Dual Roles for IFN-γ, But Not for IL-4, in Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Abstract

Spontaneous autoimmune thyroiditis (SAT) is an organ-specific autoimmune disease characterized by chronic inflammation of the thyroid by T and B lymphocytes. To investigate the roles of Th1 and Th2 cytokines in the pathogenesis of SAT, IFN-γ−/− and IL-4−/− NOD.H-2h4 mice were generated. IL-4−/− mice developed lymphocytic SAT (L-SAT) comparable to that of wild-type (WT) mice. They produced little anti-mouse thyroglobulin (MTg) IgG1, but had levels of anti-MTg IgG2b comparable to WT mice. Compared with WT mice, IFN-γ−/− mice produced significantly less anti-MTg IgG1 and IgG2b. Absence of IFN-γ resulted in abnormal proliferation of thyroid epithelial cells with minimal lymphocyte infiltration. Thyroids of IFN-γ−/− mice had markedly reduced B lymphocyte chemoattractant expression, B cell and plasma cell infiltration, and decreased MHC class II expression on thyrocytes compared with WT mice. Adoptive transfer of WT splenocytes to IFN-γ−/− mice restored the capacity to develop typical L-SAT, enhanced anti-MTg IgG1 and IgG2b production, up-regulated MHC class II expression on thyrocytes and decreased thyrocyte proliferation. These results suggest that IFN-γ plays a dual role in the development of SAT. IFN-γ is required for development of L-SAT, and it also functions to inhibit thyroid epithelial cell proliferation.