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IgG Fc Glycosylation in Human Immunity

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Fc Mediated Activity of Antibodies

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 423))

Abstract

Glycosylation of IgG Fc domains is a central mechanism in the diversification of antibody function. Modifications to the core Fc glycan impact antibody function by shifting the balance of Type I and Type II Fc gamma receptors (FcγR) that will be engaged by immune complexes. This, in turn, modulates the effector cells and functions that can be recruited during immune activation. Critically, humans have evolved to regulate Fc glycan modifications for immune homeostasis. Dysregulation in Fc glycan modifications can lead to loss of immune tolerance, symptomatic autoimmunity, and susceptibility to infectious diseases. Here, we discuss IgG Fc glycosylation and its role in human health and disease.

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References

  • Anthony RM et al (2011) Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475(7354):110–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baerenwaldt A et al (2011) Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo. Proc Natl Acad Sci U S A 108(46):18772–18777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barb AW, Brady EK, Prestegard JH (2009) Branch-specific sialylation of IgG-Fc glycans by ST6Gal-I. Biochemistry 48(41):9705–9707

    Article  CAS  PubMed  Google Scholar 

  • Boruchov AM et al (2005) Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest 115(10):2914–2923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clynes R et al (1999) Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J Exp Med 189(1):179–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Jong JM et al (2006) Dendritic cells, but not macrophages or B cells, activate major histocompatibility complex class II-restricted CD4+ T cells upon immune-complex uptake in vivo. Immunology 119(4):499–506

    Article  PubMed  PubMed Central  Google Scholar 

  • Debre M et al (1993) Infusion of Fcγ fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342(8877):945–949

    Article  CAS  PubMed  Google Scholar 

  • Dhodapkar KM et al (2005) Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci U S A 102(8):2910–2915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhodapkar KM et al (2007) Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program. J Exp Med 204(6):1359–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Z et al (2016) IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8α(-) conventional dendritic cells. Sci Rep 6:28290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Endy TP et al (2004) Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis 189(6):990–1000

    Article  PubMed  Google Scholar 

  • Engdahl C et al (2018) Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res Ther 20(1):84

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrara C et al (2006) Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous β1, 4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II. Biotechnol Bioeng 93(5):851–861

    Article  CAS  PubMed  Google Scholar 

  • Ferrara C et al (2011) Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A 108(31):12669–12674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiebiger BM et al (2015) Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Proc Natl Acad Sci U S A 112(18):E2385–E2394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flynn GC et al (2010) Naturally occurring glycan forms of human immunoglobulins G1 and G2. Mol Immunol 47(11–12):2074–2082

    Article  CAS  PubMed  Google Scholar 

  • Fokkink WJ et al (2014) IgG Fc N-glycosylation in Guillain-Barre syndrome treated with immunoglobulins. J Proteome Res 13(3):1722–1730

    Article  CAS  PubMed  Google Scholar 

  • Fukuyama H, Nimmerjahn F, Ravetch JV (2005) The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 6(1):99–106

    Article  CAS  PubMed  Google Scholar 

  • Getahun A et al (2004) IgG2a-mediated enhancement of antibody and T cell responses and its relation to inhibitory and activating Fcγ receptors. J Immunol 172(9):5269–5276

    Article  CAS  PubMed  Google Scholar 

  • Halstead SB (2009) Antibodies determine virulence in dengue. Ann N Y Acad Sci 1171(Suppl 1):E48–E56

    Article  CAS  PubMed  Google Scholar 

  • Hjelm F, Karlsson MC, Heyman B (2008) A novel B cell-mediated transport of IgE-immune complexes to the follicle of the spleen. J Immunol 180(10):6604–6610

    Article  CAS  PubMed  Google Scholar 

  • Hodoniczky J, Zheng YZ, James DC (2005) Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol Prog 21(6):1644–1652

    Article  CAS  PubMed  Google Scholar 

  • Imbach P et al (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1(8232):1228–1231

    Article  CAS  PubMed  Google Scholar 

  • Jones MB et al (2012) Anti-inflammatory IgG production requires functional P1 promoter in β-galactoside α2,6-sialyltransferase 1 (ST6Gal-1) gene. J Biol Chem 287(19):15365–15370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones MB et al (2016) B-cell-independent sialylation of IgG. Proc Natl Acad Sci U S A 113(26):7207–7212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaneko Y, Nimmerjahn F, Ravetch JV (2006a) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313(5787):670–673

    Article  CAS  PubMed  Google Scholar 

  • Kaneko Y et al (2006b) Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 203(3):789–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kao D et al (2015) A monosaccharide residue is sufficient to maintain mouse and human IgG subclass activity and directs IgG effector functions to cellular Fc receptors. Cell Rep 13(11):2376–2385

    Article  CAS  PubMed  Google Scholar 

  • Kapur R et al (2014) A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy. Blood 123(4):471–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kono H et al (2005) FcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 14(19):2881–2892

    Article  CAS  PubMed  Google Scholar 

  • Lehmann B et al (2012) FcγRIIB: a modulator of cell activation and humoral tolerance. Expert Rev Clin Immunol 8(3):243–254

    Article  CAS  PubMed  Google Scholar 

  • Li F, Smith P, Ravetch JV (2014) Inhibitory Fcγ receptor is required for the maintenance of tolerance through distinct mechanisms. J Immunol 192(7):3021–3028

    Article  CAS  PubMed  Google Scholar 

  • Lux A et al (2013) Impact of immune complex size and glycosylation on IgG binding to human FcγRs. J Immunol 190(8):4315–4323

    Article  CAS  PubMed  Google Scholar 

  • Maamary J et al (2017) Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization. Proc Natl Acad Sci U S A

    Google Scholar 

  • Mackay M et al (2006) Selective dysregulation of the FcγIIB receptor on memory B cells in SLE. J Exp Med 203(9):2157–2164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahan AE et al (2015) A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. J Immunol Methods 417:34–44

    Article  CAS  PubMed  Google Scholar 

  • Mahan AE et al (2016) Antigen-specific antibody glycosylation is regulated via vaccination. PLoS Pathog 12(3):e1005456

    Article  PubMed  PubMed Central  Google Scholar 

  • McGaha TL, Sorrentino B, Ravetch JV (2005) Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307(5709):590–593

    Article  CAS  PubMed  Google Scholar 

  • Mimura Y et al (2007) Contrasting glycosylation profiles between Fab and Fc of a human IgG protein studied by electrospray ionization mass spectrometry. J Immunol Methods 326(1–2):116–126

    Article  CAS  PubMed  Google Scholar 

  • Ono M et al (1997) Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90(2):293–301

    Article  CAS  PubMed  Google Scholar 

  • Pagan JD, Kitaoka M, Anthony RM (2017) Engineered sialylation of pathogenic antibodies in vivo attenuates autoimmune disease. Cell

    Google Scholar 

  • Pearse RN et al (1999) SHIP recruitment attenuates FcγRIIB-induced B cell apoptosis. Immunity 10(6):753–760

    Article  CAS  PubMed  Google Scholar 

  • Pfeifle R et al (2016) Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol

    Google Scholar 

  • Rafiq S et al (2013) Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties. J Immunol 190(6):2702–2711

    Article  CAS  PubMed  Google Scholar 

  • Regnault A et al (1999) Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J Exp Med 189(2):371–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santiago-Raber ML et al (2009) Fcγ receptor-dependent expansion of a hyperactive monocyte subset in lupus-prone mice. Arthritis Rheum 60(8):2408–2417

    Article  CAS  PubMed  Google Scholar 

  • Scherer HU et al (2010) Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum 62(6):1620–1629

    Article  CAS  PubMed  Google Scholar 

  • Schwab I et al (2012) IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1. Eur J Immunol 42(4):826–830

    Article  CAS  PubMed  Google Scholar 

  • Schwab I et al (2014) Broad requirement for terminal sialic acid residues and FcγRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur J Immunol 44(5):1444–1453

    Article  CAS  PubMed  Google Scholar 

  • Selman MH et al (2012a) Changes in antigen-specific IgG1 Fc N-glycosylation upon influenza and tetanus vaccination. Mol Cell Proteomics 11(4):M111 014563

    Article  Google Scholar 

  • Selman MH et al (2012b) Fc specific IgG glycosylation profiling by robust nano-reverse phase HPLC-MS using a sheath-flow ESI sprayer interface. J Proteomics 75(4):1318–1329

    Article  CAS  PubMed  Google Scholar 

  • Shalova IN et al (2012) CD16 regulates TRIF-dependent TLR4 response in human monocytes and their subsets. J Immunol 188(8):3584–3593

    Article  CAS  PubMed  Google Scholar 

  • Shinkawa T et al (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278(5):3466–3473

    Article  CAS  PubMed  Google Scholar 

  • Sonneveld ME et al (2016) Glycosylation pattern of anti-platelet IgG is stable during pregnancy and predicts clinical outcome in alloimmune thrombocytopenia. Br J Haematol 174(2):310–320

    Article  CAS  PubMed  Google Scholar 

  • Su K et al (2004) A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 172(11):7186–7191

    Article  CAS  PubMed  Google Scholar 

  • Tackenberg B et al (2009) Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci U S A 106(12):4788–4792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan SW et al (2016) Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages. Thromb Haemost 115(3):646–656

    Article  PubMed  Google Scholar 

  • Wang J et al (2011) Fc-glycosylation of IgG1 is modulated by B-cell stimuli. Mol Cell Proteomics 10(5):M110 004655

    Article  Google Scholar 

  • Wang TT et al (2015) Anti-HA glycoforms drive B cell affinity selection and determine influenza vaccine efficacy. Cell 162(1):160–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang TT et al (2017) IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science 355(6323):395–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Washburn N et al (2015) Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. Proc Natl Acad Sci U S A

    Google Scholar 

  • Wuhrer M et al (2009) Regulated glycosylation patterns of IgG during alloimmune responses against human platelet antigens. J Proteome Res 8(2):450–456

    Article  CAS  PubMed  Google Scholar 

  • Wuhrer M et al (2015a) Skewed Fc glycosylation profiles of anti-proteinase 3 immunoglobulin G1 autoantibodies from granulomatosis with polyangiitis patients show low levels of bisection, galactosylation, and sialylation. J Proteome Res 14(4):1657–1665

    Article  CAS  PubMed  Google Scholar 

  • Wuhrer M et al (2015b) Pro-inflammatory pattern of IgG1 Fc glycosylation in multiple sclerosis cerebrospinal fluid. J Neuroinflammation 12:235

    Article  PubMed  PubMed Central  Google Scholar 

  • Yeap WH et al (2016) CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes. Sci Rep 6:34310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Support was received from Stanford University, the Chan Zuckerberg Biohub and the Searle Scholars Program. Research reported in this publication was supported in part by the Bill & Melinda Gates Foundation (OPP1188461) and the National Institutes of Health (1R01AI139119-01A1, 5K22AI12347802, 5U19AI111825-05, UL1TR001866).

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Authors and Affiliations

  1. Department of Medicine, Division of Infectious Diseases, Department of Microbiology and Immunology, Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, 94305, USA

    Taia T. Wang

  2. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Taia T. Wang

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Correspondence to Taia T. Wang .

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Editors and Affiliations

  1. Department of Leonard Wagner Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, USA

    Jeffrey V. Ravetch

  2. Department of Biology, University of Erlangen-Nürnberg, Erlangen, Bayern, Germany

    Falk Nimmerjahn

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Wang, T.T. (2019). IgG Fc Glycosylation in Human Immunity. In: Ravetch, J., Nimmerjahn, F. (eds) Fc Mediated Activity of Antibodies. Current Topics in Microbiology and Immunology, vol 423. Springer, Cham. https://doi.org/10.1007/82_2019_152

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