Molecular Mechanisms in Autoimmune Thyroid Disease

Abstract

The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto's thyroiditis). Hashimoto's thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases. This review summarizes the most common genetic, epigenetic, and environmental mechanisms involved in autoimmune thyroid disease.

Keywords: Graves-Basedow; Hashimoto; autoimmunity; environmental; epigenetic; genetic; pathogenesis; thyroid.

Figure 1

PRISMA flow diagram. Method for the selection of articles for this review.

Figure 2

Summary of the mechanisms leading to AITD in the non–obese diabetic (NOD) mice. After the administration of 0.05% NaI in the drinking water, there were findings of chronic inflammation in the following 3–4 weeks. Subsequently, the synthesis of autoantibodies increases (initially against Tg and later against TPO). At the same time, there is an increase in the secretion of proinflammatory cytokines and cell infiltration [mediated initially by TL (CD4+) and then by TL (CD8+), macrophages, and, finally, by BL, although other cells, such as TL, NK, and DCs, among others, also participate in this process]. Additionally, there is an increased production of ADCC, perforin/granzyme, IFN–γ, and TNF–α. TReg depletion increases the severity of the immune response, with loss of immune tolerance and the development of AITD. Abbreviations: ADCC: antibody dependent cell cytotoxicity, BL: B lymphocyte, DCs: dendritic cells, NK: natural killer, Tg: thyroglobulin, TL: T lymphocyte, TPO: thyroid peroxidase, Treg: regulatory T lymphocyte.

Figure 3

Interaction between genetic susceptibility and epigenetic factors in AITD. Genetic risk by itself confers a low-moderate risk for AITD; however, risk is increased when there is synergy with epigenetic modifications of regulatory regions that are capable of controlling gene expression. Abbreviations: AITD: autoimmune thyroid disease, XCI: X-chromosome inactivation.

Figure 4

Summary of the mechanisms that lead to AITD. AITD is the product of multiple environmental factors that act on the basis of genetic susceptibility, together with some epigenetic mechanisms, leading to a loss of immune tolerance, with destruction of thyroid tissue and increased synthesis and secretion of autoantibodies. Finally, the Th1:Th2 imbalance directs the clinical and biochemical manifestations towards HT or GBD. Abbreviations: AITD: autoimmune thyroid disease, GBD: Graves-Basedow disease, HT: Hashimoto’s disease, Tg: thyroglobulin, TgAb: Tg autoantibodies, TPO: thyroid peroxidase, TPOAbs: TPO autoantibodies, TRAbs: thyroid stimulating hormone receptor autoantibodies.