Impact of Differential Glycosylation on IgG Activity

  • Anja Lux
  • Falk Nimmerjahn
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 780)


Immunoglobulin G (IgG) molecules are glycoproteins with dual functionality. While participating in the destruction of virally infected cells or healthy tissues during autoimmune disease, IgG antibodies are also used as a therapeutic agent to suppress IgG-triggered autoimmune disease and inflammation. Research of recent years has put the IgG-associated sugar moiety in the spotlight for regulating these opposing activities. This review will focus on how certain IgG glycovariants impact different IgG-dependent effector functions and how this knowledge might be used to further improve the therapeutic effectiveness of this class of molecules.


Sialic Acid Sugar Moiety Chronic Inflammatory Demyelinating Polyneuropathy Sialic Acid Residue Fucose Residue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the German Research Foundation (SFB 643, FOR832, GK1660, SPP1468) and the Bavarian Genome Research Network (BayGene) to F.N. We apologize to all colleagues whose important work could not be cited directly due to limitation in space. These references can be found in the review articles referred to in this manuscript.


  1. 1.
    Woof JM, Burton DR (2004) Human antibody-Fc receptor interactions illuminated by crystal structures. Nat Rev Immunol 4:89–99PubMedCrossRefGoogle Scholar
  2. 2.
    von Mehren M, Adams GP, Weiner LM (2003) Monoclonal antibody therapy for cancer. Annu Rev Med 54:343–369, Epub 2001 Dec 2003CrossRefGoogle Scholar
  3. 3.
    Waldmann TA (2003) Immunotherapy: past, present and future. Nat Med 9:269–277PubMedCrossRefGoogle Scholar
  4. 4.
    Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147–1157PubMedCrossRefGoogle Scholar
  5. 5.
    Nimmerjahn F, Ravetch JV (2007) Antibodies, Fc receptors and cancer. Curr Opin Immunol 19:239–245PubMedCrossRefGoogle Scholar
  6. 6.
    Natsume A, Niwa R, Satoh M (2009) Improving effector functions of antibodies for cancer treatment: enhancing ADCC and CDC. Drug Des Dev Ther 3:7–16Google Scholar
  7. 7.
    Kubota T, Niwa R, Satoh M et al (2009) Engineered therapeutic antibodies with improved effector functions. Cancer Sci 100:1566–1572PubMedCrossRefGoogle Scholar
  8. 8.
    Parren PW, Burton DR (2009) Immunology. Two-in-one designer antibodies. Science 323:1567–1568PubMedCrossRefGoogle Scholar
  9. 9.
    Azeredo da Silveira S, Kikuchi S, Fossati-Jimack L et al (2002) Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody. J Exp Med 195:665–672PubMedCrossRefGoogle Scholar
  10. 10.
    Carroll MC (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5:981–986PubMedCrossRefGoogle Scholar
  11. 11.
    Clynes R, Ravetch JV (1995) Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 3:21–26PubMedCrossRefGoogle Scholar
  12. 12.
    Hamaguchi Y, Xiu Y, Komura K et al (2006) Antibody isotype-specific engagement of Fc gamma receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med 203:743–753PubMedCrossRefGoogle Scholar
  13. 13.
    Hogarth PM (2002) Fc receptors are major mediators of antibody based inflammation in auto-immunity. Curr Opin Immunol 14:798–802PubMedCrossRefGoogle Scholar
  14. 14.
    Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science 310:1510–1512PubMedCrossRefGoogle Scholar
  15. 15.
    Nimmerjahn F, Ravetch JV (2008) Fc gamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47PubMedCrossRefGoogle Scholar
  16. 16.
    Takai T (2002) Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2:580–592PubMedGoogle Scholar
  17. 17.
    Sylvestre D, Clynes R, Ma M et al (1996) Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J Exp Med 184:2385–2392PubMedCrossRefGoogle Scholar
  18. 18.
    Takai T, Li M, Sylvestre D et al (1994) FcR gamma chain deletion results in pleiotropic effector cell defects. Cell 76:519–529PubMedCrossRefGoogle Scholar
  19. 19.
    Schmidt RE, Gessner JE (2005) Fc receptors and their interaction with complement in auto-immunity. Immunol Lett 100:56–67PubMedCrossRefGoogle Scholar
  20. 20.
    Shushakova N, Skokowa J, Schulman J et al (2002) C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest 110:1823–1830PubMedGoogle Scholar
  21. 21.
    Daeron M, Lesourne R (2006) Negative signaling in Fc receptor complexes. Adv Immunol 89:39–86PubMedCrossRefGoogle Scholar
  22. 22.
    Bolland S, Ravetch JV (1999) Inhibitory pathways triggered by ITIM-containing receptors. Adv Immunol 72:149–177PubMedCrossRefGoogle Scholar
  23. 23.
    Baerenwaldt A, Nimmerjahn F (2008) Immune regulation - Fc gamma RIIB - regulating the balance between protective and auto-reactive immune responses. Immunol Cell Biol 86:482–484PubMedCrossRefGoogle Scholar
  24. 24.
    Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285PubMedCrossRefGoogle Scholar
  25. 25.
    Bolland S, Yim YS, Tus K et al (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(−/−) mice. J Exp Med 195:1167–1174PubMedCrossRefGoogle Scholar
  26. 26.
    Takai T, Ono M, Hikida M et al (1996) Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature 379:346–349PubMedCrossRefGoogle Scholar
  27. 27.
    Tan Sardjono C, Mottram PL, Hogarth PM (2003) The role of FcgammaRIIa as an inflammatory mediator in rheumatoid arthritis and systemic lupus erythematosus. Immunol Cell Biol 81:374–381PubMedCrossRefGoogle Scholar
  28. 28.
    Cartron G, Dacheux L, Salles G et al (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754–758PubMedCrossRefGoogle Scholar
  29. 29.
    Weng WK, Czerwinski D, Timmerman J et al (2004) Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype. J Clin Oncol 22:4717–4724, Epub 2004 Oct 4713PubMedCrossRefGoogle Scholar
  30. 30.
    Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940–3947, Epub 2003 Sep 3915PubMedCrossRefGoogle Scholar
  31. 31.
    Baudino L, Nimmerjahn F, da Silveira SA et al (2008) Differential contribution of three activating IgG Fc receptors (Fc gamma RI, FcyRIII, and Fc gamma RIV) to IgG2a- and IgG2b-induced autoimmune hemolytic anemia in mice. J Immunol 180:1948–1953PubMedGoogle Scholar
  32. 32.
    Giorgini A, Brown HJ, Lock HR et al (2008) Fc gamma RIII and Fc gamma RIV are indispensable for acute glomerular inflammation induced by switch variant monoclonal antibodies. J Immunol 181:8745–8752PubMedGoogle Scholar
  33. 33.
    Hazenbos WL, Gessner JE, Hofhuis FM et al (1996) Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity 5:181–188PubMedCrossRefGoogle Scholar
  34. 34.
    Syed SN, Konrad S, Wiege K et al (2009) Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a. Eur J Immunol 39:3343–3356PubMedCrossRefGoogle Scholar
  35. 35.
    Otten MA, van der Bij GJ, Verbeek SJ et al (2008) Experimental antibody therapy of liver metastases reveals functional redundancy between Fc gamma RI and Fc gamma RIV. J Immunol 181:6829–6836PubMedGoogle Scholar
  36. 36.
    Bevaart L, Jansen MJ, van Vugt MJ et al (2006) The high-affinity IgG receptor, FcgammaRI, plays a central role in antibody therapy of experimental melanoma. Cancer Res 66:1261–1264PubMedCrossRefGoogle Scholar
  37. 37.
    Nimmerjahn F, Ravetch JV (2008) Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 26:513–533PubMedCrossRefGoogle Scholar
  38. 38.
    Negi VS, Elluru S, Siberil S et al (2007) Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol 27:233–245PubMedCrossRefGoogle Scholar
  39. 39.
    Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673PubMedCrossRefGoogle Scholar
  40. 40.
    Duncan AR, Winter G (1988) The binding site for C1q on IgG. Nature 332:738–740PubMedCrossRefGoogle Scholar
  41. 41.
    Nose M, Wigzell H (1983) Biological significance of carbohydrate chains on monoclonal antibodies. Proc Natl Acad Sci USA 80:6632–6636PubMedCrossRefGoogle Scholar
  42. 42.
    Koide N, Nose M, Muramatsu T (1977) Recognition of IgG by Fc receptor and complement: effects of glycosidase digestion. Biochem Biophys Res Commun 75:838–844PubMedCrossRefGoogle Scholar
  43. 43.
    Albert H, Collin M, Dudziak D et al (2008) In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci USA 105:15005–15009PubMedCrossRefGoogle Scholar
  44. 44.
    Nandakumar KS, Collin M, Olsen A et al (2007) Endoglycosidase treatment abrogates IgG arthritogenicity: importance of IgG glycosylation in arthritis. Eur J Immunol 37:2973–2982PubMedCrossRefGoogle Scholar
  45. 45.
    Collin M, Shannon O, Bjorck L (2008) IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions. Proc Natl Acad Sci USA 105:4265–4270PubMedCrossRefGoogle Scholar
  46. 46.
    Arnold JN, Wormald MR, Sim RB et al (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25:21–50PubMedCrossRefGoogle Scholar
  47. 47.
    Kobata A (2008) The N-linked sugar chains of human immunoglobulin G: their unique pattern, and their functional roles. Biochim Biophys Acta 1780:472–478PubMedCrossRefGoogle Scholar
  48. 48.
    Parekh RB, Dwek RA, Sutton BJ et al (1985) Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316:452–457PubMedCrossRefGoogle Scholar
  49. 49.
    Leirisalo-Repo M, Hernandez-Munoz HE, Rook GA (1999) Agalactosyl IgG is elevated in patients with active spondyloarthropathy. Rheumatol Int 18:171–176PubMedCrossRefGoogle Scholar
  50. 50.
    Parekh RB, Roitt IM, Isenberg DA et al (1988) Galactosylation of IgG associated oligosaccharides: reduction in patients with adult and juvenile onset rheumatoid arthritis and relation to disease activity. Lancet 1:966–969PubMedCrossRefGoogle Scholar
  51. 51.
    Mizuochi T, Hamako J, Nose M et al (1990) Structural changes in the oligosaccharide chains of IgG in autoimmune MRL/Mp-lpr/lpr mice. J Immunol 145:1794–1798PubMedGoogle Scholar
  52. 52.
    Bond A, Cooke A, Hay FC (1990) Glycosylation of IgG, immune complexes and IgG subclasses in the MRL-lpr/lpr mouse model of rheumatoid arthritis. Eur J Immunol 20:2229–2233PubMedCrossRefGoogle Scholar
  53. 53.
    van de Geijn FE, Wuhrer M, Selman MH et al (2009) Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther 11:R193PubMedCrossRefGoogle Scholar
  54. 54.
    Rook GA, Steele J, Brealey R et al (1991) Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J Autoimmun 4:779–794PubMedCrossRefGoogle Scholar
  55. 55.
    Parekh R, Roitt I, Isenberg D et al (1988) Age-related galactosylation of the N-linked oligosaccharides of human serum IgG. J Exp Med 167:1731–1736PubMedCrossRefGoogle Scholar
  56. 56.
    Satoh M, Iida S, Shitara K (2006) Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. Expert Opin Biol Ther 6:1161–1173PubMedCrossRefGoogle Scholar
  57. 57.
    Shields RL, Lai J, Keck R et al (2002) Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem 277:26733–26740, Epub 22002 May 26731PubMedCrossRefGoogle Scholar
  58. 58.
    Shinkawa T, Nakamura K, Yamane N 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 278:3466–3473, Epub 2002 Nov 3468PubMedCrossRefGoogle Scholar
  59. 59.
    Niwa R, Sakurada M, Kobayashi Y et al (2005) Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. Clin Cancer Res 11:2327–2336PubMedCrossRefGoogle Scholar
  60. 60.
    Niwa R, Natsume A, Uehara A et al (2005) IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J Immunol Meth 306:151–160CrossRefGoogle Scholar
  61. 61.
    Ferrara C, Stuart F, Sondermann P et al (2006) The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem 281:5032–5036PubMedCrossRefGoogle Scholar
  62. 62.
    Shibata-Koyama M, Iida S, Okazaki A et al (2009) The N-linked oligosaccharide at Fc gamma RIIIa Asn-45: an inhibitory element for high Fc gamma RIIIa binding affinity to IgG glycoforms lacking core fucosylation. Glycobiology 19:126–134PubMedCrossRefGoogle Scholar
  63. 63.
    Lifely MR, Hale C, Boyce S et al (1995) Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and grown under different culture conditions. Glycobiology 5:813–822PubMedCrossRefGoogle Scholar
  64. 64.
    Umana P, Jean-Mairet J, Moudry R et al (1999) Engineered glycoforms of an anti-neuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 17:176–180PubMedCrossRefGoogle Scholar
  65. 65.
    Schuster M, Umana P, Ferrara C et al (2005) Improved effector functions of a therapeutic monoclonal Lewis Y-specific antibody by glycoform engineering. Cancer Res 65:7934–7941PubMedGoogle Scholar
  66. 66.
    Schachter H (1986) Biosynthetic controls that determine the branching and micro-­heterogeneity of protein-bound oligosaccharides. Adv Exp Med Biol 205:53–85PubMedGoogle Scholar
  67. 67.
    Kumpel BM, Rademacher TW, Rook GA et al (1994) Galactosylation of human IgG mono­clonal anti-D produced by EBV-transformed B-lymphoblastoid cell lines is dependent on culture method and affects Fc receptor-mediated functional activity. Hum Antibodies Hybridomas 5:143–151PubMedGoogle Scholar
  68. 68.
    Kumpel BM, Wang Y, Griffiths HL et al (1995) The biological activity of human monoclonal IgG anti-D is reduced by beta-galactosidase treatment. Hum Antibodies Hybridomas 6:82–88PubMedGoogle Scholar
  69. 69.
    Boyd PN, Lines AC, Patel AK (1995) The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H. Mol Immunol 32:1311–1318PubMedCrossRefGoogle Scholar
  70. 70.
    Rademacher TW, Williams P, Dwek RA (1994) Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc Natl Acad Sci USA 91:6123–6127PubMedCrossRefGoogle Scholar
  71. 71.
    Kuroda Y, Nakata M, Hirose S et al (2001) Abnormal IgG galactosylation in MRL-lpr/lpr mice: pathogenic role in the development of arthritis. Pathol Int 51:909–915PubMedCrossRefGoogle Scholar
  72. 72.
    Kuroda Y, Nakata M, Nose M et al (2001) Abnormal IgG galactosylation and arthritis in MRL-Fas(lpr) or MRL-FasL(gld) mice are under the control of the MRL genetic background. FEBS Lett 507:210–214PubMedCrossRefGoogle Scholar
  73. 73.
    Malhotra R, Wormald MR, Rudd PM et al (1995) Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat Med 1:237–243PubMedCrossRefGoogle Scholar
  74. 74.
    Nimmerjahn F, Anthony RM, Ravetch JV (2007) Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc Natl Acad Sci USA 104:8433–8437PubMedCrossRefGoogle Scholar
  75. 75.
    Anthony RM, Nimmerjahn F, Ashline DJ et al (2008) Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320:373–376PubMedCrossRefGoogle Scholar
  76. 76.
    Scallon BJ, Tam SH, McCarthy SG et al (2007) Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44:1524–1534PubMedCrossRefGoogle Scholar
  77. 77.
    Anthony RM, Wermeling F, Karlsson MC et al (2008) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105:19571–19578PubMedCrossRefGoogle Scholar
  78. 78.
    Kaneko Y, Nimmerjahn F, Madaio MP et al (2006) Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 203:789–797, Epub 2006 Mar 2006PubMedCrossRefGoogle Scholar
  79. 79.
    Bruhns P, Samuelsson A, Pollard JW et al (2003) Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18:573–581PubMedCrossRefGoogle Scholar
  80. 80.
    Tackenberg B, Jelcic I, Baerenwaldt A et al (2009) Impaired inhibitory Fc gamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci USA 106:4788–4792PubMedCrossRefGoogle Scholar
  81. 81.
    Crow AR, Song S, Semple JW et al (2007) A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg? Blood 109:155–158PubMedCrossRefGoogle Scholar
  82. 82.
    Baerenwaldt A, Biburger M, Nimmerjahn F (2010) Mechanisms of action of intravenous immunoglobulins. Expert Rev Clin Immunol 6:425–434PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Businees Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Biology, Institute of GeneticsUniversity of Erlangen-NurembergErlangenGermany

Personalised recommendations