Document Detail


Immunoglobulin heavy chain variable region genes contribute to the induction of thyroid-stimulating antibodies in recombinant inbred mice.
MedLine Citation:
PMID:  20407472     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
B Rapoport; R W Williams; C-R Chen; S M McLachlan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes and immunity     Volume:  11     ISSN:  1476-5470     ISO Abbreviation:  Genes Immun.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-21     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100953417     Medline TA:  Genes Immun     Country:  England    
Other Details:
Languages:  eng     Pagination:  254-63     Citation Subset:  IM    
Affiliation:
Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA 90048, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
CHO Cells
Chromosome Mapping
Cricetinae
Cricetulus
Genes, Immunoglobulin Heavy Chain / genetics*
Genome-Wide Association Study
Graves Disease / genetics,  immunology
Humans
Hyperthyroidism / genetics,  immunology
Immunization / methods
Immunoglobulin Variable Region / genetics*
Immunoglobulins, Thyroid-Stimulating / blood,  genetics,  immunology*
Mice
Mice, Inbred C3H
Mice, Inbred Strains
Receptors, Thyrotropin / genetics,  immunology
Recombination, Genetic
Grant Support
ID/Acronym/Agency:
DK19289/DK/NIDDK NIH HHS; DK54684/DK/NIDDK NIH HHS; P20-DA-21131/DA/NIDA NIH HHS; U01AA13499/AA/NIAAA NIH HHS; U01CA105417/CA/NCI NIH HHS; U24AA13513/AA/NIAAA NIH HHS; U24RR021760/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Immunoglobulin Variable Region; 0/Immunoglobulins, Thyroid-Stimulating; 0/Receptors, Thyrotropin

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