B cell subsets in atherosclerosis

Abstract

Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis by secretion of natural IgM antibodies. Conventional B-2 B cells can promote atherosclerosis through less clearly defined mechanism that may involve CD4 T cells. Yet, there may be other populations of B cells within these subsets with different phenotypes altering their impact on atherosclerosis. Additionally, the role of B cell subsets in atherosclerosis may depend on their environmental niche and/or the stage of atherogenesis. This review will highlight key findings in the evolving field of B cells and atherosclerosis and touch on the potential and importance of translating these findings to human disease.

Keywords: B cell; IgM; atherosclerosis; cytokines; lipids.

Figure 1

Characteristics of advanced atherosclerotic disease. As luminal LDL is deposited into the subendothelial space of the blood vessel wall, it becomes oxidized. Oxidized lipids trigger the recruitment of leukocytes to the subendothelial space. Monocytes differentiate into dendritic cells or tissue macrophages that take up oxidized lipids and become foam cells. Without effective clearance of these apoptotic-prone cells, they accumulate, secrete pro-inflammatory cytokines and undergo apoptosis and necrosis, dumping their lipid contents into the extracellular space to create a necrotic core. Cytokines and immunoglobulins produced by vessel wall and immune cells can further modulate atherosclerosis. ATLOs are found in the adventitia of diseased vessels and are composed of T cells, B cells, macrophages, and other leukocytes. Soluble factors can cross into the media through conduits and may contribute to plaque development. Abbreviation: oxLDL, oxidized LDL; ATLO, aortic tertiary lymphoid organ; EC, endothelial cell; SMC, smooth muscle cell; Adip, adipocyte; Mono, monocyte; Mac, macrophage; FC, foam cell; DC, dendritic cell.

Figure 2

Known and putative roles for B cell subsets in atherosclerosis. Conventional, follicular B-2 B cells may promote atherosclerosis by skewing CD4 T cell differentiation to IFNγ producing Th1 cells and away from IL-17 producing Th17 T cells. The role of Bregs in atherosclerosis is not yet determined, but they may attenuate atherosclerosis by secretion of IL-10. Peritoneal B-1a B cells attenuate atherosclerosis through production of IgM, and potentially IL-10. PD-L2 is expressed on anti-PC B-1a B cells, potentially marking atheroprotective cells within this subset. The role of innate response activator B cells (IRA; derived from peritoneal B-1a B cells) in atherosclerosis is unknown but they produce GM-CSF, which may be linked to atherogenesis. The role of B-1b B cells in atherosclerosis is unknown. *(- - -) Role in atherosclerosis not yet reported.

Figure 3

Immune cells at homeostasis in the adventitia of C57BL/6 and Apoe^−/− mice. A healthy blood vessel is composed of an endothelial layer, an intima in between the endothelial layer and smooth muscle cell layer, and a smooth muscle cell layer (media) surrounded by the adventitia and peri-vascular fat. (A) The adventitia of a C57BL/6 mouse contains T cells, B cells, macrophages, dendritic cells, and others (neutrophils, natural killer cells, and natural killer T cells; Galkina et al., ; Jongstra-Bilen et al., 2006). (B) Apoe^−/− mice have an increase in the number of T cells and macrophages, with a lesser increase in dendritic cells and other cells (neutrophils, natural killer cells, and natural killer T cells) compared to C57BL/6 (Galkina et al., 2006). Abundant adventitial B cells persist in the Apoe^−/− mouse (Galkina et al., ; Doran et al., 2012). They also have an expanded peri-vascular fat pad compared to (A). Abbreviation: Mac, macrophage; DC, dendritic cell; EC, endothelial cell; SMC, smooth muscle cell; Adip, adipocyte.