title: The anti-CD20 antibody rituximab reduces the Th17 cell response.
abstract: OBJECTIVE
  Rituximab has been shown to be successful in the treatment of rheumatoid arthritis (RA), and this unexpected finding indicates that B cells have an important role in this disease. The present study was undertaken to investigate the mechanism of action of rituximab in RA.
  
  
  METHODS
  Twelve patients with active RA were treated with rituximab. Disease activity was evaluated using the 28-joint Disease Activity Score. Synovial biopsy samples obtained at baseline and 12 weeks after treatment initiation were analyzed by microarray, quantitative polymerase chain reaction, and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and from 4 patients with X-linked agammaglobulinemia were stimulated with the Th17-inducing stimulus Candida albicans, and the response in the presence and absence of rituximab was examined.
  
  
  RESULTS
  In RA patients, rituximab reduced expression of retinoic acid-related orphan receptor γt and interleukin-22 (IL-22) and numbers of Th17-positive cells in synovial tissue, and this correlated with better clinical outcome. Rituximab did not affect tumor necrosis factor α (TNFα), Th1 cell, or Treg cell responses. Rituximab strongly reduced in vitro IL-17 and IL-22 production induced by C albicans. This effect was not observed in PBMCs from patients with X-linked agammaglobulinemia.
  
  
  CONCLUSIONS
  Rituximab reduced the local Th17 response in RA patients, whereas it did not influence Th1 cell, Treg cell, or TNFα responses. The decreased Th17 response was associated with reduced inflammation and better clinical outcome. Moreover, inhibition of the Th17 response by rituximab was lost in the absence of B cells, providing evidence that the effects of rituximab are due to B cell depletion. These data demonstrate an unexpected role of B cells in the development of Th17 responses, which could possibly lead to B cell-based strategies for the treatment of Th17-related autoimmune diseases.
authors.affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation, and Immunity, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Bernard
authors.initials: B
authors.lastname: Lauwerys
authors.forename: Renoud J
authors.initials: RJ
authors.lastname: Marijnissen
authors.forename: Kim
authors.initials: K
authors.lastname: Timmermans
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Ilse
authors.initials: I
authors.lastname: Gutierrez-Roelens
authors.forename: Patrick
authors.initials: P
authors.lastname: Durez
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000361:Agammaglobulinemia / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology; D018501:Antirheumatic Agents / Q000276:immunology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000276:immunology; D000069283:Rituximab; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D016896:Treatment Outcome; D000097043:Interleukin-22
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D020381:Interleukin-17; D007378:Interleukins; D018168:Receptors, Retinoic Acid; D000069283:Rituximab; D000097043:Interleukin-22