Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart.
Complement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1beta levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220(low) B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.
Fairweather
DeLisa
D
Department of Environmental Health Sciences, Johns Hopkins University and Bloomberg School of Public Health, 615 North Wolfe Street, Rm. E7628, Baltimore, MD 21205, USA. dfairwea@jhsph.edu
Frisancho-Kiss
Sylvia
S
Njoku
Dolores B
DB
Nyland
Jennifer F
JF
Kaya
Ziya
Z
Yusung
Susy A
SA
Davis
Sarah E
SE
Frisancho
J Augusto
JA
Barrett
Masheka A
MA
Rose
Noel R
NR
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004770:Enterovirus / Q000502:physiology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000503:physiopathology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017463:Receptors, Complement 3b; D013154:Spleen / Q000166:cytology / Q000821:virology; D013601:T-Lymphocytes / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C081470:Cr1l protein, mouse; D007375:Interleukin-1; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D014409:Tumor Necrosis Factor-alpha