Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered FcγR Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment

Abstract

ObjectivesFc receptors (FcR) interacting with immune complexes (ICs) is a central event in the immune pathogenesis of rheumatoid arthritis (RA). Here we asked if a specific FcR is linked to RA pathogenesis and if FcR activities relate to disease and treatment outcome in early RA.Material and MethodsTwenty autoantibody-positive RA patients and 33 HC were included. The patients were evaluated before and after treatment with methotrexate and prednisolone. At follow-up, the EULAR response criteria were applied to determine the individual treatment outcomes. Serum immunoglobulin levels were measured and the expression of FcR for IgG (FcγR) and IgA (FcαR) on peripheral blood monocytes were determined by flow cytometry. The monocytic FcγR function was evaluated by human IgG1 and IgG3 IC-binding and TNFα stimulated release. Plasma levels of soluble FcRs (sFcRs) were determined with ELISA.ResultsThe IgG1 and IgG3 levels were elevated in the RA sera. The RA monocytes expressed more CD64 and cell surface-bound IgG than HC monocytes, and showed an impaired FcγR function as reflected by changes in IC-binding and decreased IC-stimulated TNFα secretion. These findings correlated significantly with different disease activity markers. Furthermore, sFcRs were elevated in the patient plasma, and sCD64 was specific for RA (compared with a reference group of patients with active psoriatic arthritis). Following treatment, immunoglobulins and sFcR levels were reduced, whereas membrane CD64 was only decreased in patients with good response to treatment.ConclusionsEarly RA patients display increased membrane and soluble CD64 and an impaired FcγR function correlating with joint disease activity. Beneficial responses of anti-rheumatic treatment in patients reduce CD64. These data suggest sCD64 as an important objective biomarker in RA.

Overexpression of CD64 on CD14++CD16‑ and CD14++CD16+ monocytes of rheumatoid arthritis patients correlates with disease activity

“…An assessment of the expression of the characteristic phenotypic markers CD40, CD64, CD163, CD206, HLA-DR, CD80 and CD86 helped to characterize further the monocyte response in patients with RA. In consistent with the results of other researches (16,29), we found that the expression of CD64 on monocytes was significantly elevated in RA patients compared to HV, no changes of other markers between patients with RA and HV. The increased expression of CD64 on monocytes in patients with active RA may suggest the progression of the disease (16), and may also reflect the activation of the monocytes.…”

“…that CD64 play a important role in RA pathogenesis (14,15). However, previous monocyte CD64 expression studies in RA have reported conflicting findings, showing increased, decreased or similar expressions compared with health volunteers (HV) (16)(17)(18). The role of CD64 on monocytes in the pathogenesis of RA remains to be clarified.…”

Validation of Neutrophil CD64 Blood Biomarkers to Detect Mucosal Inflammation in Pediatric Crohn’s Disease

“…Plasma levels of sCD64 were found to be significantly elevated in untreated adults with rheumatoid arthritis compared with controls. 17 The authors also reported a significant reduction of sCD64 in rheumatoid arthritis patients responding to treatment. 17 In our study, the sCD64 produced similar testing characteristics to the blood and fecal biomarkers for patients with suspected IBD but was more modest in accurately detecting endoscopic inflammation in established CD patients receiving treatment.…”

“…17 The authors also reported a significant reduction of sCD64 in rheumatoid arthritis patients responding to treatment. 17 In our study, the sCD64 produced similar testing characteristics to the blood and fecal biomarkers for patients with suspected IBD but was more modest in accurately detecting endoscopic inflammation in established CD patients receiving treatment. The observed difference in the testing characteristics of all the CD64 biomarkers could be attributable to the higher inflammatory burden in new CD (SES-CD median, 13; range, 3–31) compared with the established CD patients with endoscopically active inflammation (SES-CD median, 10; range, 3–34; P < 0.01) or a reflection of the biomarker’s limitations in detecting subtle, low-grade inflammation.…”

Neuronal FcγRI mediates acute and chronic joint pain

“…Further work is therefore warranted to explore whether TRPC3 is involved Second, FcγRI expression and function were upregulated within DRG in the AIA model. In RA patients, FcγRI is expressed de novo in the synovium (44), and its expression level in neutrophils, monocytes, and synovial macrophages is upregulated (19,45,46). The mechanisms underlying the upregulation of FcγRI signaling require further study.…”