title: New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland.
abstract: Sixty to seventy percent of IFN-γ(-/-) NOD.H-2h4 mice given sodium iodide (NaI)-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell (TEC) hyperplasia and proliferation (H/P). TEC H/P develops much earlier in CD28(-/-) mice and nearly 100% (both sexes) have severe TEC H/P at 4 mo of age. Without NaI supplementation, 50% of 5- to 6-mo-old CD28(-/-)IFN-γ(-/-) mice develop severe TEC H/P, and 2-3 wk 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 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 in IFN-γ(-/-)CD28(-/-) mice is a result of reduced regulatory T cell (Treg) numbers, as CD28(-/-) mice have significantly fewer Tregs, and transfer of CD28(+) Tregs inhibits TEC H/P. Essentially all female IFN-γ(-/-)CD28(-/-) NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 mo of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 mo of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.
authors: Department of Medicine, University of Missouri, Columbia, MO 65212;
authors: Timothy Daniel
authors: TD
authors: Kayes
authors: Department of Biochemistry, University of Missouri, Columbia, MO 65211; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; and.
authors: Gary A
authors: GA
authors: Weisman
authors: Department of Biochemistry, University of Missouri, Columbia, MO 65211; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; and.
authors: Jean M
authors: JM
authors: Camden
authors: Department of Biochemistry, University of Missouri, Columbia, MO 65211; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; and.
authors: Lucas T
authors: LT
authors: Woods
authors: Department of Medicine, University of Missouri, Columbia, MO 65212;
authors: Cole
authors: C
authors: Bredehoeft
authors: Department of Medicine, University of Missouri, Columbia, MO 65212;
authors: Edward F
authors: EF
authors: Downey
authors: Department of Medicine, University of Missouri, Columbia, MO 65212;
authors: James
authors: J
authors: Cole
authors: Department of Medicine, University of Missouri, Columbia, MO 65212; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212 mullenh@health.missouri.edu.
authors: Helen
authors: H
authors: Braley-Mullen
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D018106:CD28 Antigens / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D006965:Hyperplasia; D007037:Hypothyroidism / Q000209:etiology*; D007371:Interferon-gamma / Q000502:physiology; D007455:Iodine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D012466:Salivary Gland Diseases / Q000209:etiology*; D013601:T-Lymphocytes / Q000502:physiology; D013959:Thyroid Diseases / Q000209:etiology*; D013961:Thyroid Gland / Q000473:pathology; D013974:Thyroxine / Q000097:blood
chemical_list: D018106:CD28 Antigens; D019013:CD40 Antigens; D007371:Interferon-gamma; D007455:Iodine; D013974:Thyroxine