P096 The role of the IL-23/Th17 axis as modulator of B cell-mediated (auto)immune responses
Authors: R Pfeifle, J Kittler, T Rothe, G Schett, G Krönke
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Rheumatoid arthritis (RA) is characterized by chronic synovitis and joint destruction. Autoantibodies and autoreactive B cells are a hallmark of RA. Furthermore, Th17 cells have been demonstrated to be crucial for disease development. However, checkpoints and mechanisms regulating the onset of rheumatoid arthritis (RA) remain largely unclear. <h3>Objectives</h3> Recently, we have demonstrated, that Th17 cells suppress the enzyme ST6 a-galactoside b-2,6-sialyltransferase in developing plasma cells. Thereby, Th17 cells are able to increase the inflammatory activity of autoantibodies in an IL-23 dependent manner by regulating the degree of Fc-glycosylation. However, the molecular mechanisms that mediate this IL-23/Th17-mediated proinflammatory reprogramming of B cells and the relevance for arthritis remains to be determined in detail. <h3>Methods</h3> K/BxN mice were treated twice a week with neutralizing antibodies against IL-17A and IL-22 from week 1 until week 9. Both, clinical, histological and immunological parameters of arthritis were assessed. Serum was collected weekly and autoantibody titers were determined using ELISA. Collected Sera were used for K/BxN serum transfer to evaluated IgG activity. Additionally, the expression levels of the corresponding interleukin receptors (IL17RA and IL22Ra1) were analyzed during collagen-induced arthritis. <h3>Results</h3> Here we show, that in contrast the upregulation of IL-22Ra1 on plasmablasts in the spleen, lymph node and bone-marrow during collagen-induced arthritis, its blockade during K/BxN arthritis did not prevent the onset of arthritis. Also, the IgG from K/BxN mice remained its inflammatory activity. We also show, that while IL17RA is basically absent on B cells during arthritis, the neutralization of IL-17A during K/BxN arthritis led to a strongly delayed development of autoimmune arthritis. Furthermore, depletion of IL17A led to a decreased titer of autoantibodies during early phases of K/BxN arthritis. However, in the K/BxN serum transfer mice which received serum that was produced in the absence of IL-17 were not protected against inflammatory arthritis. <h3>Conclusions</h3> Our data indicate that IL-22 is not directly involved in the regulation of IgG activity during K/BxN arthritis. Furthermore, our data indicate that IL-17A is indeed a crucial cytokine during inflammatory processes inside the joint and may be involved in the germinal center reaction or plasma cell survival. However, neither IL-17 nor IL-22 is involved in the IL-23/Th17-mediated proinflammatory reprogramming of B cells to produce highly pathogenic autoantibodies. Therefore, other cytokines produced by Th17 cells and/or mechanisms depending on cell-cell contact proteins might orchestrate the Th17/B-cell crosstalk leading to the downregulation of St6gal1 in developing plasma cells. <h3>Disclosure of Interest</h3> None declared.