Hashimoto's thyroiditis (HT) is one of the most prevalent autoimmune diseases provoked in genetically susceptible individuals by several triggers. Immune-regulatory genes such as HLA, CTLA-4, and PTPN22 play a major role in the pathogenesis of autoimmune thyroiditis. The thyroid-specific gene currently showing the association with HT (and also Graves' disease) is the gene for thyroglobulin (Tg). The VDR gene is another HT predisposing gene, common for other organ-specific autoimmune diseases such as type-I diabetes or Addison's disease. Furthermore, cytokine genes such as IFN-γ, IL-4, or TGF-β indicate the association with the development and severity of HT. A complex interaction between genetic and non-genetic factors results in enhanced thyroid antigen presentation and reduced immune tolerance leading to predominantly Th1-type autoimmunity, thyroid destruction, and clinical disease. The exact mechanisms of initiation and progression of HT are yet to be clarified. This chapter explores the pathogenesis of Hashimoto's disease.
TopIntroduction
Hashimoto’s thyroiditis is the most prevalent autoimmune thyroid disorder, where lymphocytic infiltration of the thyroid gland may be followed by a gradual destruction and fibrous replacement of the thyroid parenchymal tissue. The thyroid gland may or may not be enlarged. There are multiple suggested mechanisms, though not fully understood, by which the pathology of Hashimoto's thyroiditis develops.
Various auto-antibodies may be present against thyroid peroxidase (TPO), thyroglobulin (Tg) and thyroid stimulating hormone (TSH) receptors, although a small percentage of people may have none of these antibodies present. At the same time, as indicated in various twin studies, a percentage of the population may also have these antibodies without developing Hashimoto's thyroiditis. Nevertheless, antibody-dependent cell-mediated cytotoxicity is a substantial factor behind the apoptotic fall-out of Hashimoto's thyroiditis. Activation of cytotoxic T-lymphocytes (CD8+ T-cells) in response to cell-mediated immune response affected by helper T-lymphocytes (CD4+ T-cells) is central to thyrocyte destruction. As is characteristic of type IV hyper-sensitivity, recruitment of macrophages is another effect of the helper T-lymphocyte activation, with Th1 axis lymphocytes producing certain inflammatory cytokines within the thyroid tissue for further macrophage activation and migration into the thyroid gland for direct effect.
In Hashimoto's thyroiditis, the immunological attack appears to be typically aggressive and destructive, rather than stimulatory, as in Graves' disease, and the difference is most likely due to the characteristics of the immune response. Hashimoto's thyroiditis is reported to occur in two varieties, an atrophic variety, perhaps associated with human leukocytic antigen-DR3 (HLA-DR3) gene inheritance, and a goitrous form associated with HLA-DR5 (Zeitlin et al., 2008).
Many of the genes associated with autoimmune thyroid disease (AITD) are also associated with other autoimmune diseases, which highlights a key role for disrupted T-cell central tolerance, antigen monitoring and peripheral immune tolerance in autoimmune onset. In studies of autoimmune hypothyroidism in monozygotic twins, the concordance rate is below 1 and thus, environmental factors are also etiologically important (Brix et al., 2008).