The pathogenesis of coxsackievirus B3-induced autoimmune myocarditis

Coxsackievirus B3 (CB3), shown to induce intracardiac interferon-gamma (IFN-γ) and nitric oxide (NO) production, causes heart lesions ranging from viral myocarditis to autoimmune myocarditis in susceptible mouse strains. We hypothesized that IFN-γ-induced NO production is important in disease pathogenesis: initially it prevents viral myocarditis whereas later it induces autoimmune myocarditis through its antiviral activity and immune modulating capability, respectively.; First, we examined B 10.M mice (H-2f) for gender-specific susceptibility to the development of autoimmune myocarditis. Using the CB3- and myosin-induced disease models, female mice developed autoimmune myocarditis, based on cardiac interstitial infiltrates and murine cardiac myosin (MCM)-specific splenocyte proliferation, whereas male mice did not, Successful transfer of disease with splenocytes in female mice further supported their susceptibility to autoimmune disease.; Second, we proposed that NO exerts both antiviral and autoimmune disease promoting effects in CB3-infection. Aminoguanidine (AG) blockage of inducible-nitric oxide synthase enzyme (I-NOS) early (days 0–7) after virus-inoculation enhanced cardiac necrotizing (viral) lesions in B 10.M male and female mice without affecting the cardiac viral titers. Late (days 10–20) blockage of I-NOS reduced the severity of cardiac interstitial (autoimmune) lesions in susceptible female B 10.M mice independent of MCM-specific severity. We concluded that NO plays a protective role in the viral disease and a detrimental role during the autoimmune disease.; Third, we hypothesized that IFN-γ-dependent NO production is important in CB3-induced disease. Blocking circulating IFN-γ in A.CA mice (H-2 f) using a monoclonal rat anti-mouse IFN-γ antibody early (days -1 + 3) in infection reduced the severity of cardiac lesions and decreased urinary NO levels on day 8 after CB3-inoculation. Late (days 7 + 11) anti-IFN-γ treatment failed to alter the disease severity on day 21 after virus-inoculation. Early IFN-γ production contributes to the development of cardiac histopathologic lesions through a NO-independent mechanism during viral disease, but may be important in NO-dependent cardiac lesions during the autoimmune disease.; NO plays a dichotomous role in CB3-infection by preventing cardiac viral lesions while concurrently enhancing cardiac autoimmune lesions in susceptible B 10.M female mice. IFN-γ contributes to disease pathogenesis through NO-dependent and NO-independent effector functions.