P096 The role of the IL-23/Th17 axis as modulator of B cell-mediated (auto)immune responses

Abstract

Career situation of first and presenting authorPost-doctoral fellow.IntroductionRheumatoid 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.ObjectivesRecently, 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.MethodsK/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.ResultsHere 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.ConclusionsOur 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.Disclosure of InterestNone declared.

Anti-Inflammatory Polymeric Nanoparticles Based on Ketoprofen and Dexamethasone

“…Interleukin-12 (IL12) and interleukin-23 (IL23) have recently emerged as therapeutic targets in the treatment of autoimmune/inflammatory diseases and chronic inflammatory diseases in which the T cell dominates as the primary dysfunctional cells [1][2][3]. IL12 and IL23 are mainly produced by antigen-presenting cells like macrophages and dendritic cells, and they play a key role in naïve T-cells differentiation to Th1 and Th17 cells, respectively [4]. Their combined inhibition has demonstrated potential in the treatment of a wide range of autoimmune/inflammatory diseases [5][6][7][8].…”

Polymeric Nanoparticles that Combine Dexamethasone and Naproxen for the Synergistic Inhibition of Il12b Transcription in Macrophages

“…It has been reported that Il12b -/mice are completely protected from CIA. [46] Therefore, if this synergistic repression of Il12b occurs also under inflammatory conditions, it might be the reason for the Dx dose-sparing capacity of NAP in the treatment of this disease. On the other hand, figure 8b shows that, as expected, no statistically significant over-expression of M 2 markers is observed for either free Dx or encapsulated Dx (2.55 μм) as the concentration of Dx is higher than 100 nм which is the reported limit concentration for polarization.…”

“…IL12 is decisive in regulating lineage commitment to T helper 1 cells (Th1) development, whereas IL23 is essential for the maturation and stability of IL17-producing T helper 17 cells (Th17). [46] Therefore, Dx/NAP combination and, in particular, the newly described Dx-loaded NAP bearing NPs have potential for the treatment of diseases in which IL12 and IL23 are overexpressed and Th1 and Th17 play a key role in pathogenesis. That is the case of autoimmune/inflammatory disorders like Crohn's disease, ulcerative colitis, psoriatic arthritis, rheumatoid arthritis, human multiple sclerosis, psoriasis… [51,52] This combination of FDA-approved drugs acts at a genetic level inhibiting Il12b expression levels by macrophages, a IL12-p40 subunit codifying gene, and, hence, decreasing IL12 and IL23 levels.…”