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CHISTIAKOV
Immunogenetics of Hashimoto's thyroiditis.Chistiakov
DA.
"Hashimoto's thyroiditis (HT) is an organ-specific T-cell mediated disease. It is a complex disease, with a strong genetic component. To date, significant progress has been made towards the identification and functional characterization of HT susceptibility genes. In this review, we will summarize the recent advances in our understanding of the genetic input to the pathogenesis of HT."
"Iodine is a necessary component of normal thyroid hormonogenesis. Incorporation of iodine into thyrosine residues of Tg leads to the formation of mono-iodotyrosine and di-idothyrosine derivates that subsequently undergo an oxidative coupling event resulting in the producing of T3 and T4. Iodine can promote antithyroid immunity in a number of ways. Several studies suggest that iodination of Tg is crucial for recognition by Tg-reactive T cells. Iodine excess can affect the Tg molecule directly, creating new epitopes or exposing "cryptic" epitopes. It has been demonstrated that a highly iodinated thyroglobulin molecule is a better immunogen than Tg of low iodine content. Therefore, highly iodinated Tg may facilitate antigen uptake and processing by APC. Additionally, high doses of iodine were shown to directly affect macrophages, dendritic cells, B and T lymphocytes, resulting in stimulation of macrophage myeloperoxidase activity, acceleration of the maturation of dendritic cells, increasing the number of circulating T cells and stimulating B cell immunoglobulin production. Excessive amounts of iodide ion are rapidly oxidized by TPO, thereby generating excessive amounts of reactive intermediates such as hypoiodous acid and oxygen radicals. These oxidative species damage thyrocyte cell membrane by oxidation of membrane lipids and proteins causing thyrocyte necrosis. The state of severe iodine deficiency itself namely leads to a lowering of thyroid autoimmunity and an immunodeficient state in autoimmune-prone BB-DP rats. This hampers the autoreactive T-cell generation and autoantibody production. A lower degree of Tg iodination also makes this molecule less antigenic."
"Thyroglobulin, the main protein synthesized in the thyroid, serves both in the synthesis and in the storage of thyroid hormones. Human Tg molecules contain at least four thyroid hormone synthesis sites from the iodinated tyrosine residues at positions 5, 2553, 2567 and 2746. The hormone synthesis sites and the iodine content of Tg play an important role in its autoantigenicity. Tg is one of the major autoantigens in thyroid autoimmunity and serologic studies have shown that there are at least 40 antigenic epitopes on human Tg. Tg-antibodies are detected in almost all patients with AITD. Anti-thyroglobulin antibodies were also reported in up to 27% of normal individuals. However, numerous studies have clearly shown that the epitope recognition pattern of the natural anti-Tg antibodies is different from that of AITD-associated anti-Tg antibodies. Most studies have demonstrated a restricted epitope recognition pattern of AITD subjects by anti-Tg antibodies, in contrast to polyclonal reactivity observed with anti-Tg antibodies from healthy individuals. Human or mouse Tg immunization induces experimental autoimmune thyroiditis (EAT) in mice. The EAT induction is HLA-dependent implying an interaction between the Tg molecule and the MHC glycoproteins. In addition, alterations to Tg could explain interactions between genetic and environmental factors in the aetiology of HT."
"Thyroid peroxidase is another significant autoantigen in the thyroid of patients affected with HT and AITD. This enzyme catalyses the oxidation of iodine to an iodinating species that forms iodotyrosines in a Tg molecule and subsequently iodotyrosines. TPO antibodies are heterogeneous. To date, around 180 human TPO antibodies have been cloned and sequenced. This allows for the possible identification of major features of the TPO-directed antibodies repertoire during AITD. In Graves' disease patients, heavy chain VH domains of anti-TPO antibodies preferentially use D proximal IGHV1 genes. IGHV3 genes, mainly located in the middle of the immunoglobulin heavy chain gene (IGH) cluster on chromosome 15q11, characterize HT patients more frequently. A large proportion of the anti-TPO heavy chain VH domain comes about following a VDJ recombination process that uses inverted D genes." "Autoantibodies against other thyroid-specific antigens such as thyrotropin receptor and sodium iodide symporter were also found in serum of HT patients. However, these antibodies occur at low frequency and do not appear to contribute any diagnostic power for HT."
"In common with probably all autoimmune disorders, the harmful interaction between internal (genetic) and external (environmental and endogenous) factors is required to initiate Hashimoto's disease. Environmental triggers of HT include iodine intake, bacterial and viral infections, cytokine therapy and probably pregnancy. The role of dietary iodine is well defined in epidemiological studies and in animal models and seems to be the most significant environmental factor to induce thyroiditis."
"AITD can be initiated in individuals genetically predisposed to AITD by non-genetic (environmental) triggers such as dietary iodine, infection, pregnancy, cytokine therapy. This interaction leads to different clinical phenotypes of thyroid autoimmunity such as Graves' disease, Hashimoto's thyroiditis or production of thyroid antibodies. HT and GD are two distinct but related clinical outcomes of AITD. It seems that both thyroid diseases have common pathogenic mechanisms as their initial steps including breakdown of the immune tolerance and accumulation of T lymphocytes in the thyroid gland."
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