Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity

Abstract

Autoimmune thyroid diseases (AITD) are one of the most common organ-specific autoimmune disorders, of which Hashimoto's thyroiditis (HT) and Graves' disease (GD) are 2 of the most common clinical expressions. HT is characterized by hypothyroidism that results from the destruction of the thyroid by thyroglobulin-specific T cell-mediated autoimmune response. In contrast, GD is characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. Cytokines play a crucial role in modulating immune responses that affect the balance between maintenance of self-tolerance and initiation of autoimmunity. However, the role of cytokines is often confusing and is neither independent nor exclusive of other immune mediators. A regulatory cytokine may either favor induction of tolerance against thyroid autoimmune disease or favor activation and/or exacerbation of autoimmune responses. These apparently contradictory functions of a given cytokine are primarily influenced by the nature of co-signaling delivered by other cytokines. Consequently, a thorough understanding of the role of a particular cytokine in the context of a specific immune response is essential for the development of appropriate strategies to modulate cytokine responses to maintain or restore health. This review provides a summary of recent research pertaining to the role of cytokines in the pathogenesis of AITD with a particular emphasis on the therapeutic applications of cytokine modulation.

FIG. 1.

The role of cytokines in EAT. EAT in mice is induced by immunization with mTg emulsified in the presence of Complete Freund's adjuvant. The antigen is taken up by the antigen presenting cells such as DCs, which undergo maturation to become potent antigen presenting cells. These cells present mTg-derived peptides to T cells in the draining lymph nodes. The activated DCs secrete pro-inflammatory cytokines that initiate a T helper response. Based on the type of cytokines secreted by these DCs, a Th1, Th2, or a Th17 response can be initiated. The Th1 cells predominantly secrete IFN-γ and IL-12, whereas the Th2 cells secrete IL-4, and Th17 cells secrete IL-17. The Th1 and Th17 cells have been shown to infiltrate the thyroid resulting in inflammation and ultimately death of the thyrocytes in EAT. EAT, experimental autoimmune thyroiditis; CFA, complete Freund's adjuvant; DCs, dendritic cells; mTg, mouse thyroglobulin; IFN, interferon; IL, interleukin.

FIG. 2.

GM-CSF induces tolerogenic DCs and suppresses EAT. Pro-inflammatory cytokines play a crucial role in the generation of an inflammatory response and the subsequent induction of EAT. Treatment of mice with GM-CSF induces semi-matured tolerogenic DCs that are characterized by the reduced levels of pro-inflammatory cytokines such as IL-1β and IL-12. These tolerogenic DCs, instead of activating pathogenic Teff, induce or expand Tregs that produce IL-10 and TGF-β. These regulatory cytokines counteract the role of the pro-inflammatory cytokines resulting in the suppression/prevention of EAT. GM-CSF, granulocyte-macrophage colony-stimulating factor; Teff, effector T cells; Tregs, regulatory T cells; TGF-β, transforming growth factor-β.