Abstract
While autoantibodies are used in the diagnosis of rheumatoid arthritis (RA), the function of B cells in the inflamed joint remains elusive. Extensive flow cytometric characterization and SPICE algorithm analyses of single-cell synovial tissue from patients with RA revealed the accumulation of switched and double-negative memory programmed death-1 receptor–expressing (PD-1–expressing) B cells at the site of inflammation. Accumulation of memory B cells was mediated by CXCR3, evident by the observed increase in CXCR3-expressing synovial B cells compared with the periphery, differential regulation by key synovial cytokines, and restricted B cell invasion demonstrated in response to CXCR3 blockade. Notably, under 3% O2 hypoxic conditions that mimic the joint microenvironment, RA B cells maintained marked expression of MMP-9, TNF, and IL-6, with PD-1+ B cells demonstrating higher expression of CXCR3, CD80, CD86, IL-1β, and GM-CSF than their PD-1– counterparts. Finally, following functional analysis and flow cell sorting of RA PD-1+ versus PD-1– B cells, we demonstrate, using RNA-Seq and emerging fluorescence lifetime imaging microscopy of cellular NAD, a significant shift in metabolism of RA PD-1+ B cells toward glycolysis, associated with an increased transcriptional signature of key cytokines and chemokines that are strongly implicated in RA pathogenesis. Our data support the targeting of pathogenic PD-1+ B cells in RA as a focused, novel therapeutic option.
Highlights
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy and is characterized primarily by the presence of circulating autoantibodies, first described in the 1940s
While the exact mechanism leading to disease amelioration following B cell depletion is not fully elucidated, at-risk individuals who received a single dose of rituximab had a significant delay in disease onset that did not correlate with a reduction in IgG-rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPAs) [10, 11]
No significant differences were observed in the frequency of IgM-only memory B cells or plasma cells between RA and healthy controls (HCs), a significant reduction in the frequency of transitional CD24hiCD38hi enriched for IL-10–producing B cells was observed in RA patient compared with HC peripheral blood (P = 0.04) (Figure 1B)
Summary
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy and is characterized primarily by the presence of circulating autoantibodies, first described in the 1940s. It often has a progressive and debilitating course, with significant impact on the patient’s quality of life. B cell depletion leads to significant but limited reduction in anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), with studies showing clinical benefit for both autoantibody-positive and autoantibody-negative patients with RA [8, 9]. While the exact mechanism leading to disease amelioration following B cell depletion is not fully elucidated, at-risk individuals who received a single dose of rituximab had a significant delay in disease onset that did not correlate with a reduction in IgG-RF or ACPA [10, 11]
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