPN22, are shared between these 2 thyroid conditions, as well as many other autoimmune diseases [reviewed in 3]. Several environmental factors have been delineated but some of these remain controversial and of unknown action, such as smoking and stress [4, 5]. Evidence for the involvement of infections is lacking (thyroid autoimmunity rarely follows subacute thyroiditis, for instance), but there does appear to be an association between congenital rubella infection and subsequent thyroid autoimmunity [6].

Failure of Self-Tolerance

Genetic and environmental factors predispose to autoimmune disease through their effects on immunological tolerance (table 1). It is well established that most autoreactive T cells are deleted in the thymus, and this involves the intrathymic expression of self-antigens during development. This process is most clearly demonstrated in autoimmune polyglandular syndrome type 1, in which there is a defect in the autoimmune regulator (AIRE) gene, which prevents transcription of self antigens in medullary thymic epithelial cells and, as a result, there is a failure to negatively select organ-specific thymocytes [7]. However, the main autoimmune endocrinopathies in this syndrome do not include thyroid disease, although there is a slightly higher frequency of this disorder than expected in patients with the syndrome. Therefore, the expression of

Table 1. Mechanisms to ensure immunological self tolerance and prevent autoimmune disease

Deletion or anergy of autoreactive T and B cells during fetal life

Peripheral tolerance, including deletion or anergy of T cells by antigen presentation in the absence of a co stimulatory signal Sequestration of autoantigen, including tissue expression of Fas ligand (immunological privilege) causing apoptosis in Fas-expressing autoreactive T cells Clonal ignorance; absence of activated CD4+ cells required for CD8+ T or B cells Active suppression of autoreactive T cells; particularly by CD4 +, CD25 + T regulatory cells Mutual inhibition of Th1 and Th2 cytokine pathways thyroid autoantigens in the thymus may be regulated by other transcription factors, or other mechanisms may be important in regulating tolerance.

One likely additional mechanism involves T regulatory cells. Once again, a disorder caused by a single gene defect in man in revealing in illustrating the importance of this type of tolerance mechanism. In the IPEX (immune dysreg-ulation, polyendocrinopathy, enteropathy, X-linked) syndrome, there is a defect in the FOXP3 gene which encodes a transcription factor essential for the function of CD4+, CD25+ T cells with immunoregulatory properties, and such patients have a fatal disorder with severe autoimmune disease including that against the thyroid [8]. In fact, the existence of T regulatory cells was first defined by elegant experiments on experimental autoimmune thyroiditis induced in rats by neonatal thymectomy and sublethal irradiation [9]. Disease could be prevented by transfer of cells from healthy donors, which subsequently led to identification of this important CD4+, CD25+ subset.

Another clinical illustration of this pathway appears to be the common autosomal dominant condition, autoimmune polyglandular syndrome type 2, which of course includes thyroid autoimmunity as 1 of the 3 cardinal endo-crinopathies, alongside Addison's disease and type 1 diabetes mellitus. Although there are no quantitative differences, CD4+, CD25+ T cells from patients with this syndrome have markedly reduced suppressive capacity compared to controls or patients with isolated endocrinopathies [10]. Disturbances in these or other populations of immunoregulatory T cells may be responsible to 'reconstitution' Graves' disease, in which thyroid disease appears as lymphocyte counts rise in patients with previously low counts, such as occurs after HAART treatment in HIV disease [11].

A final important pathway for T cell tolerance is likely to be induced by the expression of HLA class II molecules on thyroid epithelial cells in response to 7-interferon released by any local inflammation. In the absence of costimula-tion mediated through CD80 or CD82 (which thyroid cells do not express), antigen presented by class II thyroid cells is able to induce anergy and tolerance in naive T cells, rather than their activation [12]. Unfortunately, in an already initiated autoimmune response, in which autoreactive, memory T cells have been exposed to costimulation delivered by professional antigen-presenting cells, HLA class II + thyroid cells are able to induce further T cell activation, leading to exacerbation of the autoimmune response. Overall the relative importance of these and other tolerogenic pathways in thyroid autoimmunity is unclear, but unlikely to be similar in all patients.

Mechanisms of Disease

Although thyroglobulin (TG) and thyroid peroxidase (TPO) autoantibodies are useful diagnostic markers, their role in causing tissue injury, at least primarily, is minimal. They may, however, be important in causing secondary damage, through antibody dependent cellular cytotoxicity (ADCC) or complement fixation (TPO antibodies) [13]. TSAb are obviously central to the pathogenesis of Graves' disease and there have been several recent studies which have shown the potency of monoclonal TSAb in causing thyroid cell activation [14]. Indeed, there is now a real issue over the exact relationship between the hyperthy-roidism and the thyroid lymphocytic infiltrate which is so frequently accepted as an inevitable accompaniment of Graves' disease [15]. Perhaps Graves' disease is a 'pure' B cell-mediated disorder that is very frequently associated with T cell-dependent thyroiditis, and whether one leads to the other becomes a critical question. The main mechanism of thyroid destruction in autoimmune thyroid disease is probably T cell-mediated cytotoxicity, but a number of pathways of tissue injury are involved (fig. 2) [15].

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