Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs

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• 作者：Carolin M. Oefner ; MSc^a ; ^&lowast ; ; André ; Winkler ; MSc^a ; ^&lowast ; ; Constanze Hess ; PhD^a ; ^&lowast ; ; Alexandra K. Lorenz ; BSc^a ; Vivien Holecska ; Tech^a ; Melanie Huxdorf ; MSc^a ; Tim Schommartz ; MSc^b ; Dominique Petzold ; MSc^b ; ^c ; Josephine Bitterling ; Tech^b ; Anna-Lena Schoen ; MSc^b ; Alexander D. Stoehr ; PhD^a ; Dana Vu Van ; MSc^d ; ^e ; Yasemin Darcan-Nikolaisen ; PhD^f ; Vé ; ronique Blanchard ; PhD^c ; Inken Schmudde ; MSc^g ; Yves Laumonnier ; PhD^g ; Heike A. Strö ; ver ; MSc^g ; Ahmed N. Hegazy ; MD^h ; ⁱ ; Susanne Eiglmeier ; PhD^a ; Carolin T. Schoen ; PhD^a ; Maria M.M. Mertes ; PhD^a ; Christoph Loddenkemper ; MD^j ; ^k ; Max Lö ; hning ; PhD^h ; Peter Kö ; nig ; MD^l ; ^m ; Arnd Petersen ; PhDⁿ ; Elke O. Luger ; PhD^o ; Mattias Collin ; PhD^p ; Jö ; rg Kö ; hl ; MD^g ; ^m ; Andreas Hutloff ; PhD^d ; ^e ; Eckard Hamelmann ; MD^f ; ^q ; Markus Berger ; PhD^c ; Hedda Wardemann ; PhD^r ; Marc Ehlers ; PhD^a ; ^b ; ^m ; ^{Marc.Ehlers@uk-sh.de}
• 关键词：Tolerance ; IgG antibodies ; IgG sialylation ; dendritic cells ; allergy ; asthma ; antigen-specific immunotherapy ; antigen-specific tolerance ; antibody therapy
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 出版时间：June, 2012
• 年：2012
• 卷：129
• 期：6
• 页码：1647-1655.e13
• 全文大小：1678 K

文摘

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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 ¦Á2,6-sialyltransferase and producing desialylated IgGs. In contrast, plasma cells induced on tolerance induction did not downregulate ¦Á2,6-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.