Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease

• DOI: 10.1038/ni.3579
• Publication Date: 2016-11-07T19:42:55Z
• Authors: René Pfeifle; Tobias Rothe; Natacha Ipseiz; Hans U Scherer; Stephan Culemann; Ulrike Harre; Jochen A Ackermann; Martina Seefried; Arnd Kleyer; Stefan Uderhardt; Benjamin Haugg; Axel J Hueber; Patrick Daum; Gordon F Heidkamp; Changrong Ge; Sybille Böhm; Anja Lux; Wolfgang Schuh; Iryna Magorivska; Kutty S Nandakumar; Erik Lönnblom; Christoph Becker; Diana Dudziak; Manfred Wuhrer; Yoann Rombouts; Carolien A Koeleman; René Toes; Thomas H Winkler; Rikard Holmdahl; Martin Herrmann; Stephan Blüml; Falk Nimmerjahn; Georg Schett; Gerhard Krönke
• Keywords: 0301 basic medicine; Glycosylation; Cells; 610; Sialyltransferases/genetics/metabolism; Inbred C57BL; Lymphocyte Activation; Interleukin-23; Arthritis, Rheumatoid; Mice; 03 medical and health sciences; Interleukins/metabolism; *Immune Tolerance; Immune Tolerance; Animals; Humans; Autoantibodies/*metabolism; Immunoglobulin G/*metabolism; Interleukin-23/*metabolism; beta-D-Galactoside alpha 2-6-Sialyltransferase; Cells, Cultured; Th17 Cells/*immunology; Autoantibodies; B-Lymphocytes/*immunology; B-Lymphocytes; Cultured; Animal; Arthritis; Interleukins; Immunology in the medical area; Cell Differentiation; Sialyltransferases; 3. Good health; Rheumatoid/*immunology; Mice, Inbred C57BL; Disease Models, Animal; Immunologi inom det medicinska området; Immunoglobulin G; Disease Models; Th17 Cells; Signal Transduction

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.