Myocarditis is an important cause of heart failure among adolescents and young adults. While about 33% of myocarditis patients recover, the remainder may develop chronic dilated cardiomyopathy, which accounts for 25% of all heart failures in North America. CB3 infections have been implicated in around 4 % of myocarditis cases. Studies of CB3-induced myocarditis in mice have provided valuable information about the role of the adaptive, acquired immune response to CB3 in the development of autoimmune myocarditis. Recently we have examined the role of the innate immune response to CB3 infection on the development of myocarditis and have found significantly increased levels of acute viral and autoimmune myocarditis in males. Although the adaptive T cell response to CB3 is known to play a role in exacerbating disease in males, little is understood about the underlying mechanisms that determine the sex-based difference. The goal of this application is to characterize the immune and hormonal differences between the male and female immune response to CB3 infection in order to determine the factors that lead to increased disease in males. We hypothesize that the early hormonal and cytokine environment after CB3 infection determines the later adaptive immune response that results in increased myocarditis in males. To investigate this hypothesis, we propose two Specific Aims: (1) to characterize the differences between the male and female immune response to CB3 infection, and (2) to identify the hormonal factors that influence the immune response to CB3 infection resulting in increased severity of myocarditis in males. The findings generated by these studies will aid in understanding the sex- based differences in severity in this model of infection-induced autoimmune disease.
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