B cells and humoral immunity in atherosclerosis

Abstract

Insights into the important contribution of inflammation and immune functions in the development and progression of atherosclerosis have greatly improved our understanding of this disease. Although the role of T cells has been extensively studied for decades, only recently has the role of B cells gained more attention. Recent studies have identified differential effects of different B-cell subsets and helped to clarify the still poorly understood mechanisms by which these act. B1 cells have been shown to prevent lesion formation, whereas B2 cells have been suggested to promote it. Natural IgM antibodies, mainly derived from B1 cells, have been shown to mediate atheroprotective effects, but the functional role of other immunoglobulin classes, particularly IgG, still remains elusive. In this review, we will focus on recent insights on the role of B cells and various immunoglobulin classes and how these may mediate their effects in atherosclerotic lesion formation. Moreover, we will highlight potential therapeutic approaches focusing on B-cell depletion that could be used to translate experimental evidence to human disease.

Keywords: B-lymphocytes; antibodies; atherosclerosis; complement system proteins; immunity, humoral; immunoglobulin M.

Figure 1. B1 and B2 cells have different immunoglobulin production profiles in mice

B cells are divided in 2 main subfamilies, the B1 and B2 cells. B1 cells produce germline-encoded natural IgM and IgA antibodies. B2 cells respond to T-cell help on antigen stimulation and produce adaptive IgM, followed by IgG (IgG1, IgG2a/c, IgG3), IgA, or IgE antibodies via a process termed class switching.

Figure 2. Role of immunoglobulins in lesion development

Different immunoglobulins are present in atherosclerotic plaques, which are directed against relevant antigens such heat shock proteins (HSPs) and oxidized low-density lipoproteins (OxLDLs). IgM antibodies may mediate atheroprotection by neutralizing the proinflammatory properties of OxLDL, inhibiting the uptake of OxLDL by macrophages, and by promoting apoptotic cell clearance. Their protective capacity may be largely dependent on their ability to recognize oxidation-specific epitopes (OSEs) present on both OxLDL and apoptotic cells. OxLDL-specific IgG antibodies could activate macrophages via Fcγ receptor engagement, thereby promoting atherogenesis, but may also exhibit protective neutralizing capacities. IgM and IgG immune complexes with LDL carrying OSEs are also found in the circulation and may promote clearance of proatherogenic LDL particles. HSP60/65-specific IgG recognize stressed endothelial cells and induce damage via antibody-dependent cellular cytotoxicity. IgE antibodies activate mast cells and macrophages via the engagement FcεRI resulting in plaque destabilization. Specificities of IgE for atherosclerosis antigens, for example, OxLDL, remain to be shown. The role of IgA antibodies in atherosclerosis is still elusive. Opsonization of apoptotic cells with C3b and iC3b enhances their uptake by macrophages. EC indicates endothelial cells; IC, immune complexes; IFN-γ interferon-γ; IL-6, interleukin-6; SMCs, smooth muscle cells; and SR, scavenger receptors.