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Shared and Unique Susceptibility Genes in a Mouse Model of Graves’ Disease Determined in BXH and CXB Recombinant Inbred Mice

Autoimmune Disease Unit (S.M.M., H.A.A., P.N.P., C.-R.C., B.R.), Cedars-Sinai Research Institute and University of California, Los Angeles, School of Medicine, Los Angeles, California 90048; and Department of Anatomy and Neurobiology (R.W.W.), University of Tennessee Health Science Center, Memphis, Tennessee 38163

Address all correspondence and requests for reprints to: Sandra M. McLachlan, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048. E-mail: mclachlans{at}cshs.org.

Susceptibility genes for TSH receptor (TSHR) antibodies and hyperthyroidism can be probed in recombinant inbred (RI) mice immunized with adenovirus expressing the TSHR A-subunit. The RI set of CXB strains, derived from susceptible BALB/c and resistant C57BL/6 (B6) mice, were studied previously. High-resolution genetic maps are also available for RI BXH strains, derived from B6 and C3H/He parents. We found that C3H/He mice develop TSHR antibodies, and some animals become hyperthyroid after A-subunit immunization. In contrast, the responses of the F1 progeny of C3H/He x B6 mice, as well as most BXH RI strains, are dominated by the B6 resistance to hyperthyroidism. As in the CXB set, linkage analysis of BXH strains implicates different chromosomes (Chr) or loci in the susceptibility to induced TSHR antibodies vs. hyperthyroidism. Importantly, BXH and CXB mice share genetic loci controlling the generation of TSHR antibodies (Chr 17, major histocompatibility complex region, and Chr X) and development of hyperthyroidism (Chr 1 and 3). Moreover, some chromosomal linkages are unique to either BXH or CXB strains. An interesting candidate gene linked to thyroid-stimulating antibody generation in BXH mice is the Ig heavy chain locus, suggesting a role for particular germline region genes as precursors for these antibodies. In conclusion, our findings reinforce the importance of major histocompatibility complex region genes in controlling the generation of TSHR antibodies measured by TSH binding inhibition. Moreover, these data emphasize the value of RI strains to dissect the genetic basis for induced TSHR antibodies vs. their effects on thyroid function in Graves’ disease.

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