title: Enhanced response to mouse thyroid-stimulating hormone (TSH) receptor immunization in TSH receptor-knockout mice.
abstract: Graves-like hyperthyroidism is induced in BALB/c mice by immunization with adenovirus expressing the human TSH receptor (TSHR) A-subunit (amino acids 1-289). However, because of nonidentity between the human and mouse TSHR ( approximately 87% amino acid homology), we compared the responses of mice immunized with adenoviruses expressing either the mouse or the human TSHR A-subunit. Wild-type (wt) BALB/c mice immunized with the mouse A-subunit developed neither TSHR antibodies (measured by flow cytometry) nor thyroid lymphocytic infiltration. However, wt C57BL/6 mice developed sparse intrathyroidal lymphocyte infiltration without antibody production. Depletion of naturally occurring regulatory CD4(+)CD25(+) T cells had little effect. These results indicate the inability to break tolerance to the mouse TSHR in wt mice. In contrast, TSHR knockout (KO) BALB/c mice generated mouse TSHR antibodies in response to mouse A-subunit immunization and augmented human TSHR antibody response to human A-subunit immunization. Thyroid-stimulating antibody titers measured in a functional bioassay were comparable in human A-subunit immunized wt mice and in TSHR KO mice immunized with either the mouse or human A-subunit. In conclusion, immune response to the mouse TSHR is readily induced in TSHR KO but not in wt mice. Only in the former does immunization with adenovirus expressing the mouse A-subunit generate antibodies capable of activating the mouse TSHR. TSHR KO mice are, therefore, of value for future studies dissecting the autoimmune response to the mouse TSHR.
authors.affiliation: Department of Medical Gene Technology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Nakahara
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Chun-Rong
authors.initials: CR
authors.lastname: Chen
authors.forename: Basil
authors.initials: B
authors.lastname: Rapoport
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007114:Immunization; D018828:Immunoglobulins, Thyroid-Stimulating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin