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A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8.

Abstract
Genome-wide analyses have shown that the MHC class II region is the principal locus that confers susceptibility to a number of human autoimmune diseases. Due to the high degree of linkage disequilibrium across the MHC, it has been difficult to dissect the contribution of individual genes to disease susceptibility. As a result, intensive efforts have been made to generate mice transgenic for human class II molecules as models of autoimmune disease. However, in every case, additional manipulations-such as immunization with Ag in adjuvant, expression of immunostimulants on target tissues, or coexpression of TCR transgenes-have been required to induce disease. In this study, we show that expression of the human HLA-DQ8 (DQA1*0301/DQB1*0302) molecule alone in three lines of transgenic nonobese diabetic murine class II-deficient (mII(-/-)) mice results in the spontaneous development of autoimmune myocarditis. The disease shares key features of human myocarditis and was characterized by lymphocytic infiltrates in the myocardium and cardiac myocyte destruction, circulating IgG autoantibodies against cardiac myosin heavy chain, and premature death due to heart failure. We demonstrate that myocarditis could be transferred into healthy HLA-DQ8(+)RAG-1(-/-)mII(-/-) nonobese diabetic recipients with lymphocytes, but not sera. It has been widely thought that autoimmune myocarditis is of infectious etiology, with the immune responses arising secondary to cardiac damage from pathogens. These studies provide direct experimental evidence that spontaneous autoimmune myocarditis can occur in the absence of infection and that expression of HLA-DQ8 confers susceptibility to this organ-specific autoimmune disease.
AuthorsJacqueline A Taylor, Evis Havari, Marcia F McInerney, Roderick Bronson, Kai W Wucherpfennig, Myra A Lipes
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 172 Issue 4 Pg. 2651-8 (Feb 15 2004) ISSN: 0022-1767 [Print] United States
PMID14764740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Immunoglobulin G
Topics
  • Adoptive Transfer
  • Animals
  • Autoantibodies (biosynthesis, blood)
  • Autoimmune Diseases (genetics, immunology, pathology)
  • CD4-Positive T-Lymphocytes (immunology)
  • Crosses, Genetic
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • HLA-DQ Antigens (biosynthesis, genetics, physiology)
  • Humans
  • Immunoglobulin G (biosynthesis, blood)
  • Lymphocyte Transfusion
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Myocarditis (genetics, immunology, pathology)
  • Spleen (cytology, transplantation)

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