The Contribution of Autoantibodies to Inflammatory Cardiovascular Pathology

Abstract

Chronic inflammation and resulting tissue damage underlie the vast majority of acquired cardiovascular disease (CVD), a general term encompassing a widely diverse array of conditions. Both innate and adaptive immune mechanisms contribute to chronic inflammation in CVD. Although maladies, such as atherosclerosis and cardiac fibrosis, are commonly conceptualized as disorders of inflammation, the cellular and molecular mechanisms that promote inflammation during the natural history of these diseases in human patients are not fully defined. Autoantibodies (AAbs) with specificity to self-derived epitopes accompany many forms of CVD in humans. Both adaptive/induced iAAbs (generated following cognate antigen encounter) and also autoantigen-reactive natural antibodies (produced independently of infection and in the absence of T cell help) have been demonstrated to modulate the natural history of multiple forms of CVD including atherosclerosis (atherosclerotic cardiovascular disease), dilated cardiomyopathy, and valvular heart disease. Despite the breadth of experimental evidence for the role of AAbs in CVD, there is a lack of consensus regarding their specific functions, primarily due to disparate conclusions reached, even when similar approaches and experimental models are used. In this review, we seek to summarize the current understanding of AAb function in CVD through critical assessment of the clinical and experimental evidence in this field. We additionally highlight the difficulty in translating observations made in animal models to human physiology and disease and provide a summary of unresolved questions that are critical to address in future studies.

Keywords: atherosclerosis; autoantibodies; autoimmunity; cardiovascular; inflammation.

Figure 1

AAbs in myocarditis and dilated cardiomyopathy. Left panel: a diagram of cardiac anatomy with relevant structures labeled, including the coronary arteries and associated plaques. Middle panel: a generalized schematic for AAbs in atherogenesis showing opposing roles for B-1 cell-derived IgM NAb and B-2 cell-derived IgG iAAb. Right panel: foam cell formation and feed-forward inflammatory activation within vessel plaques through enhanced uptake of oxidized lipids during atherogenesis. Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein; NAbs, natural antibodies; iAAb, induced autoantibodies; Ig, immunoglobulin; oxLDL, oxidized low-density lipoprotein; OSE, oxidation-specific epitope; RA, right atrium; LA, left atrium; IVC, inferior vena cava; SVC, superior vena cava; RV, right ventricle; LV, left ventricle; PA, pulmonary artery.

Figure 2

B-1 and B-2 cells as modulators of cardiovascular inflammation through AAb production. Left panel: B-1 B cells inhabiting the body cavities are interleukin-5 dependent and produce polyreactive natural antibodies, predominantly of the IgM isotype. Right panel: B-2 lymphocytes generate adaptive immunoglobulin under the control of inflammatory cytokine programming. Abbreviations: T_H0, naive CD4⁺ T lymphocyte; T_H1, type 1 inflammation-polarized CD4⁺ helper T lymphocyte; T_H2, type 2 inflammation-polarized CD4⁺ helper T lymphocyte; IFN-γ, interferon gamma.