TY - JOUR
T1 - Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs
AU - Oefner, Carolin M.
AU - Winkler, André
AU - Hess, Constanze
AU - Lorenz, Alexandra K.
AU - Holecska, Vivien
AU - Huxdorf, Melanie
AU - Schommartz, Tim
AU - Petzold, Dominique
AU - Bitterling, Josephine
AU - Schoen, Anna Lena
AU - Stoehr, Alexander D.
AU - Vu Van, Dana
AU - Darcan-Nikolaisen, Yasemin
AU - Blanchard, Véronique
AU - Schmudde, Inken
AU - Laumonnier, Yves
AU - Ströver, Heike A.
AU - Hegazy, Ahmed N.
AU - Eiglmeier, Susanne
AU - Schoen, Carolin T.
AU - Mertes, Maria M.M.
AU - Loddenkemper, Christoph
AU - Löhning, Max
AU - König, Peter
AU - Petersen, Arnd
AU - Luger, Elke O.
AU - Collin, Mattias
AU - Köhl, Jörg
AU - Hutloff, Andreas
AU - Hamelmann, Eckard
AU - Berger, Markus
AU - Wardemann, Hedda
AU - Ehlers, Marc
PY - 2012/6/1
Y1 - 2012/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861691610&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2012.02.037
DO - 10.1016/j.jaci.2012.02.037
M3 - Journal articles
C2 - 22502800
AN - SCOPUS:84861691610
SN - 0091-6749
VL - 129
SP - 1647
EP - 1655
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -