AB0016 THE IMPACT OF IL-17A THERAPY ON IGG SIALYLATION IN HUMANS

Background: Rheumatoid arthritis (RA) is characterized by autoreactive B- and T cells. Autoantibodies are a hallmark of RA and contribute to synovial inflammation. We have recently demonstrated that Th17 cells suppress the enzyme ST6 a-galactoside b-2,6-sialyltransferase (ST6GAL1) in developing plasma cells. Thereby, Th17 cells regulate the degree of autoantibody sialylation leading to the increased inflammatory activity of autoantibodies. These events correlate with the onset of RA, arguing for a crucial role of the IL-23/Th17 axis during the transition of asymptomatic autoimmunity into active RA. Therefore, treatment against the IL-23/TH17-axis might present an attractive therapeutic approach to halt or delay RA’s onset. However, the effects of Th17 cytokines like IL-17 on IgG glycosylation in humans are so far poorly studied. Objectives: To explore whether anti-IL17A treatment can inhibit pro-inflammatory IgG glycosylation patterns in humans. Methods: Total IgG from patient cohorts suffering from psoriatic arthritis (PsA) treated with Secukinumab (anti-IL-17 blockade, n=26) or Ustekinumab (anti-IL12/23 blockade, n=14) was compared with patients treated with anti-TNFa blockade as a control (n=20). The cohorts were age- and sex-matched and included patients being on therapy for at least six months. Total IgG was isolated using Protein G columns, and IgG glycopeptides of IgG1, IgG2, and IgG4 were analyzed using the LC-MS technique. The effect of IL-17 depletion on IgG glycosylation was analyzed in psoriatic arthritis patients who have been treated with secukinumab for at least six months. Furthermore, in a longitudinal approach, IgG1, IgG2, and IgG4 glycosylation were analyzed from samples, isolated before the beginning of anti-IL-17 blockade and after at least six months of therapy (n=16). Results: Cross-sectional comparison of cohorts treated with Ustekinumab, Sekukinumab, and anti-TNFa therapy did not show any significant differences in sialylation, galactosylation, or fucosylation of IgG1 and IgG2. IgG4 from anti-TNFa treated patients displayed a small increase of sialylation when compared to the Ustekinumab treated cohort. Longitudinal analyses, however, showed that IL-17A blockade during Secukinumab therapy caused a significant increase of sialic acid-rich IgG glycoforms on IgG1, IgG2 IgG4 patients, while the galactosylation, fucosylation remained unaffected. Conclusion: This data indicates that IL-17A blockade specifically affects IgG sialylation, while other Fc-glycan modifications remain unaltered. This data confirms our recent findings in mice, where cytokines of the IL-23/Th17 axis specifically induce the production of hypo-sialylated, proinflammatory autoantibodies in rheumatoid arthritis (RA) [2]. Therefore, neutralizing IL-17 might be a therapeutic option during the asymptomatic autoimmune prodromal phase in autoimmune diseases like RA, where TH17 cytokines orchestrate the emergence of a pro-inflammatory autoantibody response and the transition into active RA. References: [1]McInnes IB, G. Schett, The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-19. [2]Pfeifle R et al, Regulation of autoantibody activity by the IL-23-Th17 axis determines the onset of autoimmune disease. Nat Immunol. 2017, Jan;18(1):104-113. Disclosure of Interests: Rene Pfeifle Grant/research support from: Novartis AG., Julia Kittler: None declared, Manfred Wuhrer: None declared, Georg Schett: None declared, Gerhard Kronke Grant/research support from: Novartis AG