Immunoglobulin heavy chain variable region and major histocompatibility region genes are linked to induced graves' disease in females from two very large families of recombinant inbred mice

Sandra M. McLachlan, Holly Aliesky, Bianca Banuelos, Jessica Magana, Robert Williams, Basil Rapoport

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Abstract

Graves' hyperthyroidism is caused by antibodies to the TSH receptor (TSHR) that mimic thyroid stimulation by TSH. Stimulating TSHR antibodies and hyperthyroidism can be induced by immunizing mice with adenovirus expressing the human TSHR A-subunit. Prior analysis of induced Graves' disease in small families of recombinant inbred (RI) female mice demonstrated strong genetic control but did not resolve trait loci for TSHR antibodies or elevated serum T4. We investigated the genetic basis for induced Graves' disease in female mice of two large RI families and combined data with earlier findings to provide phenotypes for 178 genotypes. TSHR antibodies measured by inhibition of TSH binding to its receptor were highly significantly linked in the BXD set to the major histocompatibility region (chromosome 17), consistent with observations in 3 other RI families. In the LXS family, we detected linkage between T4levels after TSHR-adenovirus immunization and the Ig heavy chain variable region (Igvh, chromosome 12). This observation is a key finding because components of the antigen binding region of Igs determine antibody specificity and have been previously linked to induced thyroid-stimulating antibodies. Data from the LXS family provide the first evidence in mice of a direct link between induced hyperthyroidism and Igvh genes.Arole for major histocompatibility genes hasnowbeenestablished for genetic susceptibility to Graves' disease in both humans and mice. Future studies using arrays incorporating variation in the complexhumanIg gene locus will be necessary to determine whether Igvh genes are also linked to Graves' disease in humans. Copyright

Original languageEnglish (US)
Pages (from-to)4094-4103
Number of pages10
JournalEndocrinology
Volume155
Issue number10
DOIs
StatePublished - Oct 1 2014

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Immunoglobulin Heavy Chains
Histocompatibility
Graves Disease
Hyperthyroidism
Thyrotropin Receptors
Genes
Thyroid-Stimulating Immunoglobulins
Human Adenoviruses
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 17
Antibody Specificity
Genetic Predisposition to Disease
Adenoviridae
Immunization
Thyroid Gland
Genotype
Phenotype
Antigens
thyrotropin-binding inhibitory immunoglobulin
Serum

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Immunoglobulin heavy chain variable region and major histocompatibility region genes are linked to induced graves' disease in females from two very large families of recombinant inbred mice. / McLachlan, Sandra M.; Aliesky, Holly; Banuelos, Bianca; Magana, Jessica; Williams, Robert; Rapoport, Basil.

In: Endocrinology, Vol. 155, No. 10, 01.10.2014, p. 4094-4103.

Research output: Contribution to journalArticle

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