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Recent advances in the immunopathogenesis and genetics of autoimmune thyroid disorders

Graves' disease (GD) and Hashimoto's thyroiditis (HT) represent two distinct, highly prevalent, interrelated autoimmune traits that affect thyroid gland. In addition to the well established role of the environmental modifiers, major histocompatibility complex and CTLA4 region, a number of other non- HLA immunological pathways exert important influences on the phenotypic diversity that is seen among polygenic autoimmune disorders. Traditionally, induction, progression and outcome of HT or GD are related to the predominance of TH1 or TH2 cytokines, respectively, resulting ultimately in differentially deregulated CD95-mediated thyrocyte apoptosis. Recently, this basic paradigm has been substantially expanded and refined by evidences postulating complex interplay between the innate, adaptive, and regulatory components of the immune system, centered around the role of TH17 gateways to autoimmunity, mechanisms of lymphoid neogenesis, and the role of tolerogenic mechanisms, particularly CD4+CD25+ regulatory T-lymphocytes in disease pathogenesis. Parallelly, we have witnessed the emergence of new candidate genes and diverse regulatory pathways, encompassing thyroid autoantigens and immunoregulatory properties of the chemokine network, non-receptor protein tyrosine phosphatases, nuclear factor-κ B signaling module and the NR1 subfamily of transcription factors, led by a growing list of non-classic immunosuppressive, regulatory and pro-tolerogenic effects of the vitamin D receptor endocrine system. Due to the pivotal role played by these molecules and pathways in the immune cell biology, much emphasis has been placed on search for genetic traits that modify phenotypic properties, disease susceptibility and severity. Here, the most recent advances that extend our understanding of how these network signaling modules function in a combinatorial manner to coordinately affect the expression of autoimmune phenotypes are described. Recent highlights and limitations are reviewed in the areas of molecular pathogenesis, gene expression studies and genetic epidemiology, with particular emphasis given to the genetic associations claimed for autoimmune thyroid disorders.

Thyroiditis, Autoimmune, Graves Disease, Immune System, Etiology, Genes, Cytokines

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