Polymorphisms of this gene are associated with a 20–30% increase in translation of CD40 mRNA transcripts in patients with AITDs ( 23). Currently, both HLA-DR3 and CTLA-4 are considered to be the main genes associated with the development of AITD.ĬD40 is expressed on thyroid follicular cells and on B cells. This genetic abnormality also stimulates higher levels of thyroid-specific autoantibodies and clinical thyroid disease when interacting with other loci ( 4, 20– 22). For instance, in a study of 379 patients with GD in the United Kingdom, 42% had a particular allele (G allele) of the CTLA-4 gene compared to 32% of the controls ( 20). Polymorphism in certain alleles of CTLA-4 predispose to GD and HT ( 17– 21). There are associations with a number of immune-related genes, other than HLA genes, which have also been found in many other ADs and presumably underpin the inherited susceptibility to autoimmunity. Likewise, atrophic and subacute thyroiditis are strongly associated with HLA-B35 in many ethnic groups while painless thyroiditis is associated with HLA-DR3 ( 11, 12, 16).
There are, in turn, studies that suggest alleles from HLA-DQ might be genetic markers that confer resistance to the development of AITD ( 15). They were able to identify the thyroglobulin peptides that could be presented by HLA-DR pockets containing arginine at position beta 74 to T cells and, therefore, initiate the autoimmune process ( 14). ( 13, 14) reported similar findings for this disease. ( 11) identified arginine at position 74 of the HLA-DRβ1 (DRβ-Arg74) as the critical DR amino acid (a.a) conferring susceptibility to GD, and glutamine at position 74 as a protective a.a. In fact, it has been discovered that HLA-DR3 and HLA-DR5 are linked to HT and provide a greater risk for the disease ( 4). HLA-DR locus plays an important role since HLA-DR3 is present in up to 55% of the patients with GD compared to the 30% prevalence in the general population ( 4).
Thus, the pathological findings for both GD and HT are similar, and are associated with particular HLA-B and HLA-DR, suggesting that inherited risk factors are important in the development of these entities ( 11, 12). The association between HLA alleles and AITD is well known, but the primary etiological variant in this region is still uncertain ( 1). These genes include both immunological-synapse genes and regulatory T–cell genes (e.g., FOXP3, CD25) ( 3). For instance, it is calculated that up to 80% of the susceptibility for the development of GD is secondary to the presence of determined genes ( 10). In fact, a number of immune-related genes have been implicated in genetic susceptibility to AITD. Genetics play a key role in the pathogenesis of AITD. The main environmental factors are smoking, stress, and iodine consumption ( 6). Candidate genes include immunoregulators and others specific to the thyroid (e.g., TSH receptors, thyroglobulin, etc.).
Some of these genes are specific for GD and HT while others are mutual for both diseases, which indicates a genetic predisposition shared in these processes together. Generally, while T lymphocytes are the main cell type infiltrating the gland in HT, a B cell response predominates and determines the presence of GD ( 7).Īs with other ADs, there is a multifactorial etiology with a complex interaction of environmental factors in genetically susceptible individuals ( 8) ( Figure 1). The injury is caused when the autoantibodies and/or sensitized T cells react with the thyroid cells causing the inflammatory reaction and, in some cases, cell lysis ( 6). The lymphocytic infiltration causes tissue damage and alters the function of the thyroid gland. They reflect the loss of immunological tolerance and share the presence of cell and humoral immune response against antigens from the thyroid gland with reactive infiltration of T cells and B cells, autoantibody generation and, subsequently, the development of clinical manifestations ( 4, 5). HT and GD are the major causes of hypothyroidism and hyperthyroidism, respectively ( 3). AITD include Graves’ Disease (GD) and Hashimoto Thyroiditis (HT), among others.
Autoimmune thyroid diseases (AITD) are the most prevalent organ-specific autoimmune diseases (ADs) and affect 2 - 5% of the population ( 1) with great variability between genders (i.e., women 5–15% and men 1–5%) ( 2).
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