Regulation of B cell activating factor (BAFF) receptor expression by NF-κB signaling in rheumatoid arthritis B cells

Abstract

B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). High levels of B cell activating factor (BAFF) are detected in autoimmune diseases. BAFF and BAFF receptor (BAFF-R) are expressed in B and T cells of RA synovium. The study was undertaken to identify the NF-κB signal pathway involved in the induction of BAFF-R in human B cells. Immunohistochemical staining of NF-κB p65, NF-κB p50, BAFF, and BAFF-R was performed on sections of synovium from severe and mild RA and osteoarthritis (OA) patients. Peripheral blood mononuclear cells (PBMCs) were isolated from control and RA patients and B cells were isolated from controls. BAFF-R was analyzed by flow cytometry, realtime PCR and confocal staining after treatment with NF-κB inhibitors. NF-κB p65, NF-κB p50, BAFF, and BAFF-R were highly expressed in severe RA synovium relative to mild RA synovium or OA synovium. BAFF-R expression was reduced by NF-κB inhibitors in PBMCs and B cells from normal controls. We also showed reduction in expression of BAFF-R via inhibition of the NF-κB pathway in PBMCs of RA patients. BAFF/BAFF-R signaling is an important mechanism of pathogenesis in RA and that BAFF-R reduction by NF-κB blocking therapy is another choice for controlling B cells in autoimmune diseases such as RA.

The Roles of the TNF-Family Member B-Cell Activation Factor Belonging to the TNF-Family (BAFF) in Autoimmunity

“…Although the BAFF-R expressions on PBMCs and B cells were reduced, BAFF-R in synovial tissues from RA patients was highly expressed [86].…”

BAFF System in Rheumatoid Arthritis: from Pathobiology to Therapeutic Targets

“…Abnormal BAFF/BAFF receptor-signaling pathways were reported in several autoimmune disorders including systemic lupus erythematosus, Sjogren's syndrome, ANCA-associated vasculitis, and RA [2,4,5]. Of interest, elevated BAFF levels were detected in synovial luid, serum, and saliva in very early stages of RA, suggesting its involvement in cell-cell interactions network in the synovial microenvironment, as well as B-cell activation and the development of autoreactive B cells [2][3][4].…”

“…Acting as an innate cytokine mediator, BAFF is known to modulate peripheral B-and T-cell homeostasis, promoting speciic downstream signaling events through three diferent types of receptors [2,4,5].…”

“…Of interest, elevated BAFF levels were detected in synovial luid, serum, and saliva in very early stages of RA, suggesting its involvement in cell-cell interactions network in the synovial microenvironment, as well as B-cell activation and the development of autoreactive B cells [2][3][4]. Furthermore, the overexpression of BAFF receptors, as well as disturbed autocrine and paracrine BAFF network, seems to be related to inlammatory events and RA progression [1][2][3][4][5][6].…”

“…Recent data highlighted the role of signaling crosstalk in B-lymphocytes, particularly of B-cell-activating factor (BAFF) and its receptors in early steps of the disease, advancing clinical development of BAFF antagonists for the treatment of RA [2][3][4][5]. Acting as an innate cytokine mediator, BAFF is known to modulate peripheral B-and T-cell homeostasis, promoting speciic downstream signaling events through three diferent types of receptors [2,4,5].…”