Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Recently, IL-23-Th17 cells axis and hyposialylation of antibodies were proved to be linked to experimental and rheumatoid arthritis. However it remains uncertain how Tfh, including IL-17 producing Tfh (Tfh17) cells, behaves as regulator of antibody hyposialylation. The aim of this study is to explore the molecular mechanisms of Tfh17 cells-associated autoantibody hyposialylation using glucose-6-phosphate isomerase (GPI) induced arthritis (GIA) model and peripheral blood of RA patients.
Methods: 1) Fluctuation of Tfh cells and their cytokine production in draining lymph nodes were analyzed in GIA. Cell surface molecule expression of Tfh cells was examined.
2) Expression of st6gal1, the responsible enzyme for sialylation, in plasmablasts (PBs) was followed during arthritis course. Sialic acid in purified anti-GPI antibodies obtained at the arthritis onset (day 7) and resolving phase (day 28) was quantified by mass spectrometry. Dendritic cells (DCs) were stimulated with anti-GPI antibodies from both phases. Artificial sialic acid removal/supplement was performed in vitro and vivo.
3) Expression of st6gal1 in co-cultured PBs with Tfh cells was measured. OX40-OX40 ligand (OX40L) pathway was blocked with mAbs both in vivo and vitro.
4) Correlation between circulating Tfh17 cells, ACPA titers and st6gal1 expression in PBs were analyzed in treatment-naïve patients with RA. OX40 expression of Tfh17 cells was analyzed.
Results: 1) Tfh cells, especially IL-17 producing Tfh17 cells were increased at day 7 in GIA. They highly expressed OX40.
2) St6gal1 expression in PBs was significantly decreased at day 7 and 14 (arthritis peak) and gradually recovered. Mass spectrometric analysis revealed significant hyposialylation of day 7 antibodies. DCs produced more TNFα and CXCL1 when stimulated with day 7 antibodies than with those of day 28. Sialic acid-removed antibodies became stronger stimulants for DCs and GIA was ameliorated when sialic acid was supplied to mice.
3) Decreased expression of st6gal1 was observed in PBs co-cultured with Tfh cells. OX40-OX40L pathway blockade rescued this decrease in vitro. By the blockade, GIA was ameliorated accompanied by sialylated anti-GPI antibodies and diminished Tfh17 cells in vivo.
4) Proportion of circulating Tfh17 cells had positive correlation with ACPA tiers in RA patients. Moreover, they negatively correlated with the st6gal1 expression in RA patients (R2= -0.596). OX40 was highly expressed in their Tfh17 cells.
Conclusion: Our findings suggested Tfh, including Tfh17 cells could have a crucial role in the development of arthritis via regulation of autoantibody sialylation through OX40-OX40L axis in experimental and rheumatoid arthritis.
To cite this abstract in AMA style:Kurata I, Matsumoto I, Mikami N, Ohyama A, Osada A, Kondo Y, Tsuboi H, Sumida T. Potential Involvement of OX40 Expressing Tfh Cells on Regulation of Autoantibody Sialylation in Experimental and Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/potential-involvement-of-ox40-expressing-tfh-cells-on-regulation-of-autoantibody-sialylation-in-experimental-and-rheumatoid-arthritis/. Accessed December 3, 2021.
« Back to 2019 ACR/ARP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/potential-involvement-of-ox40-expressing-tfh-cells-on-regulation-of-autoantibody-sialylation-in-experimental-and-rheumatoid-arthritis/