title: Generation of a transgenic animal model of hyperthyroid Graves' disease.
abstract: Graves' disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (thyroid-stimulating antibodies, TSAb), which mimic the thyrotropin (TSH) action, are thought to cause GD. The precise immunological mechanism of TSAb production, however, remains elusive. Previous immunization approaches using TSH receptor led to transient hyperthyroidism, but did not seem sufficient for comprehensive understanding of the development of autoimmune responses. To create GD-related autoimmunity in mice, we here generated TSAb-transgenic mice in which a patient-derived TSAb is expressed in B cells. Expression of the human TSAb in mice resulted in various manifestations of hyperthyroidism including increased free thyroxine levels with concomitantly decreased TSH levels, increased thyroid uptake of technetium pertechnetate, hyperthermia and thyroid hyperplasia. We found a correlation between the serum levels of human TSAb immunoglobulin and free thyroxine. In addition, conventional B cells expressing the TSAb were partially deleted in the periphery while B1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous demonstrations that the maintenance of B1 cells plays an important role in the development of autoimmune diseases. Thus, our transgenic mouse may provide a novel and useful animal model for elucidating the pathogenesis and pathophysiology of GD.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Kim-Saijo
authors.forename: Takashi
authors.initials: T
authors.lastname: Akamizu
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikuta
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iida
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ohmori
authors.forename: Kazumi
authors.initials: K
authors.lastname: Matsubara
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Misao
authors.initials: M
authors.lastname: Suzuki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion; D004195:Disease Models, Animal; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D006980:Hyperthyroidism / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D018828:Immunoglobulins, Thyroid-Stimulating; D051379:Mice; D008822:Mice, Transgenic; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013667:Technetium / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; C094372:thyrotropin-binding inhibitory immunoglobulin; D013667:Technetium