Abstract
Viral myocarditis (VMC) is the major cause of sudden death in adolescents. To date, no effective treatment has been identified for VMC. Studies have shown that T helper (Th) cells such as Th1, Th2, Th17, and Th22 cells are involved in the pathogenesis of VMC. However, the role of B cells and their impact on Th cells in VMC is unclear. In this study, we investigated the role of B cells in Th cell differentiation in myocardial damage in an animal model of VMC. C57BL/6 mice were infected with Coxsackievirus B3 (CVB3) intraperitoneally or injected with phosphate-buffered saline as a control condition. At day 7, samples from these mice were analyzed by histology, ELISA, flow cytometry, and gene expression assays. We found that TNF-α-, IL-6-, and IL-17-producing B cell numbers were significantly increased, while IL-4-producing B cell population was significantly reduced in acute VMC. Furthermore, we performed B cell knockout (BKO), SCID, and SCID+B cells reconstitution experiments. We found that BKO alleviated the cardiac damage following CVB3 infection, may hamper the differentiation of Th1 and Th17 cells, may promote the differentiation of Th2 cells, and proved ineffective for the differentiation of Th22 cells. In contrast, SCID+B cells reconstitution experiment exacerbated the cardiac damage. Ex vivo studies further revealed that B cells promote the differentiation of Th1 and Th17 cells and inhibit the differentiation of Th2 cells. Our study shows that B cells are activated and have strong abilities of antigen presentation and producing cytokines in VMC; B cells not only play a pathogenic role in VMC independent of T cells but also promote Th1 and Th17 cell differentiation, and hamper Th2 cell differentiation in VMC.
Highlights
Myocarditis is an inflammatory disease of the heart muscle
We found that TNF-α, IL-6, and IL-17-producing B cell numbers were significantly increased, while IL-4-producing B cell population was significantly reduced in acute Viral myocarditis (VMC)
We found that B cell knockout (BKO) alleviated the cardiac damage following Coxsackievirus B3 (CVB3) infection, may hamper the differentiation of Th1 and Th17 cells, may promote the differentiation of Th2 cells, and proved ineffective for the differentiation of Th22 cells
Summary
Myocarditis is an inflammatory disease of the heart muscle. It accounts for about one in nine cases of non-ischemic heart failure clinically, and remains the main reason for heart transplantation worldwide [1]. No specific treatments for viral myocarditis (VMC) have been identified, owing to its poorly understood pathogenesis. Studies have shown that CD4+T helper (Th) cell-mediated (Th1, Th2, Th17, and Th22) immune response plays a crucial role in the pathogenesis of VMC [2,3,4,5], they fail to completely illuminate its regulatory mechanisms. This study revealed that by producing cytokines, B cells play a key role in a mouse model of chemically-induced asthma without the help of T cells [7]. Many studies have shown that B cells play a pathogenic role in autoimmune diseases such as systemic lupus erythematosus (SLE) [8], multiple sclerosis [9], and rheumatoid arthritis (RA) [10].
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