B Cells in Atherosclerosis: Mechanisms and Potential Clinical Applications

Abstract

Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell-linked therapeutic approaches, including immunization and B cell-targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.

Keywords: APRIL, A proliferation−inducing ligand; ApoE, apolipoprotein E; B-cell; BAFF, B-cell–activating factor; BAFFR, B-cell–activating factor receptor; BCMA, B-cell maturation antigen; BCR, B-cell receptor; Breg, regulatory B cell; CAD, coronary artery disease; CTLA4, cytotoxic T-lymphocyte–associated protein 4; CVD, cardiovascular disease; CXCR4, C-X-C motif chemokine receptor 4; GC, germinal center; GITR, glucocorticoid-induced tumor necrosis factor receptor–related protein; GITRL, glucocorticoid-induced tumor necrosis factor receptor–related protein ligand; GM-CSF, granulocyte-macrophage colony–stimulating factor; ICI, immune checkpoint inhibitor; IFN, interferon; IL, interleukin; IVUS, intravascular ultrasound; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; MDA-LDL, malondialdehyde-modified low-density lipoprotein; MI, myocardial infarction; OSE, oxidation-specific epitope; OxLDL, oxidized low-density lipoprotein; PC, phosphorylcholine; PD-1, programmed cell death protein 1; PD-L2, programmed death ligand 2; PDL1, programmed death ligand 1; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TACI, transmembrane activator and CAML interactor; TNF, tumor necrosis factor; Treg, regulatory T cell; atherosclerosis; immunoglobulins; mAb, monoclonal antibody.

Graphical abstract

Figure 1

Broad Overview of Subsets of Murine B Cells That Are Involved in Atherosclerosis Murine B cells can be divided into B cell subsets based on established cell surface markers. The B1 B cells are atheroprotective and can be divided into B1a and B1b based on CD5 expression with B1a being CD5+ and B1b being CD5-. B1a and B1b have unique capability to produce atheroprotective IgM in a T cell independent manner. In response to LPS, B1a cells can migrate to spleen and produce GM-CSF, promoting extramedullary hematopoiesis and atherogenesis (IRA B cells). Both B1 and B2 cells can give rise to IL-10 producing regulatory B cells (Breg). Breg is defined by its capability to produce anti-inflammatory cytokines like IL-10. B2, on the other hand, promotes atherosclerosis through production of atherogenic IgG, activation of T cells, and induced production of inflammatory cytokines (eg, IFN). GM-CSF = granulocyte-macrophage colony-stimulating factor; IgG = immunoglobulin G; IgM = immunoglobulin M; IL = interleukin; IFN = interferon; LPS = lipopolysaccharide.

Figure 2

Immunization Various types of antigens (eg, MDA-LDL, PC, ApoB-100 peptide) were shown to have an atheroprotective effect in pre-clinical models. Whether any of these antigens work and how they work in human are still unanswered questions. A potential mechanism underlining atheroprotective effect of the immunization includes stimulation of antigen specific immunoglobulin (IgM or IgG) production. These immunoglobulins can potentially bind to oxidized LDL to prevent formation of foam cells leading to a plaque formation. However, detailed characterization of B cells responsible for immunoglobulin production to limit atherosclerosis is still needed. ApoB = apoliprotein B; MDA-LDL = malondialdehyde modified low density lipoprotein; OxLDL = oxidized low density lipoprotein; other abbreviations as in Figure 1.

Figure 3

B-Cell Therapies That Target BCR Modulation and Activation Binding of Ag to the B cell receptor (BCR) induces a signaling cascade that increases intracellular Ca²⁺ and also results in transcription of genes that increase chemokine release. Ibrutinib and acalabrutinib inhibit BTK, a key step in the cascade, thus possibly decreasing release of chemokines such as CCL3 and CCL4, which enhances tissue infiltration by monocytes and T cells. Similarly, epratuzumab is an agonist of CD22, which, when activated, results in inhibition of the BCR activation cascade. BLNK = B cell linker protein; BTK - Bruton tyrosine kinase; ERK = extracellular signal-regulated kinase; NF-kB1 = nuclear factor kappa Beta subunit 1; PKC = protein kinase C.

Figure 4

B-Cell and Plasma Cell Depletion Therapies These therapies target surface receptors that are pan markers of B cells (CD20, CD19, CD22) and plasma cells (CD38, CD19, SLAMF7, BCMA). The impact of these therapies on atherosclerosis is unknown but maybe governed by the B cell subtypes/plasma cells that are depleted.

Figure 5

B-Cell Therapies That Target B-Cell Survival Inhibit Interaction of APRIL and BAFF With TACI, BCMA, and BAFFR on B Cells Binding of APRIL and BAFF ligands activates an intracellular signaling cascade via NF-κB that results in transcription of genes that enhance B cell survival. Atacicept inhibits binding of APRIL on BCMA and TACI and binding of BAFF on BAFFR, while belimumab, blisibimod and ianalumab target only binding between BAFF and BAFFR. APRIL = A proliferation-inducing ligand; BAFF = B-cell activating factor; BAFFR = B-cell activating factor receptor; BCMA = B-cell maturation antigen; BCR = B cell receptor; TACI = transmembrane activator and CAML interactor; other abbreviations as in Figure 2.

Figure 6

Therapies Targeting Interactions of Immune Checkpoint Receptors to Disrupt T-Cell Activation Through T- and B-Cell Communication This family of therapies can be divided into immune checkpoint inhibitors (ICIs) and T cell co-stimulation classes. ICIs mainly target interactions between PD-1 and PD-L1/L2 or CTLA4 and CD80/86, which generally inhibits T cell activation and proliferation caused by TCR and MHCII interaction. Therefore, ICIs increase T cell activation which could result in atherogenic effects. T cell costimulation serves to promote T cell response to foreign antigens and to limit undesired responses to self-antigens. This class of drugs mainly targets CD28-CD80/86, CD40L/CD40, GITR/GITRL, OX40/OX40L, and CD137/CD137L interactions. IL2 = interleukin-2; MHCII =major histocompatibility complex class II molecules; TNFα = tumor necrosis factor- alpha; other abbreviation as in Figure 2.

Central Illustration

Roles of B Cells in Atherosclerosis and Implications of B-Cell–Targeted Therapies for Cardiovascular Disease IgG = immunoglobulin G; IgM = immunoglobulin M.