IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.,Journal of Allergy and Clinical Immunology

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IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.jaci.2020.04.059
Yannic C Bartsch ₁ , Simon Eschweiler ₁ , Alexei Leliavski ₁ , Hanna B Lunding ₁ , Sander Wagt ₂ , Janina Petry ₁ , Gina-Maria Lilienthal ₁ , Johann Rahmöller ₃ , Noortje de Haan ₄ , Alexandra Hölscher ₅ , Raghu Erapaneedi ₆ , Anastasios D Giannou ₇ , Lilian Aly ₈ , Ryota Sato ₉ , Louise A de Neef ₄ , André Winkler ₁₀ , Dominique Braumann ₁₁ , Juliane Hobusch ₁ , Kyra Kuhnigk ₁ , Vanessa Krémer ₁ , Moritz Steinhaus ₁ , Véronique Blanchard ₁₂ , Timo Gemoll ₁₃ , Jens K Habermann ₁₃ , Mattias Collin ₁₄ , Gabriela Salinas ₁₅ , Rudolf A Manz ₁₆ , Hidehiro Fukuyama ₉ , Thomas Korn ₁₇ , Ari Waisman ₁₈ , Nir Yogev ₁₉ , Samuel Huber ₇ , Björn Rabe ₂₀ , Stefan Rose-John ₂₀ , Hauke Busch ₂₁ , Friederike Berberich-Siebelt ₂₂ , Christoph Hölscher ₂₃ , Manfred Wuhrer ₄ , Marc Ehlers ₂₄

Affiliation

Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany.
Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Department of Anesthesiology and Intensive Care, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Infection Immunology, Research Center Borstel, Borstel, Germany.
Institute for Pathology, University of Würzburg, Würzburg, Germany.
First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Germany.
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Laboratory of Tolerance and Autoimmunity at the German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany.
Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Section for Translational Surgical Oncology & Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany.
Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
NGS-Integrative Genomics, Institute Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Germany; Munich Cluster for Systems Neurology, SyNergy, Germany.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Clinic and Polyclinic for Dermatology and Venerology, University Hospital Cologne, Cologne, Germany.
Institute of Biochemistry, Kiel University, Kiel, Germany.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Institute for Pathology, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
Infection Immunology, Research Center Borstel, Borstel, Germany; German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany.
Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Laboratory of Tolerance and Autoimmunity at the German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany; Airway Research Center North, University of Lübeck, German Center for Lung Research, Lübeck, Germany.

Background

Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.

Objective

We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants.

Methods

Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns.

Results

Different adjuvants induce distinct IgG⁺ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3^– follicular helper T (T_FH) cell–inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor–dependent IFN-γ⁺ T_FH1 cells, IL-6/IL-23–dependent IL-17A⁺ T_FH17 cells, and high ratios of T_FH cells to Foxp3⁺ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor.

Conclusion

This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.

中文翻译：

用不同的佐剂免疫后，在生发中心反应过程中调节IgG Fc唾液酸化。

背景

IgG Abs的效应子功能受其Fc N-糖基化模式的调节。缺少半乳糖和末端唾液酸残基的IgG Fc聚糖与炎性（自身）免疫疾病的严重程度相关，并且还与针对病毒感染的保护有关，并在疫苗诱导的保护中进行了讨论。相反，唾液酸化的IgG Ab显示出免疫抑制作用。

目的

我们试图研究在用外源蛋白抗原和不同佐剂免疫小鼠后的生发中心（GC）反应过程中的IgG糖基化程序设计。

方法

分析了小鼠的GC T细胞，B细胞和浆细胞反应，以及抗原特异性血清IgG亚类效价和Fc糖基化模式。

结果

不同的佐剂以特定的转录组和负责IgG唾液酸化的α2,6-唾液酸转移酶的表达水平诱导不同的IgG ⁺ GC B细胞反应，这对应于不同的血清IgG Fc糖基化模式。GC B细胞中的低IgG Fc唾液酸化程序总体上高度依赖于Foxp3 ^–卵泡辅助性T（T _FH）细胞诱导的细胞因子IL-6，这里特别是由油包水佐剂和结核分枝杆菌诱导。此外，低IgG Fc唾液酸化程序依赖于诱导IL-27受体依赖性IFN-γ ⁺ T _FH1细胞，IL-6 / IL-23依赖性IL-17A ⁺ T _{FH17的佐剂。}T _FH细胞与Foxp3 ⁺卵泡调节性T细胞的比例很高。在此，后两个依赖于结核分枝杆菌及其脐带因子。