beta2-microglobulin-associated regulation of interferon-gamma and virus-specific immunoglobulin G confer resistance against the development of chronic coxsackievirus myocarditis.
To gain insight into the strategies of the immune system to confer resistance against the development of chronic coxsackievirus B3 (CVB3) myocarditis we compared the course of the disease in C57BL/6 mice, beta2-microglobulin knockout (beta2m(-/-)) mice, and perforin-deficient (perforin(-/-)) mice. We found that perforin(-/-) mice as well as immunocompetent C57BL/6 mice reveal a resistant phenotype with complete elimination of the virus from the heart in the course of acute myocarditis. In contrast, myocardial CVB3 infection of beta2m(-/-) mice was characterized by a significantly higher virus load associated with a fulminant acute inflammatory response and, as a consequence of virus persistence, by the development of chronic myocarditis. Interferon-gamma secretion of stimulated spleen cells was found to be significantly delayed in beta2m(-/-) mice compared to perforin(-/-) mice and C57BL/6 control mice during acute myocarditis. In addition, generation of virus-specific IgG and neutralizing antibodies were found to be significantly decreased in beta2m(-/-) mice during acute infection. From these results we conclude that protection against the development of chronic myocarditis strongly depends on the expression of beta2m, influencing the catabolism of IgG as well as the production of protective cytokines, such as interferon-gamma. Moreover, CVB3-induced cardiac injury and prevention of chronic myocarditis was found to be unrelated to perforin-mediated cytotoxicity in our model system.
Klingel
Karin
K
Department of Molecular Pathology, University Hospital Tuebingen, Tuebingen, Germany. karin.klingel@med.uni-tuebingen.de
Schnorr
Jens-Jörg
JJ
Sauter
Martina
M
Szalay
Gudrun
G
Kandolf
Reinhard
R
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D002522:Chlorocebus aethiops; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004770:Enterovirus / Q000472:pathogenicity*; D005786:Gene Expression Regulation / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014709:Vero Cells; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D001613:beta 2-Microglobulin; D054353:Perforin; D007371:Interferon-gamma