The role of the IL-23/Th17 axis as modulator of B cell-mediated (auto)immune responses
Rheumatology
Final Report Abstract
IL-23-dependent Th17 cells express a spectrum of different pro-inflammatory cytokines such as interleukin (IL)-17, IL-22 and GM-CSF, which directly act on cells of the innate immune system as well as on certain stromal and epithelial cells. Th17 cells thereby promote inflammation and have been accordingly implicated in the pathogenesis of a whole repertoire of immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis (RA) or multiple sclerosis. Also, B cells and B cell-derived autoantibodies seem to be major drivers of many autoimmune inflammatory diseases such as RA. However, our understanding of the crosstalk between Th17 cells 2 and B cells as well as the autoantibody response has remained scarce. We have previously identified Th17 cells that display a T follicular helper cell signature and that accumulate in germinal centers of secondary lymphatic organs, where these cells imprint on the developing B cell response. Th17 cells thereby control the Fc-glycosylation and the inflammatory activity of IgG fostering the production of pro-inflammatory autoantibodies and the onset of autoimmune disease. In the current project, we have sought to identify the molecular basis of this crosstalk between Th17 cells and the B cell response in order to better understand the pathogenesis of IMIDs such as RA and to identify novel therapeutic targets for the treatment of inflammatory autoimmune diseases. We have focused on the potential role of different Th17 cell-derived cytokines including IL-17, IL-22 and GM-CSF during Th17/B cell crosstalk in RA as a classical B cell-driven inflammatory autoimmune disease. These experiments showed that the Th17 signature cytokine IL-17, although acting as a potent pro-inflammatory cytokine, did not influence the B cell or autoantibody response. Analysis of the role of the Th17 cell-derived cytokine GM-CSF, in turn, showed that this T cell-derived cytokine heavily influenced B cell- and autoantibody-mediated inflammation. Notably, GM-CSF was essentially involved in the control of IgG glycosylation and consequently regulated the inflammatory activity of autoantibodies. Analysis of human B cells in the peripheral blood of healthy controls and RA patients, respectively, confirmed that different B cell subpopulations expressed the GM-CSF receptor. Together these data thus indicate a major role of Th17 cell-derived GM-CSF during the regulation of the B cell response as well as of autoantibody activity during IMIDs such as RA.
Publications
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Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature, 572(7771), 670-675.
Culemann, Stephan; Grüneboom, Anika; Nicolás-Ávila, José Ángel; Weidner, Daniela; Lämmle, Katrin Franziska; Rothe, Tobias; Quintana, Juan A.; Kirchner, Philipp; Krljanac, Branislav; Eberhardt, Martin; Ferrazzi, Fulvia; Kretzschmar, Elke; Schicht, Martin; Fischer, Kim; Gelse, Kolja; Faas, Maria; Pfeifle, René; Ackermann, Jochen A.; Pachowsky, Milena ... & Krönke, Gerhard
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Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion. Nature Communications, 11(1).
Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario M.; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; Corte, Giulia; Morf, Harriet; Leppkes, Moritz; Kremer, Andreas E.; Ramming, Andreas; Pachowsky, Milena; Schuch, Florian ... & Schett, Georg
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Humoral and Cellular Immune Responses to SARS–CoV‐2 Infection and Vaccination in Autoimmune Disease Patients With B Cell Depletion. Arthritis & Rheumatology, 74(1), 33-37.
Simon, David; Tascilar, Koray; Schmidt, Katja; Manger, Bernhard; Weckwerth, Leonie; Sokolova, Maria; Bucci, Laura; Fagni, Filippo; Manger, Karin; Schuch, Florian; Ronneberger, Monika; Hueber, Axel; Steffen, Ulrike; Mielenz, Dirk; Herrmann, Martin; Harrer, Thomas; Kleyer, Arnd; Krönke, Gerhard & Schett, Georg
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Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes. Journal of Experimental Medicine, 220(6).
Culemann, Stephan; Knab, Katharina; Euler, Maximilien; Wegner, Anja; Garibagaoglu, Hilal; Ackermann, Jochen; Fischer, Kim; Kienhöfer, Deborah; Crainiciuc, Georgiana; Hahn, Jonas; Grüneboom, Anika; Nimmerjahn, Falk; Uderhardt, Stefan; Hidalgo, Andrés; Schett, Georg; Hoffmann, Markus H. & Krönke, Gerhard
