Increased susceptibility of male BALB/c mice to coxsackievirus B3-induced myocarditis: role for CD1d

BALB/c male mice infected with the H3 variant of coxsackievirus B3 (CVB3) develop fulminant myocarditis. Age-matched female mice show little myocarditis due to decreased virus receptor expression on cardiac cells. TNF alpha and IL-1 beta levels were increased in males by 3 days after infection. IFN gamma levels increased more slowly throughout the 7-day observation period. CD4(+), CD8(+), macrophage (Mac3(+)) and gamma delta(+) cells all accumulated in male hearts, with gamma delta(+) cells showing early (day 3) infiltration. Females also accumulated CD4(+) cells, but few of the other cell types. CD4(+) cells in male hearts predominately produced IFN gamma, indicating a Th1 cell phenotype, whereas CD4(+) cells in females produced IL-4, but little IFN gamma, indicating a Th2 phenotype. CD1d, a major histocompatibility complex I-like molecule often implicated in innate immunity, was increased in CVB3-infected male but not female cardiocytes both in vivo and in vitro. These results demonstrate that CVB3 infections produce gender-specific differences in both innate and adaptive immunity, which may explain the difference in disease susceptibility.