Ongoing Coxsackievirus Myocarditis Is Associated with Increased Formation and Activity of Myocardial Immunoproteasomes

• Published in: The American journal of pathology Vol. 168; no. 5; pp. 1542 - 1552
• Main Authors: Szalay, Gudrun, Meiners, Silke, Voigt, Antje, Lauber, Jörg, Spieth, Christian, Speer, Nora, Sauter, Martina, Kuckelkorn, Ulrike, Zell, Andreas, Klingel, Karin, Stangl, Karl, Kandolf, Reinhard
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.05.2006; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Antigen Presentation - physiology; Biological and medical sciences; Cardiology. Vascular system; Coxsackievirus Infections - immunology; Coxsackievirus Infections - metabolism; Disease Models, Animal; Disease Susceptibility; Electrophoresis, Gel, Two-Dimensional; Enterovirus B, Human - immunology; Heart; Heart - physiology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Multienzyme Complexes - metabolism; Myocarditis - chemically induced; Myocarditis - etiology; Myocarditis - immunology; Myocarditis - metabolism; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Organ Specificity; Original Research Paper; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Peptide Hydrolases - metabolism; Proteasome Endopeptidase Complex - physiology; Virus; Myocarditis; Coxsackievirus; Anatomic pathology; Association; Picornaviridae; Heart disease; Cardiovascular disease; Enterovirus; Myocardial disease; Biological activity
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2006.050865

A growing body of evidence indicates that viral infections of the heart contribute to ongoing myocarditis and dilated cardiomyopathy. Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the human disease and allow identification of susceptibility factors that modulate the course of viral myocarditis. Susceptible mouse strains develop chronic myocarditis on the basis of restricted viral replication, whereas resistant strains recover after successful virus elimination. In comparative whole-genome microarray analyses of infected hearts, several genes involved in the processing and presentation of viral epitopes were found to be uniformly up-regulated in acutely CVB3-infected susceptible mice compared with resistant animals. In particular, expression of the catalytic subunits LMP2, LMP7, and MECL-1, immunoproteasome proteins important in the generation of major histocom-patibility complex (MHC) class I-restricted peptides, was clearly enhanced in the susceptible host. Increased expression resulted in enhanced formation of immunoproteasomes and altered proteolytic activities of proteasomes in the heart. This was accompanied by a concerted up-regulation of the antigen-presenting machinery in susceptible mice. Thus, we propose that increased formation of immunoproteasomes in susceptible mice affects the generation of antigenic peptides and the subsequent T-cell-mediated immune responses.