The role of B cells in heart failure and implications for future immunomodulatory treatment strategies

Abstract

Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.

Keywords: B cells; Heart failure; Inflammation; Therapeutics.

Figure 1

Antibody‐dependent mechanisms. (A) IgG3 antibodies can exert their function by being recognized through their Fc by Fc (fragment crystallizable region) γ‐receptor (FCγR) (1, 2) or by binding to specific surface receptors influencing their activity, as occurs with M₂‐adrenergic and β₁‐adrenergic receptors (3). (B) Antibody‐mediated disease may also induce the activation of the complement system via the classical pathway ending in membrane attack complex (C5b‐9) formation and chemotaxis of myeloid cells, allowing inflammation, fibrosis, and tissue dysfunction promoting hypertrophy and arrhythmias. C5aR, C5a receptor; TNF‐α, tumour necrosis factor‐α; TGF‐β, transforming growth factor‐β. Original image created with BioRender®.

Figure 2

Antibody‐independent mechanisms. After cardiac ischaemic and non‐ischaemic injury, B cells become activated and proliferate in response to damage‐associated molecular patterns (DAMPs) that are released (from damaged cells and tissues) in response to cardiac injury. Their activation has been associated with chemotaxis of LyC6 + CCR2⁺ monocytes, which are involved in pathogenic remodelling and inflammation (1), though CCL7. The secretion of pro‐inflammatory cytokines is associated with fibrosis and detrimental function (2) as well as with proper cell activation and cell differentiation. The promotion of T‐cell activation and differentiation to the Th1 phenotype might be mediated by antigen cell presentation by B cells. This response contributes to the inflammatory milieu and may subsequently stimulate cardiac fibrosis through cardiac fibroblasts (3). BAFF‐R, B cell‐activating factor receptor; BCR, B cell receptor; CCL7, C–C motif chemokine ligand 7; CCR2, C–C chemokine receptor type 2; CD, cluster of differentiation (CD19 and CD20); IFN‐γ, interferon‐γ; IL‐1β, interleukin‐1β; Th1, type 1 helper T cell; TGF‐β, transforming growth factor‐β; TNF‐α, tumour necrosis factor‐α. Original image created with BioRender®.

Figure 3

B cells play a central role in heart failure. After the cardiac injury, damage‐associated molecular patterns (DAMPs) are recognized, processed, and presented by resident B cells that become activated in a T‐dependent mechanism. In response, B cells secrete cytokines and chemokines that contribute with the inflammatory milieu along with the activated T cells mainly by a Th1 response (tumour necrosis factor‐α and interferon‐γ). Cell recruitment as monocytes (Mn) become activated, promoting fibrosis, hypertrophy, and tissue remodelling. The inflammatory milieu allows autoreactive B cells to become fully activated and differentiated into a memory B cell or plasma cell that produces mainly IgG3 antibodies against cardiac proteins. This induces further myocardial damage by antibody‐dependent mechanisms.