Autoimmunity in Coxsackievirus B3 induced myocarditis: role of estrogen in suppressing autoimmunity

Abstract

Picornaviruses are small, non-enveloped, single stranded, positive sense RNA viruses which cause multiple diseases including myocarditis/dilated cardiomyopathy, type 1 diabetes, encephalitis, myositis, orchitis and hepatitis. Although picornaviruses directly kill cells, tissue injury primarily results from autoimmunity to self antigens. Viruses induce autoimmunity by: aborting deletion of self-reactive T cells during T cell ontogeny; reversing anergy of peripheral autoimmune T cells; eliminating T regulatory cells; stimulating self-reactive T cells through antigenic mimicry or cryptic epitopes; and acting as an adjuvant for self molecules released during virus infection. Most autoimmune diseases (SLE, rheumatoid arthritis, Grave's disease) predominate in females, but diseases associated with picornavirus infections predominate in males. T regulatory cells are activated in infected females because of the combined effects of estrogen and innate immunity.

Figure 1

Effects of estrogen on innate and adaptive immune responses. Estrogen signals through two receptors (ESR1 and ESR2). ESR1 suppresses expression of one of the two known coxsackievirus B3 receptors, decay accelerating factor (DAF) which will restrict virus infection and replication. Lower virus loads will result in less direct virus mediated injury by reducing numbers of infected cells and will also reduce Toll-like receptor (TLR) signaling which will restrict pro-inflammatory cytokine expression. Reduced virus loads will also decrease the amount of viral epitopes which mimic self molecules and thus prevent induction of autoimmunity through this mechanism. ESR1 also promotes antibody responses and increased virus neutralizing antibody will further inhibit virus infection. Finally signaling through ESR1 promotes T regulatory cell responses which will further suppress immunopathogenic T cell activation. ESR2 has the opposite effects of ESR1 as signaling through this receptor increases virus receptor expression/virus infection and suppresses T regulatory cell response.