Recombinant cardiac myosin fragment induces experimental autoimmune myocarditis via activation of Th1 and Th17 immunity

• Published in: Autoimmunity (Chur, Switzerland) Switzerland), 2008-01, Vol.41 (6), p.490-499
• Main Authors: Daniels, Melvin D., Hyland, Kenneth V., Wang, Kegiang, Engman, David M.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Autoimmunity; Cardiac Myosins - immunology; Cardiac Myosins - metabolism; Cells, Cultured; epitope spreading; Interferon-gamma - biosynthesis; Interleukin-17 - biosynthesis; Interleukin-4 - biosynthesis; Interleukin-6 - biosynthesis; Male; Mice; myocarditis; Myocarditis - immunology; Myocarditis - metabolism; Recombinant Proteins - immunology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Th immunity; Th1 Cells - immunology; Th1 Cells - metabolism
• ISSN: 0891-6934; 1607-842X
• DOI: 10.1080/08916930802167902

The specificity and function of T helper (Th) immune responses underlying the induction, progression, and resolution of experimental autoimmune myocarditis (EAM) in A/J mice are unclear. Published data suggest involvement of both Th1 and Th2 responses in EAM; however, the previous inability to assess antigen-specific in vivo and in vitro T-cell responses in cardiac myosin-immunized animals has confounded our understanding of this important model of autoimmune myocarditis. The goal of our study was to develop an alternative model of EAM based on a recombinant fragment of cardiac myosin, in hopes that the recombinant protein will permit measurement of functional T-cell responses that is not possible with purified native protein. A/J mice immunized with a recombinant fragment of cardiac myosin spanning amino acids 1074-1646, termed Myo4, developed severe myocarditis characterized by cardiac hypertrophy, massive mononuclear cell infiltration and fibrosis, three weeks post-immunization. The mice also developed an IgG1 dominant humoral immune response specific for both Myo4 and purified cardiac myosin. The in vitro stimulation of splenocytes harvested from Myo4-immunized animals with Myo4 resulted in cellular proliferation with preferential production of the Th1- and Th17-associated cytokines, IFN-γ, IL-17, and IL-6, respectively. Production of IL-4 was negligible by comparison. This study describes a new model of EAM, inducible by immunization with a specific fragment of cardiac myosin, from which antigen-specific analyses reveal an importance for both Th1 and Th17 immunity.