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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 Mice¹

Sarah L. Hayward^*,, Norma Bautista-Lopez^2,*, Kunimasa Suzuki^*,, Alexey Atrazhev^3,*, Peter Dickie^* and John F. Elliott^4,*,,

^* Department of Medical Microbiology and Immunology, Alberta Diabetes Institute, and Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

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/Ab⁰; DQA1*0301, DQB1*0302) 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/Ab⁰ mice transgenic for a different DQ allele, DQ6, (DQA1*0102, DQB1*0602) would also develop myocarditis. NOD.DQ6/Ab⁰ 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/Ab⁰ animals with Rag1 knockout (Rag1⁰), Ig H chain knockout (IgH⁰), and ₂-microglobulin knockout (₂m⁰) lines. Adoptive transfer of purified CD4 T cells from NOD.DQ8/Ab⁰ mice with complete heart block (an indication of advanced myocarditis) into younger NOD.DQ8/Ab⁰ Rag1⁰ 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/Ab⁰IgH⁰ animals still developed complete heart block, whereas NOD.DQ8/Ab⁰₂m⁰ 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.

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The JI 2006 176: 7141-7142. [Full Text]  

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