Autoimmune thyroid diseases: genetic susceptibility of thyroid‐specific genes and thyroid autoantigens contributions

Abstract

Autoimmune thyroid diseases are common polygenic multifactorial disorders with the environment contributing importantly to the emergence of the disease phenotype. Some of the disease manifestations, such as severe thyroid-associated ophthalmopathy, pretibial myxedema and thyroid antigen/antibody immune complex nephritis are unusual to rare. The spectrum of autoimmune thyroid diseases includes: Graves' disease (GD), Hashimoto's thyroiditis (HT), atrophic autoimmune thyroiditis, postpartum thyroiditis, painless thyroiditis unrelated to pregnancy and thyroid-associated ophthalmopathy. This spectrum present contrasts in terms of thyroid function, disease duration and spread to other anatomic location. The genetic basis of autoimmune thyroid disease (AITD) is complex and likely to be due to genes of both large and small effects. In GD the autoimmune process results in the production of thyroid-stimulating antibodies and lead to hyperthyroidism, whereas in HT the end result is destruction of thyroid cells and hypothyroidism. Recent studies in the field of autoimmune thyroid diseases have largely focused on (i) the genes involved in immune response and/or thyroid physiology with could influence susceptibility to disease, (ii) the delineation of B-cell autoepitopes recognized by the main autoantigens, thyroglobulin, thyroperoxidase and TSH receptor, to improve our understanding of how these molecules are seen by the immune system and (iii) the regulatory network controlling the synthesis of thyroid hormones and its dysfunction in AITD. The aim of the present review is to summarize the current knowledge regarding the relation existing between some susceptibility genes, autoantigens and dysfunction of thyroid function during AITD.

Hashimoto's Disease

“…In fact, they are localized in chromosomal regions found linked using the genome scan approach (2q33 and 8q23 respectively). At the statistical level, these two regions share a significant value of lod score (MLS= 4.2 and 3.77 for 2q33 and 8q23 respectively) (reviewed in Hadj Kacem et al, 2009).We have to get in mind that the chromosomal region 2q33 (harboring CTLA-4 gene) was linked with positive antibody rather than HT.…”

“…There were two areas of linkage to HT, designated HT-1 and HT-2 on chromosome 13q32 and 12q22, respectively (Tomer et al, 1999). Since, many genome screenings were conducted and revealed regions with suggestive linkage (MLS<3.3), except the chromosomal region 8q23-q24 which has given a value of MLS=3.77 (Reviewed in Hadj Kacem et al, 2009). Therefore, it could be considered as "significantly linked" to HT.…”

“…Comprehension of physiopathological mechanism behind has been improved over the last few decades. In the literature, a number of excellent reviews have been published on the genetic background of AITDs (Eschler et al, 2011;Hadj Kacem et al, 2009). However, there is still a paucity concerning HT.…”

No major impact of insertion/deletion polymorphism of the angiotensin-converting enzyme gene on thyroid-associated ophthalmopathy

“…TO is seen most frequently in relatives of TO patients. It is documented that candidate genes including human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), intercellular adhesion molecule-1 (ICAM-1), and thyroid-stimulating hormone receptor (TSHR) play roles in the pathogenesis of TO (3). In orbital soft tissue, TO-induced chronic inflammation leads to edema, glucosaminoglycan synthesis, proliferation of fibroblasts and adipocytes (early phase), and fibrosis (late phase).…”

Immune Profile and Signal Transduction of T-Cell Receptor in Autoimmune Thyroid Diseases

“…Differently, within the group of autoimmune thyroid diseases, Graves' disease (GD) occurs in a unique situation in autoimmunity, with dysfunction in T and B cells, however producing an autoantibody IgG, with great affinity to specific regions of the TSH (TSH-R) 96 receptor that determines hyperfunction, hypertrophy of the thyroid follicle, abnormal dynamics of activation, or even blockade of TSH-R and hyperthyroidism itself (Hadj-Kacem, Rebuffat et al, 2009). Production of TRAb stimulator and sometimes blocker is an expression of the break of tolerance to TSH-R specific epitopes with biological effect similar to TSH, yet with longer lasting and slower signaling to thyrocytes.…”