B Cells at the Cross-Roads of Autoimmune Diseases and Auto-Inflammatory Syndromes

Abstract

Whereas autoimmune diseases are mediated primarily by T and B cells, auto-inflammatory syndromes (AIFS) involve natural killer cells, macrophages, mast cells, dendritic cells, different granulocyte subsets and complement components. In contrast to autoimmune diseases, the immune response of patients with AIFS is not associated with a breakdown of immune tolerance to self-antigens. Focusing on B lymphocyte subsets, this article offers a fresh perspective on the multiple cross-talks between both branches of innate and adaptive immunity in mounting coordinated signals that lead to AIFS. By virtue of their potential to play a role in adaptive immunity and to exert innate-like functions, B cells can be involved in both promoting inflammation and mitigating auto-inflammation in disorders that include mevalonate kinase deficiency syndrome, Kawasaki syndrome, inflammatory bone disorders, Schnitzler syndrome, Neuro-Behçet's disease, and neuromyelitis optica spectrum disorder. Since there is a significant overlap between the pathogenic trajectories that culminate in autoimmune diseases, or AIFS, a more detailed understanding of their respective roles in the development of inflammation could lead to designing novel therapeutic avenues.

Keywords: B cell; Kawasaki syndrome; Neuro-Behçet’s disease; Schnitzler syndrome; autoimmunity; autoinflammation; inflammatory bone disorders; mevalonate kinase deficiency syndrome; neuromyelitis optica spectrum.

Figure 5

Genetic predisposition, environmental factors, and defective immune regulation underlie initiation of both autoimmune diseases and auto-inflammatory syndromes. The BLK and CD40 loci are known to be associated with AIDs, such as lupus, arthritis and Crohn’s disease, as well as AIFS, such as Kawazaki syndrome. Environmental triggers have been documented in several AID and AIFS. Defects in development or functions of cells of both innate and adaptive immunity may lead to abnormal functionalities in these cells and altered or hyperactive immune responses [56,70]. These various factors, in isolation or in combination, can result in tissue injury. By virtue of their roles in both the innate and adaptive immune systems, B cells are at the crossroads of autoimmune diseases and auto-inflammatory syndromes.

Figure 1

B cell cytokine-mediated pro-inflammatory pathways that act on innate immunity. B cells can exert multiple immune activities that promote inflammatory processes by producing cytokines that act on immune cells that mediate inflammation, such as macrophages and natural killer cells. Through their interactions with the skeletal system, they can promote bone erosion 46. In the central nervous system, their potential to secrete inflammatory cytokines can aggravate neuroinflammation.

Figure 2

B cell contact-dependent mechanisms that modulate innate immunity. B cell modulating activities are not limited to cytokine production. Co-stimulatory interactions with dendritic cells or T cells can lead to immune suppression. In the innate branch of the immune system, B cells can modulate expression of invariant natural killer T (iNKT) cells through presentation of lipid antigens via the CD1d receptor, leading to expansion of inflammatory INF-gamma production.

Figure 3

B cells produce cytokines that can mitigate various pro-inflammatory pathways. Anti-inflammatory activities of B cells that act on cells of the innate immune system have been well documented. Thus, human B cells can exert multiple immune suppressive activities on cells of both the adaptive and innate immune systems. They can inhibit CD8+ T cell-mediated cytotoxicity and suppress Th1 and Th17 inflammatory responses. In parallel, they also promote the differentiation of CD4+ T cells into IL-10+ T regulatory-1 (Tr1) cells and FoxP3+ Tregs cells. In addition to impacting adaptive immune responses, B cells reduce TNF-α production by monocytes, and reduce functions of iNKT cells.

Figure 4

B cell contact-dependent mechanisms modulating innate immunity by inhibitory receptors expressed by B cells. B cells can contact and suppress other effector cells through inhibitory receptors, including PD-1. The immunosuppressive PD-1 receptor is expressed by B lymphocytes, including germinal center B cells and plasma cells [65,66], and its PD-L1 and PD-L2 receptors are expressed by non-lymphoid cells, including monocytes and macrophages. Thus, this pathway represents another regulatory mechanism that enables B cells to impact a key player of innate immunity, i.e., the monocyte.