CD200/CD200R1Pathway In Pathogenesisof Rheumatoid Arthritis

Objective Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by persistent synovitis and progressive bone erosion. Current biological and nonbiological treatments have focused on inhibition of synovitis, but such treatments do not adequately repair damaged bone, thereby emphasize the importance of opening new avenues for the immunomodulatory therapy of RA targeting stop or reverse bone erosion other than alleviating synovitis. CD200/CD200R1signaling has an immunoregulatory effect in activation threshold of inflammatory immune response and maintains immune homeostasis. thus, highlight themselves as a potential anti-inflammatory intervention in autoimmune diseases. However, information on the role of the CD200/CD200R1axis in human diseases, especially in RA is very limited. We, therefore, explored the expression and function of this pathway in subjects with RA.Methods Altogether, a total of30chronic active untreated patients fulfilling the American College of Rheumatology (ACR)1987revised criteria of RA were enrolled in the study (13men and27women), age ranged43-67ys with mean age of42.73±5.2yrs. The mean disease duration at evaluation was8.76years.10gender-and age-matched healthy volunteers were recruited as healthy controls (HCs). Peripheral blood was collected and peripheral blood mononuclear cells(PBMC) were prepared by Ficoll-Hypaque density gradient centrifugation. CD4±T cells and CD14±monocytes were further isolated by using a human CD4+T Cell Isolation Kit and human CD14MicroBeads. The expressions of CD200and CD200R1by CD4±cells, CD14±cells and synovium were examined by flow cytometry and immunohistochemistry, and compared between RA patients before and after treatment with TNF-a blockage, and also healthy controls (HCs). Sorted CD4T T cells were stained with CFSE and Annexin V/propidium iodide for evaluating the effect of CD200on cell proliferation and apoptosis. Moreover, the effect of CD200on osteoclastogenesis and on Th17differentiation and function were determined by TRAP±staining, immunocytochemistry, flow cytometry and by transwell migration assay.Results In RA patients, the numbers of CD200cells and CD200R1+cells from PBMC, CD4+cells and CD14+cells were significantly lower than that in HCs, whereas the expressions of CD200+cells was higher in RA synovium compared to that in HCs. These abnormal expressions were corrected after treatment with TNF-ablockage and correlated with less radiographic progression as evaluated by DAS28. Importantly, the engagement of CD200receptor on CD14+T cells with CD200-Fc fusion protein in vitro reduced the osteoclastogenesis and inhibited CD14’monocytes-like synoviocyte (MLS)-driven Th17differentiation. Whereas the engagement of CD200receptor on CD4+T cells with CD200-Fc fusion protein in vitro inhibited CD4T cells proliferation, promoted its apoptosis, and reduced CD4+T cells differentiation into Th17cells as well as down-regulated CCR6-mediated Th17chemotaxis in RA.Conclusion CD200and CD200R1expression and function are abnormal in RA and may contribute to the immunopathogenesis of RA involved in irritating th17cells and osteoclastogenesis.Thereby, restoring defective CD200/CD200R1signal in RA will facilitate future therapeutic interventions in treating such disease.