Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves' hyperthyroidism in BALB/c mice.
Dendritic cells (DCs) are the most potent antigen-presenting cells and a prerequisite for the initiation of primary immune response. This study was performed to investigate the contribution of DCs to the initiation of Graves' hyperthyroidism, an organ-specific autoimmune disease in which the thyrotrophin receptor (TSHR) is the major autoantigen. DCs were prepared from bone marrow precursor cells of BALB/c mice by culturing with granulocyte macrophage-colony stimulating factor and interleukin-4. Subcutaneous injections of DCs infected with recombinant adenovirus expressing the TSHR (but not beta-galactosidase) in syngeneic female mice induced Graves'-like hyperthyroidism (8 and 35% of mice after two and three injections, respectively) characterized by stimulating TSHR antibodies, elevated serum thyroxine levels and diffuse hyperplasitc goiter. TSHR antibodies determined by ELISA were of both IgG1 (Th2-type) and IgG2a (Th1-type) subclasses, and splenocytes from immunized mice secreted interferon-gamma (a Th1 cytokine), not interleukin-4 (a Th2 cytokine), in response to TSHR antigen. Surprisingly, IFN-gamma secretion, and induction of antibodies and disease were almost completely suppressed by co-administration of alum/pertussis toxin, a Th2-dominant adjuvant, whereas polyriboinosinic polyribocytidylic acid, a Th1-inducer, enhanced splenocyte secretion of IFN-gamma without changing disease incidence. These observations demonstrate that DCs efficiently present the TSHR to naive T cells to induce TSHR antibodies and Graves'-like hyperthyroidism in mice. In addition, our results challenge the previous concept of Th2 dominance in Graves' hyperthyroidism and provide support for the role of Th1 immune response in disease pathogenesis.
Kita-Furuyama
M
M
First Department of Internal Medicine and Department of Pharmacology 1, Nagasaki University School of Medicine, Nagasaki, Japan.
Nagayama
Y
Y
Pichurin
P
P
McLachlan
S M
SM
Rapoport
B
B
Eguchi
K
K
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006111:Graves Disease / Q000276:immunology*; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D011989:Receptors, Thyrotropin / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D011989:Receptors, Thyrotropin; D007371:Interferon-gamma