Exceptional Hyperthyroidism and a role for both major histocompatibility class I and class II genes in a murine model of graves' disease

Sandra M. McLachlan, Holly A. Aliesky, Chun Rong Chen, Robert Williams, Basil Rapoport

Research output: Contribution to journalArticle

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Abstract

Autoimmune hyperthyroidism, Graves' disease, can be induced by immunizing susceptible strains of mice with adenovirus encoding the human thyrotropin receptor (TSHR) or its A-subunit. Studies in two small families of recombinant inbred strains showed that susceptibility to developing TSHR antibodies (measured by TSH binding inhibition, TBI) was linked to the MHC region whereas genes on different chromosomes contributed to hyperthyroidism. We have now investigated TSHR antibody production and hyperthyroidism induced by TSHR A-subunit adenovirus immunization of a larger family of strains (26 of the AXB and BXA strains). Analysis of the combined AXB and BXA families provided unexpected insight into several aspects of Graves' disease. First, extreme thyroid hyperplasia and hyperthyroidism in one remarkable strain, BXA13, reflected an inability to generate non-functional TSHR antibodies measured by ELISA. Although neutral TSHR antibodies have been detected in Graves' sera, pathogenic, functional TSHR antibodies in Graves' patients are undetectable by ELISA. Therefore, this strain immunized with A-subunit-adenovirus that generates only functional TSHR antibodies may provide an improved model for studies of induced Graves' disease. Second, our combined analysis of linkage data from this and previous work strengthens the evidence that gene variants in the immunoglobulin heavy chain V region contribute to generating thyroid stimulating antibodies. Third, a broad region that encompasses the MHC region on mouse chomosome 17 is linked to the development of TSHR antibodies (measured by TBI). Most importantly, unlike other strains, TBI linkage in the AXB and BXA families to MHC class I and class II genes provides an explanation for the unresolved class I/class II difference in humans.

Original languageEnglish (US)
Article numbere21378
JournalPLoS One
Volume6
Issue number6
DOIs
StatePublished - Jun 30 2011

Fingerprint

hyperthyroidism
MHC Class II Genes
Histocompatibility
Graves Disease
Hyperthyroidism
Genes
animal models
antibodies
Antibodies
Adenoviridae
genes
linkage (genetics)
Enzyme-Linked Immunosorbent Assay
Thyroid-Stimulating Immunoglobulins
Human Adenoviruses
Thyrotropin Receptors
Immunoglobulin Heavy Chains
enzyme-linked immunosorbent assay
immunoglobulin heavy chains
Immunization

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Exceptional Hyperthyroidism and a role for both major histocompatibility class I and class II genes in a murine model of graves' disease. / McLachlan, Sandra M.; Aliesky, Holly A.; Chen, Chun Rong; Williams, Robert; Rapoport, Basil.

In: PLoS One, Vol. 6, No. 6, e21378, 30.06.2011.

Research output: Contribution to journalArticle

McLachlan, Sandra M. ; Aliesky, Holly A. ; Chen, Chun Rong ; Williams, Robert ; Rapoport, Basil. / Exceptional Hyperthyroidism and a role for both major histocompatibility class I and class II genes in a murine model of graves' disease. In: PLoS One. 2011 ; Vol. 6, No. 6.
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