CD21^−/low B cells associate with joint damage in rheumatoid arthritis patients

Abstract

Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21^-/low B cells). In this study, we sought to determine whether there was any correlation between CD21^-/low B cells and clinical outcome in patients with established RA, either ACPA⁺ /RF⁺ (n = 27) or ACPA^- /RF^- (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21^-/low CD27^- IgD^- memory B cell subset in peripheral blood (PB) was significantly increased in ACPA⁺ /RF⁺ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21^-/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21^-/low , approximately 40% of that population was CD27^- IgD^- , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27^- IgD^- subset of CD21^-/low B cells may mediate joint destruction in patients with ACPA⁺ /RF⁺ RA.