Immune mechanisms are critically involved in the pathogenesis of atherosclerosis and its clinical manifestations. Associations of specific antibody levels and defined B cell subsets with cardiovascular disease activity in humans as well as mounting evidence from preclinical models demonstrate a role of B cells and humoral immunity in atherosclerotic cardiovascular disease. These include all aspects of B cell immunity, the generation of antigen-specific antibodies, antigen presentation and co-stimulation of T cells, as well as production of cytokines. Through their impact on adaptive and innate immune responses and the regulation of many other immune cells, B cells mediate both protective and detrimental effects in cardiovascular disease. Several antigens derived from (oxidised) lipoproteins, the vascular wall and classical autoantigens have been identified. The unique antibody responses they trigger and their relationship with atherosclerotic cardiovascular disease are reviewed. In particular, we focus on the different effector functions of specific IgM, IgG, and IgE antibodies and the cellular responses they trigger and highlight potential strategies to target B cell functions for therapy.

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The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, a therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to proteasome inhibition. The ATPase valosin-containing protein (VCP; p97) is an essential regulator of protein degradation in multiple pathways and has emerged as a target for cancer therapy. We found that pharmacological depletion of VCP enzymatic activity with mechanistically different inhibitors robustly induced proteotoxic stress in solid cancer and multiple myeloma cells, including cells that were insensitive, adapted, or clinically resistant to proteasome inhibition. VCP inhibition had an impact on two key regulators of protein synthesis, eukaryotic initiation factor 2α (eIF2α) and mechanistic target of rapamycin complex 1 (mTORC1), and attenuated global protein synthesis. However, a block on protein translation that was itself cytotoxic alleviated stress signaling and reduced cell death triggered by VCP inhibition. Some of the proteotoxic effects of VCP depletion depended on the eIF2α phosphatase, protein phosphatase 1 regulatory subunit 15A (PPP1R15A)/PP1c, but not on mTORC1, although there appeared to be cross-talk between them. Thus, cancer cell death following VCP inhibition was linked to inadequate fine-tuning of protein synthesis and activity of PPP1R15A/PP1c. VCP inhibitors also perturbed intracellular amino acid levels, activated eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4), and enhanced cellular dependence on amino acid supplies, consistent with a failure of amino acid homeostasis. Many of the observed effects of VCP inhibition differed from the effects triggered by proteasome inhibition or by protein misfolding. Thus, depletion of VCP enzymatic activity triggers cancer cell death in part through inadequate regulation of protein synthesis and amino acid metabolism. The data provide novel insights into the maintenance of intracellular proteostasis by VCP and may have implications for the development of anti-cancer therapies.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide 1,2 . Atherosclerotic plaque formation is initiated upon trapping of low-density lipoprotein (LDL) in the subendothelial space of large and medium size arteries that initially involves binding of LDL to heparan-sulfate proteoglycans (HSPGs) 3 , followed by a chronic inflammation and remodelling of the artery wall 3 . A Proliferation Inducing Ligand (APRIL), a cytokine produced by many cell types, binds to HSPGs 4 , but the physiology of this interaction is largely unknown. Here, we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice.Mechanistically, we demonstrate that APRIL confers atheroprotection via binding to heparan sulfate (HS) chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits LDL retention, macrophage accumulation and necrotic core formation. Indeed, antibody-mediated depletion of APRIL in mice expressing HS-deficient HSPG2 had no effect on atherosclerosis development.Consistent with these data, treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduces experimental atherosclerosis. Furthermore, the serum levels of a previously unknown form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long term (10-to 12-year follow up) cardiovascular mortality in patients with atherosclerosis. Our data reveal hitherto unknown properties of APRIL that have broad pathophysiological implications for vascular homeostasis.

Atherosclerosis is a lipid-driven chronic inflammatory disease that is modulated by many immune cell subsets, including B cells. Therefore, targeting the inflammatory component of cardiovascular disease represents a promising therapeutic strategy. In the past years, immunotherapy has revolutionized the treatment of autoimmunity and cancer. Many of these clinically used strategies target B cells. Given the multifaceted role of B cells in atherogenesis, it is conceivable that B-cell–directed therapies can modulate disease development. Here, we review clinically available B-cell–targeted therapies and the possible benefits or detrimental effects on cardiovascular disease.

Complement factor H (CFH) has a pivotal role in regulating alternative complement activation through its ability to inhibit the cleavage of the central complement component C3, which links innate and humoral immunity. However, insights into the role of CFH in B cell biology are limited. Here, we demonstrate that deficiency of CFH in mice leads to altered splenic B cell development characterized by the accumulation of marginal zone (MZ) B cells. Furthermore, B cells in Cf h −/− mice exhibit enhanced B cell receptor (BCR) signaling as evaluated by increased levels of phosphorylated Bruton's tyrosine kinase (pBTK) and phosphorylated spleen tyrosine kinase (pSYK). We show that enhanced BCR activation is associated with uncontrolled C3 consumption in the spleen and elevated complement receptor 2 (CR2, also known as CD21) levels on the surface of mature splenic B cells. Moreover, aged Cf h −/− mice developed splenomegaly with distorted spleen architecture and spontaneous B cell-dependent autoimmunity characterized by germinal center hyperactivity and a marked increase in anti-double stranded DNA (dsDNA) antibodies. Taken together, our data indicate that CFH, through its function as a complement repressor, acts as a negative regulator of BCR signaling and limits autoimmunity.

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