Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis

Abstract

Cardiovascular disease (CVD) and autoimmune diseases (ADs) are the first and third highest causes of death in the USA, respectively. Men have an increased incidence of the majority of CVDs, including atherosclerosis, myocarditis, dilated cardiomyopathy and heart failure. By contrast, nearly 80% of all ADs occur in women. However, in one category of ADs, rheumatic diseases, CVD is the main cause of death. Factors that link rheumatic ADs to CVD are inflammation and the presence of autoantibodies. In this review we will examine recent findings regarding sex differences in the immunopathogenesis of CVD and ADs, explore possible reasons for the increased occurrence of CVD within rheumatic ADs and discuss whether autoantibodies, including rheumatoid factor, could be involved in disease pathogenesis.

Sex and Gender Differences in Myocarditis and Dilated Cardiomyopathy

“…Indeed, men develop atherosclerotic plaques earlier and more extensively than women, while the number of cardiovascular events in women increases strikingly with menopause, suggesting that sex hormones influence heart disease. 58,59,63 …”

“…Heart failure can be the consequence of a number of inflammatory cardiovascular conditions including atherosclerosis, myocarditis, DCM and PPCM. 63,64 Sheppard et al . found that men with myocarditis or acute DCM had higher cardiac expression of proteins associated with apoptosis, such as Fas and tumor necrosis factor receptor 1, than women, while patients with the highest levels of these apoptosis markers had minimal improvement in LVEF.…”

“…Estrogen has a well known ability to activate B cells, resulting in increased antibody responses to infection, vaccines and autoantigens, while androgens have the opposite effect 63,71,77,78 (Figure 1). However, depending on the context, estrogen can either drive T helper (Th)1 and/or Th17 responses, increasing inflammation via transcriptional activation of NFκB, or increase the regulatory arm of the adaptive immune response by enhancing tolerogenic dendritic cells, interleukin (IL)-4-driven Th2 responses, transforming growth factor (TGF)-β, regulatory T cell populations, and alternatively activated macrophages.…”

“…However, depending on the context, estrogen can either drive T helper (Th)1 and/or Th17 responses, increasing inflammation via transcriptional activation of NFκB, or increase the regulatory arm of the adaptive immune response by enhancing tolerogenic dendritic cells, interleukin (IL)-4-driven Th2 responses, transforming growth factor (TGF)-β, regulatory T cell populations, and alternatively activated macrophages. 63,79-81 Estrogen's capacity to decrease cell-mediated immune responses by increasing regulatory mechanisms may be due to its ability to inhibit components of the innate immune response including Toll-like receptor (TLR)4-induced IL-1β, IL-6, tumor necrosis factor-α and NFκB activation from macrophages. 11,71,82-84 Far less research has been conducted on the role of androgens on immunity, but in general, androgens have been found to increase Th1 responses 11,71,78,85 (Figure 1).…”

A Shift in the Balance of Regulatory T and T Helper 17 Cells in Rheumatic Heart Disease

“…41 It is known that sex difference plays an important role in the immunopathogenesis of cardiovascular and autoimmune disease. 42 The findings of our study should be interpreted in this context, and further studies that investigate the possible influence of sex difference on the T H 17/T reg ratio in RHD are needed.…”