Cardiac myosin-induced myocarditis: target recognition by autoreactive T cells requires prior activation of cardiac interstitial cells.
Immunization with cardiac myosin causes T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. The normal heart is not susceptible to T cells autoreactive with cardiac myosin; therefore, we investigated the conditions that are required to facilitate recognition of the target tissue. A.SW mice were immunized with cardiac myosin on Days 0 and 7. Major histocompatibility antigen (MHC Ag) and intercellular adhesion molecule-1 (ICAM-1) expression in the heart tissue was investigated by immunohistochemical techniques shortly before disease onset (ie, on Day 9). At this time point, cardiac interstitial cells expressing class II but not class I MHC Ag were significantly increased. In addition, endothelial ICAM-1 expression was strongly up-regulated. Myofibers did not show expression of these markers, and T cells were virtually absent. Because lipopolysaccaride (LPS) induced a similar distribution of class II MHC Ag and ICAM-1 in the myocardial tissue and because these molecules could be crucial to disease onset, we determined whether treatment with this immunomodulator renders the heart susceptible to passively transferred myosin-reactive T cells. We found that concanavalin A-activated spleen cells from myosin-immunized donors induced myocarditis in LPS-primed recipients, whereas normal mice were resistant to the injection of such cells. Increased class II MHC Ag expression after LPS-treatment was mediated by TNF because LPS-primed mice genetically lacking the TNF receptor failed to increase class II MHC Ag expression in the heart tissue. In summary, these results suggest that in cardiac myosin-induced myocarditis, expression of interstitial class II MHC Ag and/or endothelial ICAM-1 is a prerequisite for target organ recognition by autoreactive T cells.
Pummerer
C L
CL
Department of Pediatrics, University of Innsbruck Medical School, Austria.
Grässl
G
G
Sailer
M
M
Bachmaier
K W
KW
Penninger
J M
JM
Neu
N
N
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000502:physiology; D001327:Autoimmune Diseases / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007114:Immunization; D007124:Immunoenzyme Techniques; D016219:Immunotherapy, Adoptive; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009205:Myocarditis / Q000276:immunology*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D009218:Myosins / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009218:Myosins