title: A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor.
abstract: Abs that stimulate the thyrotropin receptor (TSHR), the cause of Graves' hyperthyroidism, only develop in humans. TSHR Abs can be induced in mice by immunization, but studying pathogenesis and therapeutic intervention requires a model without immunization. Spontaneous, iodine-accelerated, thyroid autoimmunity develops in NOD.H2(h4) mice associated with thyroglobulin and thyroid-peroxidase, but not TSHR, Abs. We hypothesized that transferring the human TSHR A-subunit to NOD.H2(h4) mice would result in loss of tolerance to this protein. BALB/c human TSHR A-subunit mice were bred to NOD.H2(h4) mice, and transgenic offspring were repeatedly backcrossed to NOD.H2(h4) mice. All offspring developed Abs to thyroglobulin and thyroid-peroxidase. However, only TSHR-transgenic NOD.H2(h4) mice (TSHR/NOD.H2(h4)) developed pathogenic TSHR Abs as detected using clinical Graves' disease assays. As in humans, TSHR/NOD.H2(h4) female mice were more prone than male mice to developing pathogenic TSHR Abs. Fortunately, in view of the confounding effect of excess thyroid hormone on immune responses, spontaneously arising pathogenic human TSHR Abs cross-react poorly with the mouse TSHR and do not cause thyrotoxicosis. In summary, the TSHR/NOD.H2(h4) mouse strain develops spontaneous, iodine-accelerated, pathogenic TSHR Abs in female mice, providing a unique model to investigate disease pathogenesis and test novel TSHR Ag-specific immunotherapies aimed at curing Graves' disease in humans.
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute/David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90048.
authors.forename: Basil
authors.initials: B
authors.lastname: Rapoport
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute/David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90048.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Aliesky
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute/David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90048.
authors.forename: Bianca
authors.initials: B
authors.lastname: Banuelos
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute/David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90048.
authors.forename: Chun-Rong
authors.initials: CR
authors.lastname: Chen
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Research Institute/David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90048 mclachlans@cshs.org.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006111:Graves Disease / Q000139:chemically induced / Q000276:immunology*; D006801:Humans; D007455:Iodine; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011989:Receptors, Thyrotropin / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin; D007455:Iodine
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