Immunoglobulin heavy chain variable region genes contribute to the induction of thyroid-stimulating antibodies in recombinant inbred mice.
Graves' hyperthyroidism is an autoimmune disease occurring spontaneously in humans and caused by autoantibodies that stimulate the thyrotropin receptor. In mice, inducing Graves'-like hyperthyroidism requires in vivo expression of the thyrotropin receptor using plasmid or adenovirus vectors. However, mice with different genetic backgrounds vary markedly in their susceptibility to induced hyperthyroidism. Further, in some strains major disparities exist between the induction of hyperthyroidism and detection of thyroid-stimulating antibodies. To break tolerance, virtually all Graves' mouse models involve immunization with human thyrotropin-receptor DNA and the standard thyroid-stimulating antibody bioassay uses cells expressing the human thyrotropin receptor. We hypothesized, and now report, that disparities between hyperthyroidism and thyroid-stimulating antibody bioactivity are explained, at least in part, by differential antibody recognition of the human vs the mouse thyrotropin receptor. The genetic basis for these species differences was explored using genotyped, recombinant-inbred mouse strains. We report that loci in the immunoglobulin heavy chain variable region as well as in the major histocompatibility complex region contribute in a strain-specific manner to the development of antibodies specific for the human or the mouse thyrotropin receptor. The novel finding of a role for immunoglobulin heavy chain variable region gene involvement in thyroid-stimulating antibody epitopic specificity provides potential insight into genetic susceptibility in human Graves' disease.
Rapoport
B
B
Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA 90048, USA.
Williams
R W
RW
Chen
C-R
CR
McLachlan
S M
SM
D000818:Animals; D016466:CHO Cells; D002874:Chromosome Mapping; D006224:Cricetinae; D003412:Cricetulus; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics / Q000276:immunology; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics / Q000276:immunology; D007114:Immunization / Q000379:methods; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic
D007135:Immunoglobulin Variable Region; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin
Nature. 1981 Aug 20;292(5825):768-70
6894965
J Endocrinol Invest. 1982 May-Jun;5(3):179-82
6286749
Ann Intern Med. 2003 Sep 2;139(5 Pt 1):346-51
12965943
Physiol Genomics. 2006 Oct 3;27(1):1-11
16804090
Genetics. 1994 Nov;138(3):963-71
7851788
J Clin Invest. 2003 Jun;111(12):1897-904
12813025
J Clin Endocrinol Metab. 1985 Jan;60(1):62-6
3838076
J Clin Endocrinol Metab. 1998 Sep;83(9):3290-5
9745443
Am J Hum Genet. 2003 Oct;73(4):736-47
12973666
Genome Biol. 2001;2(11):RESEARCH0046
11737945
Thyroid. 2006 May;16(5):427-34
16756463
J Immunol. 2007 Aug 15;179(4):2419-27
17675503
Hum Mol Genet. 2007 Sep 15;16(18):2149-53
17597093
Endocrinology. 2006 Jun;147(6):2789-800
16543368
Endocrinology. 2004 Apr;145(4):1539-45
14764633
Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68
7641412
Thyroid. 1999 Sep;9(9):849-55
10524562
Thyroid. 2007 Oct;17(10):911-22
17822379
Endocr Rev. 2005 Oct;26(6):800-32
15827111
J Clin Endocrinol Metab. 2006 Feb;91(2):646-53
16278270
Genomics. 2004 Mar;83(3):413-24
14962667
J Immunol. 1999 Nov 1;163(9):5157-64
10528222
Thyroid. 2006 Jul;16(7):651-8
16889488
Endocrinology. 2009 Feb;150(2):1051-60
18927213
Eur J Immunol. 1983 Dec;13(12):1017-22
6689303
Clin Endocrinol (Oxf). 1988 Jun;28(6):619-28
2908181
J Clin Endocrinol Metab. 2001 Apr;86(4):1687-93
11297604
Thyroid. 2007 Oct;17(10):949-61
17824829
Endocrinology. 2008 Apr;149(4):2001-9
18162518
J Clin Endocrinol Metab. 1998 May;83(5):1580-4
9589659
N Engl J Med. 1980 Aug 7;303(6):302-7
6247656
J Clin Endocrinol Metab. 1999 Dec;84(12):4656-64
10599734
Endocrinology. 2004 Nov;145(11):4927-33
15284197
J Immunol. 2006 Mar 15;176(6):3293-8
16517694
J Neurosci. 1998 Jan 1;18(1):138-46
9412494
J Clin Endocrinol Metab. 2001 Feb;86(2):626-30
11158020
Mol Cell Endocrinol. 1990 Oct 1;73(1):R13-8
1981364
Thyroid. 2003 Mar;13(3):233-8
12729471
Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12379-83
8618905
Int Arch Allergy Appl Immunol. 1989;89(2-3):261-3
2668202
J Clin Endocrinol Metab. 2002 Feb;87(2):489-99
11836274
J Immunol. 2002 Mar 15;168(6):2789-94
11884447
Endocrinology. 1958 Jun;62(6):865-8
13548106
Clin Endocrinol (Oxf). 1982 Oct;17(4):409-17
6291808