Aberrant B Cell Signaling in Autoimmune Diseases

Abstract

Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.

Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis

“…APRIL acts as a secreted factor and plays important roles in B cell biology [ 10 ]. The reported capacity of APRIL to stimulate tumor growth in vitro and regulate B cell functions raised the hypothesis that APRIL may be a disease promoter in autoimmune diseases such as RA [ 1 , 7 , 9 , 18 ].…”

“…Unlike most other TNF family members, APRIL is never expressed at the cell membrane. It is cleaved in the Golgi apparatus by a furin convertase to release a soluble active form, which is subsequently secreted [ 7 – 10 ]. Immune cell subsets such as monocytes, macrophages, dendritic cells, neutrophils and T-cells can express APRIL, whose activity takes place through interaction with transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) receptors [ 11 , 12 ].…”

“…Immune cell subsets such as monocytes, macrophages, dendritic cells, neutrophils and T-cells can express APRIL, whose activity takes place through interaction with transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) receptors [ 11 , 12 ]. Furthermore, APRIL is also able to interact with heparin sulfate proteoglycans (HSPGs) [ 10 , 13 – 15 ]. APRIL has been related to different autoimmune diseases including systemic lupus erythematosus (SLE); rheumatoid arthritis (RA) and diabetes [ 16 – 20 ].…”

Endogenously Synthesized n-3 fatty Acids in fat-1 Transgenic Mice Suppresses B Cell Activation

“…Recent studies have demonstrated that B cells secrete various innate cytokines in response to pathogen-associated molecular patterns and contribute to inflammation (23). The production of autoantibodies and cytokines by dysfunctional B cells is increasingly recognized to play an important role in inflammatory and autoimmune diseases (24). B cell-targeted antibodies that deplete or reduce B cell numbers have been reported as promising therapeutics for rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (25).…”

Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis

“…Immune cell subsets such as monocytes, macrophages, dendritic cells, neutrophils and T-cells can express APRIL, whose activity takes place through interaction with transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) receptors [11,12]. It is possible that the heparin sulfate proteoglycans (HSPGs) may represent a third receptor, or function as an important co-receptor [10,[13][14][15]. Originally it has been suggested that APRIL is important in the establishment and/or maintenance of autoimmune diseases including systemic lupus erythematosus (SLE); rheumatoid arthritis (RA) and diabetes [16][17][18][19].…”