Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders
Shuhei Nishiyama, Jin Myong Seok, Amy E. Wright, Itay Lotan, Takahisa Mikami, Natalia Drosu, Natasha Bobrowski‐Khoury, Monique Anderson, Philippe‐Antoine Bilodeau, Patrick Schindler, Friedemann Paul, Masashi Aoki, Michael R. Yeaman, Michael Levy, Jacinta M. Behne, Megan Behne, Jeffrey L. Bennett, Terrence F. Blaschke, Tanuja Chitnis, Lawrence J. Cook, Michael Levy, Sarah M. Planchon, Pavle Repovic, Claire Riley, Terry J. Smith, Anthony Traboulsee, Michael R. Yeaman
Abstract
Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.