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The role of B cells in atherosclerosis

Nature Reviews Cardiology volume 16, pages 180–196 (2019)Cite this article

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Abstract

The cardiovascular system is subject to hyperlipidaemic, inflammatory, and pro-oxidant stressors. Over time, these factors drive prevalent chronic diseases, of which atherosclerosis is most prominent and accounts for the majority of deaths globally. Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. The power, inducibility, and adaptability of the antibody repertoire require an equally complex range of control measures. Defects and chronic perturbations in these checkpoints lead to inappropriate antibody responses, which might have important roles in shaping the development and outcome of atherosclerotic disease. A unique aspect related to atherosclerosis is the prominent role of natural antibodies, specifically those binding to the oxidized epitopes that are abundant on modified lipoproteins and cellular debris. B cells control cellular immune responses through cell–cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted. For these reasons, a deeper understanding of how B cells influence atherosclerotic plaque development is being pursued with the hope of providing novel B cell-targeted interventions to prevent inflammation-driven cardiovascular events.

Key points

  • Atherosclerosis is associated with both innate and adaptive immune responses.

  • Inflammation in atherosclerosis is mainly driven by neo (self-)epitopes present on LDL and dying cells, which are both recognized by natural antibodies.

  • B cell responses targeting oxidation-specific epitopes might limit disease, whereas other antibodies might have pathogenic consequences.

  • Antibody-independent roles for B cells, such as cytokine production and T cell regulation, also contribute to B cell control of atherosclerosis.

  • B cell-depletion therapies and vaccination strategies show promise; however, more-precise targeting of different B cell functions is an important future goal.

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Fig. 1: B cell effector mechanisms in atherosclerotic plaques.
Fig. 2: B cell responses in lymphoid organs that regulate atherosclerosis.

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Nature Reviews Cardiology thanks K. Ley, J. Nilsson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK

    Andrew P. Sage, Dimitrios Tsiantoulas & Ziad Mallat

  2. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Christoph J. Binder

  3. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Christoph J. Binder

  4. INSERM U970, Paris Cardiovascular Research Center, Paris, France

    Ziad Mallat

  5. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Ziad Mallat

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Glossary

Oxidation-specific epitopes

(OSEs). Lipid moieties, such as malondialdehyde and phosphorylcholine, often found as adducts on biological molecules as a result of oxidative modification.

B cell receptors

(BCRs). The surface antibody proteins expressed by each B cell clone. Each clone expresses a unique BCR that derives from random recombination of germline variable region genes.

Plasma cells

Specialized B cell-derived postmitotic cells with high protein synthesis and secretion capacity that secrete high amounts of soluble antibodies into the bloodstream.

Marginal zone

(MZ). A specialized region of the spleen on the border of the white and red pulp that functions to monitor and filter the blood. The marginal zone is populated by specialized B cell and macrophage subsets.

Germinal centre

(GC). A localized region of a follicle of a lymphoid organ that arises when antigen-specific B2 cells and T cells combine; B2 cells proliferate rapidly as GC B cells.

Class switching

An individual activated B cell clone undergoes recombination at the B cell receptor genomic locus resulting in different constant (Fc) region usage and production of a new class (isotype) of antibody.

Affinity maturation

Germinal centre B cell clones reactive to a certain antigen hypermutate the B cell receptor variable region and, via competitive evolution and natural selection, clones with progressively higher affinity for the antigen emerge.

Antibody-secreting cells

A term that encompasses any B cell that secretes soluble antibodies, including plasmablasts, B1 cells, and plasma cells.

Ldlr −/− mice

LDL receptor-deficient mice are a model of atherosclerosis when fed high-cholesterol and high-fat diets owing to the inability of the liver to take up LDL.

Natural antibodies

Antibodies, mostly of IgM, IgA, and/or IgG3 isotypes, that arise early in life independently of the presence of microorganisms.

Apoe −/− mice

Apolipoprotein E is the ligand for the LDL receptor and Apoe-knockout mice have high levels of circulating cholesterol (VLDL and triglycerides), in addition to defects in phagocytosis; they are a widely used model of atherosclerosis.

Immune complexes

Molecular aggregates of antibodies and their cognate antigen. Immune complex formation is often (but not always) necessary for activation of downstream antibody effector functions.

B cell activating factor

(BAFF). Essential for B2 cell development and important in many aspects of B cell physiology but also regulates other cell types such as macrophages.

B cell-depletion therapy

Therapy that comprises a class of monoclonal antibodies that target B cell-specific surface molecules and so result in antibody-dependent cell cytotoxicity.

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Sage, A.P., Tsiantoulas, D., Binder, C.J. et al. The role of B cells in atherosclerosis. Nat Rev Cardiol 16, 180–196 (2019). https://doi.org/10.1038/s41569-018-0106-9

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