Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations

Abstract

B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF-depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed.

Is hydroxychloroquine beneficial for COVID-19 patients?

“…Various studies have shown that HCQ increases the intracellular pH and inhibits lysosomal activity in antigenpresenting cells (APCs), including plasmacytoid dendritic cells (pDCs) 35,36 and B cells 37 , and also blocks major histocompatibility complex (MHC) class II-mediated antigen presentation to CD4 + T cells, and thus prevents the differentiation of these T cells (such as T follicular helper cells) 38 . This also leads to a reduction in the production of cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-1β 38,39 .…”

Comparison of Plasma Cytokine Levels before and after Treatment with Rituximab in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus-Associated Polyautoimmunity

“…Type I IFNs increase B-cell survival factors production, such as BAFF (17). A feedback loop between BAFF and Type I IFNs has been proposed (18). Therefore, altering Type I IFN pathways can abrogate autoimmune phenomena.…”

B Cell-Activating Factor (BAFF) in Inflammatory Bowel Disease: BAFFling No Longer?

“…Nevertheless, most of the biologics are designed to inhibit either proinflammatory cytokines or affect the regulation of Th1/Th17 pathways. Although the human monoclonal BAFF antibody belimumab was approved for systemic lupus erythematosus, having a low incidence of organ damage and an excellent safety profile [8], other BAFF inhibitors were much less beneficial in clinical trials, suggesting redundancies in B cell signalling/survival pathways, which should be better understood before future clinical trials are conducted [9]. Recently, blisibimod, a potent and selective BAFF inhibitor with a unique tetravalent, ''peptibody'' structure, has been introduced in clinical evaluation for the treatment of systemic lupus erythematosus (SLE) [10].…”