CD4 T cells play major effector role and CD8 T cells initiating role in spontaneous autoimmune myocarditis of HLA-DQ8 transgenic IAb knockout nonobese diabetic mice.

Abstract	In humans, spontaneous autoimmune attack against cardiomyocytes often leads to idiopathic dilated cardiomyopathy (IDCM) and life-threatening heart failure. HLA-DQ8 transgenic IAb knockout NOD mice (NOD.DQ8/Ab(0); DQA10301, DQB10302) develop spontaneous anticardiomyocyte autoimmunity with pathology very similar to human IDCM, but why the heart is targeted is unknown. In the present study, we first investigated whether NOD/Ab(0) mice transgenic for a different DQ allele, DQ6, (DQA10102, DQB10602) would also develop myocarditis. NOD.DQ6/Ab(0) animals showed no cardiac pathology, implying that DQ8 is specifically required for the myocarditis phenotype. To further characterize the cellular immune mechanisms, we established crosses of our NOD.DQ8/Ab(0) animals with Rag1 knockout (Rag1(0)), Ig H chain knockout (IgH(0)), and beta(2)-microglobulin knockout (beta(2)m(0)) lines. Adoptive transfer of purified CD4 T cells from NOD.DQ8/Ab(0) mice with complete heart block (an indication of advanced myocarditis) into younger NOD.DQ8/Ab(0) Rag1(0) animals induced cardiac pathology in all recipients, whereas adoptive transfer of purified CD8 T cells or B lymphocytes had no effect. Despite the absence of B lymphocytes, NOD.DQ8/Ab(0)IgH(0) animals still developed complete heart block, whereas NOD.DQ8/Ab(0)beta(2)m(0) mice (which lack CD8 T cells) failed to develop any cardiac pathology. CD8 T cells (and possibly NK cells) seem to be necessary to initiate disease, whereas once initiated, CD4 T cells alone can orchestrate the cardiac pathology, likely through their capacity to recruit and activate macrophages. Understanding the cellular immune mechanisms causing spontaneous myocarditis/IDCM in this relevant animal model will facilitate the development and testing of new therapies for this devastating disease.
Authors	Sarah L Hayward, Norma Bautista-Lopez, Kunimasa Suzuki, Alexey Atrazhev, Peter Dickie, John F Elliott
Journal	Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 176 Issue 12 Pg. 7715-25 (Jun 15 2006) ISSN: 0022-1767 [Print] United States
PMID	16751419 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	HLA-DQ Antigens HLA-DQ8 antigen Histocompatibility Antigens Class II
Topics	Adoptive Transfer Animals Autoimmune Diseases (genetics, immunology, pathology) CD4-Positive T-Lymphocytes (immunology, transplantation) CD8-Positive T-Lymphocytes (immunology) Cardiomyopathy, Dilated (genetics, immunology, pathology) Disease Models, Animal HLA-DQ Antigens (genetics) Heart Block (genetics, immunology) Histocompatibility Antigens Class II (genetics) Humans Killer Cells, Natural (immunology) Lymphocyte Transfusion Macrophages (immunology) Mice Mice, Inbred NOD Mice, Knockout Mice, Transgenic

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