title: Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs.
abstract: BACKGROUND
  Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive.
  
  
  OBJECTIVE
  It was shown recently that proinflammatory or anti-inflammatory effector functions of IgG molecules are determined by different Fc N-linked glycosylation patterns. We sought to examine the Fc glycosylation and anti-inflammatory quality of IgG molecules formed on TD tolerance induction.
  
  
  METHODS
  We administered chicken ovalbumin (OVA) with or without costimulus to mice and analyzed OVA-reactive IgG Fc glycosylation. The anti-inflammatory function of differentially glycosylated anti-OVA IgGs was further investigated in studies with dendritic cell cultures and in an in vivo model of allergic airway disease. Additionally, we analyzed the Fc glycosylation pattern of birch pollen-reactive serum IgGs after successful allergen-specific immunotherapy in patients.
  
  
  RESULTS
  Stimulation with TD antigens under inflammatory conditions induces plasma cells expressing low levels of α2,6-sialyltransferase and producing desialylated IgGs. In contrast, plasma cells induced on tolerance induction did not downregulate α2,6-sialyltransferase expression and secreted immunosuppressive sialylated IgGs that were sufficient to block antigen-specific T- and B-cell responses, dendritic cell maturation, and allergic airway inflammation. Importantly, successful specific immunotherapy in allergic patients also induced sialylated allergen-specific IgGs.
  
  
  CONCLUSIONS
  Our data show a novel antigen-specific immunoregulatory mechanism mediated by anti-inflammatory sialylated IgGs that are formed on TD tolerance induction. These findings might help to develop novel antigen-specific therapies for the treatment of allergy and autoimmunity.
authors.affiliation: Laboratory of Tolerance and Autoimmunity, German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.
authors.forename: Carolin M
authors.initials: CM
authors.lastname: Oefner
authors.forename: André
authors.initials: A
authors.lastname: Winkler
authors.forename: Constanze
authors.initials: C
authors.lastname: Hess
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Lorenz
authors.forename: Vivien
authors.initials: V
authors.lastname: Holecska
authors.forename: Melanie
authors.initials: M
authors.lastname: Huxdorf
authors.forename: Tim
authors.initials: T
authors.lastname: Schommartz
authors.forename: Dominique
authors.initials: D
authors.lastname: Petzold
authors.forename: Josephine
authors.initials: J
authors.lastname: Bitterling
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Schoen
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Stoehr
authors.forename: Dana
authors.initials: D
authors.lastname: Vu Van
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Darcan-Nikolaisen
authors.forename: Véronique
authors.initials: V
authors.lastname: Blanchard
authors.forename: Inken
authors.initials: I
authors.lastname: Schmudde
authors.forename: Yves
authors.initials: Y
authors.lastname: Laumonnier
authors.forename: Heike A
authors.initials: HA
authors.lastname: Ströver
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.forename: Susanne
authors.initials: S
authors.lastname: Eiglmeier
authors.forename: Carolin T
authors.initials: CT
authors.lastname: Schoen
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Mertes
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.forename: Arnd
authors.initials: A
authors.lastname: Petersen
authors.forename: Elke O
authors.initials: EO
authors.lastname: Luger
authors.forename: Mattias
authors.initials: M
authors.lastname: Collin
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Andreas
authors.initials: A
authors.lastname: Hutloff
authors.forename: Eckard
authors.initials: E
authors.lastname: Hamelmann
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Marc
authors.initials: M
authors.lastname: Ehlers
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D003888:Desensitization, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy; D007108:Immune Tolerance / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D012799:Sialyltransferases / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; D006023:Glycoproteins
chemical_list: D000936:Antigen-Antibody Complex; D000941:Antigens; D000939:Epitopes; D007074:Immunoglobulin G; D010047:Ovalbumin; D017452:Receptors, IgG; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; C499172:Fcgr2b protein, mouse; C046179:glycosylated IgG; D006023:Glycoproteins