Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype.
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.
Afanasyeva
M
M
Departments of Pathology, the Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Wang
Y
Y
Kaya
Z
Z
Park
S
S
Zilliox
M J
MJ
Schofield
B H
BH
Hill
S L
SL
Rose
N R
NR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D007073:Immunoglobulin E / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009205:Myocarditis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D012720:Severity of Illness Index; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000473:pathology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D009218:Myosins