A new murine model of early onset autoimmune thyroiddisease/hypothyroidism and autoimmune exocrinopathy of the salivarygland

摘要

60–70 % of IFN-γ^−/− NOD.H-2h4 mice given NaI-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell hyperplasia/ proliferation (TEC H/P). TEC H/P develops much earlier in CD28^−/− mice and nearly 100 % (both sexes) have severe TEC H/P at 4 months of age. Without NaI supplementation, 50% of 5–6 month old CD28^−/−IfFN-γ^−/− mice develop severe TEC H/P, and 2–3 weeks of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid and normalization of serum thyroxine (T4) levels does not reduce TEC H/P. Activated CD4+ T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for development of severe TEC H/P, as CD40^−/−IFN-γ^−/−CD28^−/− mice develop severe TEC H/P. Accelerated development of TEC H/P inIFN-γ^−/−CD28^−/− mice is a result of reduced Treg numbersas CD28^−/− mice have significantly fewer Tregs, andtransfer of CD28-positive Tregs inhibits TEC H/P. Essentially all femaleIFN-γ^−/−CD28^−/−NOD.H-2h4 mice have substantiallymphocytic infiltration of salivary glands and reduced salivary flow by 6months of age, thereby providing an excellent new model of autoimmuneexocrinopathy of the salivary gland. This is one of very few models whereautoimmune thyroid disease and hypothyroidism develop in most mice by 4 monthsof age. This model will be useful for studying the effects of hypothyroidism onmultiple organ systems.