Role of TGFβ in development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice

Nearly 100% of NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and produce anti-mouse thyroglobulin autoantibodies when they receive 0.05% NaI in their drinking water beginning at 8 wk of age. Our previous studies showed that TGF beta1 mRNA was constitutively expressed in thyroids and spleens of normal NOD.H-2h4 mice but not other strains of mice. To determine whether TGF beta might have a role in SAT, mice were given anti-TGF beta mAb at various times during development of SAT. Anti-TGF beta markedly inhibited development of SAT and production of anti-mouse thyroglobulin IgG1 autoantibodies. Anti-TGF beta was most effective in inhibiting SAT when given during the time thyroid lesions were developing, i.e., starting 4 wk after administration of NaI water. The active form of the TGF beta1 protein was present in thyroids of mice with SAT but not in normal NOD.H-2h4 thyroids. However, thyrocytes of normal NOD.H-2h4 thyroids did express latent TGF beta1. TGF beta1 protein expression in the thyroid correlated with SAT severity scores, and administration of anti-TGF beta inhibited TGF beta1 protein expression in both the thyroid and spleen. TGF beta1 was produced primarily by inflammatory cells and was primarily localized in areas of the thyroid containing clusters of CD4(+) T and B cells. Depletion of CD8(+) T cells had no effect on TGF beta1 protein expression. Activation of splenic T cells was apparently not inhibited by anti-TGF beta, because up-regulation of mRNA for cytokines and other T cell activation markers was similar for control and anti-TGF beta -treated mice. TGF beta1 may function by promoting migration to, or retention of, inflammatory cells in the thyroid.