Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves’ Disease

Abstract

Graves’ disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments.

Comparative analysis of human leucocyte antigen between idiopathic and anti‐PD‐1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study

“…And those alleles were also reported to be susceptible to rheumatoid arthritis and type 1 diabetes mellitus . The HLA‐DPB1*05:01 allele is also one of the risk alleles in Graves' disease . Therefore, those common HLA alleles seen in other autoimmune diseases suggested an existence of susceptible HLA‐associated autoimmunity in id‐IAD.…”

“…The most well‐known role of HLA molecule is to bind and present epitopes to pathogenic T cells . Autoantigen epitope peptides are presented with HLA on the surface of antigen‐presenting cells in autoimmune diseases. On the other hand, tumour‐associated antigen or neoantigen epitope peptides are presented in malignant diseases .…”

Comprehensive research on thyroid diseases associated with autoimmunity: autoimmune thyroid diseases, thyroid diseases during immune-checkpoint inhibitors therapy, and immunoglobulin-G4-associated thyroid diseases

“…Autoimmune thyroid disease (AITD) is a thyroidspecific autoimmune disease, and Graves' disease (GD) and Hashimoto's thyroiditis (HT) are two major components of AITDs [1][2][3]. When individuals with susceptible genetic background are exposed to environmental factors (e.g.…”

“…When individuals with susceptible genetic background are exposed to environmental factors (e.g. iodine, smoking, infections, stress, and trauma), AITDs may develop [1][2][3] (Fig. 1).…”

2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism

“…Twin studies have shown that 80% of the susceptibility to GD is genetic [12]. There are well-established associations between alleles of the major histocompatibility complex with GD, with susceptibility being carried with HLA-DR3 and HLA-DR4 haplotypes [13]. Other susceptibility loci at which association has been replicated include those at cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-22, basic leucine zipper transcription factor 2, and CD40 [14].…”