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(American Journal of Pathology. 2001;159:193-203.)
© 2001 American Society for Investigative Pathology

Regular Articles

Experimental Autoimmune Myocarditis in A/J mice Is an Interleukin-4-Dependent Disease with a Th2 Phenotype

Marina Afanasyeva*{dagger}, Yan Wang*, Ziya Kaya*, Sung Park*, Michael J. Zilliox{dagger}, Brian H. Schofield{ddagger}, Susan L. Hill*{dagger} and Noel R. Rose*{dagger}{ddagger}

From the Departments of Pathology,*
Molecular Microbiology and Immunology,{dagger}
and Environmental Health Sciences,{ddagger}
the Johns Hopkins Medical Institutions, Baltimore, Maryland

Myocarditis in humans is often associated with an autoimmune process in which cardiac myosin (CM) is a major autoantigen. Experimental autoimmune myocarditis (EAM) is induced in mice by immunization with CM. We found that EAM in A/J mice exhibits a Th2-like phenotype demonstrated by the histological picture of the heart lesions (eosinophils and giant cells) and by the humoral response (association of IgG1 response with disease and up-regulation of total IgE). Blocking interleukin (IL)-4 with anti-IL-4 monoclonal antibody (mAb) reduced the severity of EAM. This reduction in severity was associated with a shift from a Th2-like to a Th1-like phenotype represented by a reduction in CM-specific IgG1; an increase in CM-specific IgG2a; an abrogation of total IgE response; a decrease in IL-4, IL-5, and IL-13; as well as a dramatic increase in interferon (IFN)-{gamma} production in vitro. Based on the latter finding, we hypothesized that IFN-{gamma} limits disease. Indeed, IFN-{gamma} blockade with a mAb exacerbated disease. The ameliorating effect of IL-4 blockade was abrogated by co-administration of anti-IFN-{gamma} mAb. Thus, EAM represents a model of an organ-specific autoimmune disease associated with a Th2 phenotype, in which IL-4 promotes the disease and IFN-{gamma} limits it. Suppression of IFN-{gamma} represents at least one of the mechanisms by which IL-4 promotes EAM.




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