Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis

Abstract

ObjectiveAn increased proportion of circulating follicular helper T (Tfh) cells was reported in rheumatoid arthritis (RA), but it remains uncertain how Tfh cells affect antibody hyposialylation. We investigated the regulation of autoantibody hyposialylation by Tfh cells in RA using murine model.MethodsBehaviours of Tfh cells and their function on B cell promotion were analysed. Change of arthritogenicity and sialylation of autoantibodies during the course of arthritis was examined by mass spectrometry. Tfh-mediated regulation of hyposialylation was investigated, and the responsible cell surface molecule was specified both in vitro and in vivo. The relation between circulating Tfh cells and hyposialylation was analysed in patients with RA.ResultsAn increase in Tfh, particularly interleukin-17 producing Tfh (Tfh17) cells, at the onset of arthritis and their enhancement of autoantibody production were found. Autoantibodies at the onset phase demonstrated stronger inflammatory properties than those at the resolution phase, and mass spectrometric analysis revealed their difference in sialylation. In vitro coculture showed enhanced hyposialylation by the Tfh cells via OX40, which was highly expressed in the Tfh and Tfh17 cells. Blockade of OX40 prevented the development of arthritis with reduction in Tfh17 cells and recovery of autoantibody sialylation. Analysis of patients with RA showed abundance of OX40-overexpressing Tfh17 cells, and their proportion correlated negatively with the expression of α2,6-sialyltransferase 1, an enzyme responsible for sialylation.ConclusionsOX40 expressed on Tfh cells can regulate autoantibody sialylation and play a crucial role in the development of autoimmune arthritis.

T follicular helper cell subsets: a potential key player in autoimmunity

“…cTfh17 than healthy controls. We also found that frequency of cTfh17 cells were higher than osteoarthritis patients and had positive correlation with ACPA titers in patients with treatment naïve RA [32]. They also highly expressed OX40 on their surface.…”

“…Increase of Tfh cells in secondary lymphoid organs of mice was reported in plural models [30][31][32]. Among them, we recently reported specific increase of Tfh17 cells in arthritis onset in glucose-6-phosphate isomerase induced arthritis [32]. They seemed to contribute to the disease development by promotion of autoantibody production and regulation of their chemical modification via OX40, which was highly expressed on Tfh17 cells.…”

“…Several studies about murine models have reported importance of Tfh cells in arthritis development. Increase of Tfh cells in secondary lymphoid organs of mice was reported in plural models [30][31][32]. Among them, we recently reported specific increase of Tfh17 cells in arthritis onset in glucose-6-phosphate isomerase induced arthritis [32].…”

“…Disease Reference RA cTfh cells", cTfh17 cells" cTfh17 cells had positive correlation with autoantibody titers [32] cTfh cells", cTfh2 cells", cTfh17 cells" [35] cTfh cells" cTfh cells had positive correlation with autoantibody titers and disease severity [36] cTfh cells" cTfh cells had positive correlation with autoantibody titers [37] cTfh cells" cTfh cells had positive correlation with disease severity [38] cTfh cells" cTfh cells had positive correlation with autoantibody titers [39] cTfh cells" cTfh cells had positive correlation with autoantibody titers [40] no difference in cTfh cells compared to healthy controls [41] [43] cTfh cells" cTfh2 cells had positive correlation with disease severity [44] cTfh cells" cTfh cells had positive correlation with autoantibody titers and disease severity [45] cTfh cells" in active SLE patients cTfh cells had positive correlation with disease severity [46] cTfh cells" cTfh cells had positive correlation with autoantibody titers and disease severity [47] cTfh cells" cTfh cells had positive correlation with autoantibody titers, but no correlation with disease severity [48] cTfh2 cells", cTfh17 cells" in active SLE patients cTfh2 cells had positive correlation with disease severity [49] cTfh1 cells"…”

“…However, literature data about cTfh and cTfh17 cells frequencies in RA is conflicting. In seven studies, it was observed increased frequencies of cTfh cells in the patients [32,[35][36][37][38][39][40] and some authors found association with the disease activity [36,[38][39][40] and with autoantibody titers [32,36,37,40]. By contrast, other ones did not found the increase of cTfh cells nor differences in the percentages of cTfh1, cTfh2, and cTfh17 subsets in RA patients, compared to healthy controls or patients with undifferentiated arthritis [41,42].…”