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in Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice1
,
Departments of
*
Internal Medicine and
Medical Microbiology and Immunology, University of Missouri School of Medicine, and
Department of Veterans Affairs Research Service, Columbia, MO 65212
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
1 mRNA
was constitutively expressed in thyroids and spleens of normal
NOD.H-2h4 mice but not other strains of mice. To determine whether
TGF might have a role in SAT, mice were given anti-TGF mAb at
various times during development of SAT. Anti-TGF markedly inhibited
development of SAT and production of anti-mouse thyroglobulin IgG1
autoantibodies. Anti-TGF 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 TGF1
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 TGF1. TGF1 protein expression in the thyroid
correlated with SAT severity scores, and administration of
anti-TGF inhibited TGF1 protein expression in both the
thyroid and spleen. TGF1 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 TGF1 protein expression.
Activation of splenic T cells was apparently not inhibited by
anti-TGF, because up-regulation of mRNA for cytokines and other
T cell activation markers was similar for control and
anti-TGF-treated mice. TGF1 may function by promoting
migration to, or retention of, inflammatory cells in the
thyroid.
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