Abstract
Over 80 different autoimmune disorders have been identified. A common denominator across most of these disorders is the presence of pathogenic autoantibodies. The pathogenic and inflammatory nature of antibodies is well accepted, and over the last three decades, evidence in humans and rodent models has revealed that antibodies can induce anti-inflammatory activities. The discovery of the relationship between immunoglobulin G (IgG) glycovariants and disease activity in autoimmune patients has provided insight into the structural and functional characteristics of IgG associated with its pro- and anti-inflammatory activity. In this chapter, we discuss evidence of the anti-inflammatory nature of IgG and the mechanisms by which this activity is exerted. Current clinical evidence of this anti-inflammatory activity is also discussed.
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References
Ackerman ME, Crispin M, Yu X, Baruah K, Boesch AW, Harvey DJ, Dugast AS, Heizen EL, Ercan A, Choi I, Streeck H, Nigrovic PA, Bailey-Kelogg C, Scanlan C, Alter G (2013) Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J Clin Invest 123(5):2183–2192
Ahmed AA, Giddens J, Pincetic A, Lomino JV, Ravetch JV, Wang LX, Bjorkman PJ (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Molec Biol 426(18):3166–3179. https://doi.org/10.1016/j.jmb.2014.07.006
Akilesh S (2004) The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 113(9):1328–1333. https://doi.org/10.1172/jci200418838
Anthony RM, Nimmerjahn F, Ashline D, Reinhold V, Paulson J, Ravetch JV (2008a) A recombinant IgG Fc that recapitulates the anti-inflammatory activity of IVIg. Science 320(5874):373–376. https://doi.org/10.1126/science.1154315
Anthony RM, Kobayashi T, Wermeling F, Ravetch JV (2011) Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475(7354):110–113. https://doi.org/10.1038/nature10134
Anthony R, Wermeling F, Karlsson M, Ravetch JV (2008b) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci U S A 105(50):19571–19578. https://doi.org/10.1073/pnas.0810163105
Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Ann Rev Immunol 25:21–50. https://doi.org/10.1146/annurev.immunol.25.022106.141702
Barreto M, Ferreira RC, Lourenco L, Moraes-Fontes MF, Santos E, Alves M, Carvalho C, Martins B, Andreia R, Viana JF, Vasconcelos C, Mota-Vieira L, Ferreira C, Demengeot J, Vicente AM (2009) Low frequency of CD4+ CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFβ gene variants. BMC Immunol 10:5. https://doi.org/10.1186/1471-2172-10-5
Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, Chevailler A, Mouthon L, Weill B, Bruneval P, Kazatchkine MD, Kaveri SV (2003) Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101(2):758–765. https://doi.org/10.1182/blood-2002-05-1447
Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW (2005) Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest 115(10):2914–2923. https://doi.org/10.1172/JCI24772
Bruhns P, Samuelsson A, Pollard J, Ravetch JV (2003) Colony-stimulating factor-1-dependent macrophages are responsible for IVIG Protection in antibody-induced autoimmune disease. Immunity 18(4):573–581. https://doi.org/10.1016/S1074-7613(03)00080-3
Bruhns P, Iannascoli B, England P, Mancardi D, Fernandez N, Jorieux S, Daeron M (2009) Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113(16):3716–3725. https://doi.org/10.1182/blood2008-09-179754
Burns JC, Franco A (2015) The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. Expert Rev Clin Immunol 11(7):819–825. https://doi.org/10.1586/1744666X.2015.1044980
Burns JC, Song Y, Bujold M, Shimizu C, Kanegaye JT, Tremoulet AH, Franco A (2013) Immune-monitoring in Kawasaki disease patients treated with infliximab and intravenous immunoglobulin. Clin Exp Immunol 174(3):337–344. https://doi.org/10.1111/cei.12182
Burton OT, Logsdon SL, Zhou JS, Medina-Tamayo J, Abdel-Gadir A, Noval Rivas M, Koleoglou KJ, Chatila TA, Schneider LC, Rachid R, Umetsu DT, Oettgen HC (2014) Oral immunotherapy induces IgG antibodies that act through FcγRIIb to suppress IgE-mediated hypersensitivity. J Allergy Clin Immunol 134(6):1310–1317 e1316. https://doi.org/10.1016/j.jaci.2014.05.042
Chi LJ, Wang HB, Zhang Y, Wang WZ (2007) Abnormality of circulating CD4(+) CD25(+) regulatory T cell in patients with Guillain-Barre syndrome. J Neuroimmunol 192(1–2):206–214. https://doi.org/10.1016/j.jneuroim.2007.09.034
Chu SY, Vostiar I, Karki S, Moore GL, Lazar GA, Pong E, Joyce PF, Szymkowski DE, Desjarlais JR (2008) Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. Mol Immunol 45(15):3926–3933. https://doi.org/10.1016/j.molimm.2008.06.027
Cines DB, Bussel JB (2005) How I treat idiopathic thrombocytopenic purpura (ITP). Blood 106(7):2244–2251. https://doi.org/10.1182/blood-2004-12-4598
Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6(4):443–446
Crow AR, Song S, Freedman J, Helgason CD, Humphries RK, Siminovitch KA, Lazarus AH (2003) IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 102(2):558–560. https://doi.org/10.1182/blood-2003-01-0023
Czajkowsky DM, Andersen JT, Fuchs A, Wilson TJ, Mekhaiel D, Colonna M, He J, Shao Z, Mitchell DA, Wu G, Dell A, Haslam S, Lloyd KA, Moore SC, Sandlie I, Blundell PA, Pleass RJ (2015) Developing the IVIG biomimetic, hexa-Fc, for drug and vaccine applications. Sci Rep 5:9526. https://doi.org/10.1038/srep09526
De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W (2008) Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood 112(8):3303–3311. https://doi.org/10.1182/blood-2008-02-138073
Debre M, Griscelli C, Bonnet MC, Carosella E, Philippe N, Reinert P, Vilmer E, Kaplan C, Fridman WH, Teillaud JL (1993) Infusion of Fcγ fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342(8877):945–949. https://doi.org/10.1016/0140-6736(93)92000-J
Delfraissy JF, Tchernia G, Laurian Y, Wallon C, Galanaud P, Dormont J (1985) Suppressor cell function after intravenous gammaglobulin treatment in adult chronic idiopathic thrombocytopenic purpura. Br J Haematol 60(2):315–322. https://doi.org/10.1111/j.1365-2141.1985.tb07417.x
Dube R, Rook GA, Steele J, Brealey R, Dwek RA, Rademacher T, Lennard-Jones J (1990) Agalactosyl IgG in inflammatory bowel disease: correlation with C-reactive protein. Gut 31(4):431–434. https://doi.org/10.1136/gut.31.4.431
Durandy A, Fischer A, Griscelli C (1981) Dysfunctions of pokeweed mitogen-stimulated T and B lymphocyte responses induced by gammaglobulin therapy. J Clin Invest 67(3):867–877. https://doi.org/10.1172/JCI110104
Engdahl C, Bondt A, Harre U, Raufer J, Pfeifle R, Camponeschi A, Wuhrer M, Seeling M, Martensson IL, Nimmerjahn F, Kronke G, Scherer HU, Forsblad-d’Elia H, Schett G (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. https://doi.org/10.1186/s13075-018-1586-z
Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, Cohen JL, Salomon BL, Kazatchkine MD, Kaveri SV, Misra N (2008) Expansion of CD4+ CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 111(2):715–722. https://doi.org/10.1182/blood-2007-03-079947
Epp A, Hobusch J, Bartsch YC, Petry J, Lilienthal GM, Koeleman CAM, Eschweiler S, Mobs C, Hall A, Morris SC, Braumann D, Engellenner C, Bitterling J, Rahmoller J, Leliavski A, Thurmann R, Collin M, Moremen KW, Strait RT, Blanchard V, Petersen A, Gemoll T, Habermann JK, Petersen F, Nandy A, Kahlert H, Hertl M, Wuhrer M, Pfutzner W, Jappe U, Finkelman FD, Ehlers M (2018) Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions. J Allergy Clin Immunol 141(1):399–402 e398. https://doi.org/10.1016/j.jaci.2017.06.021
Espy C, Morelle W, Kavian N, Grange P, Goulvestre C, Viallon V, Chereau C, Pagnoux C, Michalski JC, Guillevin L, Weill B, Batteux F, Guilpain P (2011) Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener’s). Arthritis Rheum 63(7):2105–2115. https://doi.org/10.1002/art.30362
Feige MJ, Nath S, Catharino SR, Weinfurtner D, Steinbacher S, Buchner J (2009) Structure of the murine unglycosylated IgG1 Fc fragment. J Molec Biol 391(3):599–608. https://doi.org/10.1016/j.jmb.2009.06.048
Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, Hennig M, Ruf A, Rufer AC, Stihle M, Umana P, Benz J (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. https://doi.org/10.1073/pnas.1108455108
Fickentscher C, Magorivska I, Janko C, Biermann M, Bilyy R, Nalli C, Tincani A, Medeghini V, Meini A, Nimmerjahn F, Schett G, Munoz LE, Andreoli L, Herrmann M (2015) The Pathogenicity of anti-β2GP1-IgG Autoantibodies depends on Fc glycosylation. J Immunol Res 2015:638129. https://doi.org/10.1155/2015/638129
Fiebiger BM, Maamary J, Pincetic A, Ravetch JV (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. https://doi.org/10.1073/pnas.1505292112
Fokkink WJ, Selman MH, Dortland JR, Durmus B, Kuitwaard K, Huizinga R, van Rijs W, Tio-Gillen AP, van Doorn PA, Deelder AM, Wuhrer M, Jacobs BC (2014) IgG Fc N-glycosylation in Guillain-Barre syndrome treated with immunoglobulins. J Proteome Res 13(3):1722–1730. https://doi.org/10.1021/pr401213z
Franco A, Touma R, Song Y, Shimizu C, Tremoulet AH, Kanegaye JT, Burns JC (2014) Specificity of regulatory T cells that modulate vascular inflammation. Autoimmunity 47(2):95–104. https://doi.org/10.3109/08916934.2013.860524
Gringhuis SI, Kaptein TM, Wevers BA, van der Vlist M, Klaver EJ, van Die I, Vriend LE, de Jong MA, Geijtenbeek TB (2014) Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production. Nat Commun 5:5074. https://doi.org/10.1038/ncomms6074
Gupta A, Novik BE, Rubinstein A (1986) Restoration of suppressor T-cell functions in children With AIDS following intravenous gamma globulin treatment. Am J Dis Child 140(2):143–146. https://doi.org/10.1001/archpedi.1986.02140160061033
Hansen RJ, Balthasar JP (2002) Effects of intravenous immunoglobulin on platelet count and antiplatelet antibodydisposition in a rat model of immune thrombocytopenia. Blood 100(6):2087–2093
Harre U, Lang SC, Pfeifle R, Rombouts Y, Fruhbeisser S, Amara K, Bang H, Lux A, Koeleman CA, Baum W, Dietel K, Grohn F, Malmstrom V, Klareskog L, Kronke G, Kocijan R, Nimmerjahn F, Toes RE, Herrmann M, Scherer HU, Schett G (2015) Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 6:6651. https://doi.org/10.1038/ncomms7651
Heyman B (2003) Feedback regulation by IgG antibodies. Immunol Lett 88(2):157–161. https://doi.org/10.1016/s0165-2478(03)00078-6
Houde D, Peng Y, Berkowitz S, Engen JR (2010) Post-translational modifications differentially affect IgG1 conformation and receptor binding. Mol Cell Proteomics 9(8):1716–1728. https://doi.org/10.1074/mcp.M900540-MCP200
Huang HS, Sun DS, Lien TS, Chang HH (2010) Dendritic cells modulate platelet activity in IVIg-mediated amelioration of ITP in mice. Blood 116(23):5002–5009. https://doi.org/10.1182/blood-2010-03-275123
Jain A, Olsen HS, Vyzasatya R, Burch E, Sakoda Y, Merigeon EY, Cai L, Lu C, Tan M, Tamada K, Schulze D, Block DS, Strome SE (2012) Fully recombinant IgG2a Fc multimers (stradomers) effectively treat collagen-induced arthritis and prevent idiopathic thrombocytopenic purpura in mice. Arthritis Res Ther 14(4):R192
Jefferis R, Lund J (2002) Interaction sites on human IgG-Fc for FcγR: current models. Immunol Lett 82(1–2):57–65
Kanazawa N (2007) Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells. J Dermatol Sci 45(2):77–86. https://doi.org/10.1016/j.jdermsci.2006.09.001
Kaneko Y, Nimmerjahn F, Madaio MP, Ravetch JV (2006a) Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 203(3):789–797. https://doi.org/10.1084/jem.20051900
Kaneko Y, Nimmerjahn F, Ravetch JV (2006b) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313(5787):670–673. https://doi.org/10.1126/science.1129594
Kao D, Lux A, Schaffert A, Lang R, Altmann F, Nimmerjahn F (2017) IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice. Eur J Immunol 47(12):2070–2079. https://doi.org/10.1002/eji.201747208
Kapur R, Della Valle L, Sonneveld M, Hipgrave Ederveen A, Visser R, Ligthart P, de Haas M, Wuhrer M, van der Schoot CE, Vidarsson G (2014a) Low anti-RhD IgG-Fc-fucosylation in pregnancy: a new variable predicting severity in haemolytic disease of the fetus and newborn. Br J Haematol 166(6):936–945. https://doi.org/10.1111/bjh.12965
Kapur R, Kustiawan I, Vestrheim A, Koeleman CA, Visser R, Einarsdottir HK, Porcelijn L, Jackson D, Kumpel B, Deelder AM, Blank D, Skogen B, Killie MK, Michaelsen TE, de Haas M, Rispens T, van der Schoot CE, Wuhrer M, Vidarsson G (2014b) A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy. Blood 123(4):471–480. https://doi.org/10.1182/blood-2013-09-527978
Kaufman GN, Massoud AH, Audusseau S, Banville-Langelier AA, Wang Y, Guay J, Garellek JA, Mourad W, Piccirillo CA, McCusker C, Mazer BD (2011) Intravenous immunoglobulin attenuates airway hyperresponsiveness in a murine model of allergic asthma. Clin Exp Allergry 41(5):718–728. https://doi.org/10.1111/j.1365-2222.2010.03663.x
Kemna MJ, Plomp R, van Paassen P, Koeleman CAM, Jansen BC, Damoiseaux J, Cohen Tervaert JW, Wuhrer M (2017) Galactosylation and sialylation levels of IgG predict relapse in patients with PR3-ANCA associated vasculitis. EBioMedicine 17:108–118. https://doi.org/10.1016/j.ebiom.2017.01.033
Kiener PA, Lioubin MN, Rohrschneider LR, Ledbetter JA, Nadler SG, Diegel ML (1997) Co-ligation of the antigen and Fc receptors gives rise to the selective modulation of intracellular signaling in B cells. J Biol Chem 272(6):3838–3844
Krapp S, Mimura Y, Jefferis R, Huber R, Sondermann P (2003) Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity. J Mol Biol 325(5):979–989. https://doi.org/10.1016/s0022-2836(02)01250-0
Kurowska W, Kuca-Warnawin EH, Radzikowska A, Maslinski W (2017) The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis. Cent Eur J Immunol 42(4):390–398. https://doi.org/10.5114/ceji.2017.72807
Leontyev D, Katsman Y, Ma XZ, Miescher S, Kasermann F, Branch DR (2012) Sialylation-independent mechanism involved in the amelioration of murine immune thrombocytopenia using intravenous gammaglobulin. Transfusion 52(8):1799–1805. https://doi.org/10.1111/j.1537-2995.2011.03517.x
Li N, Zhao M, Hilario-Vargas J, Prisayanh P, Warren S, Diaz LA, Roopenian DC, Liu Z (2005) Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest 115(12):3440–3450. https://doi.org/10.1172/JCI24394
Li T, DiLillo DJ, Bournazos S, Giddens JP, Ravetch JV, Wang LX (2017) Modulating IgG effector function by Fc glycan engineering. Proc Natl Acad Sci U S A 114(13):3485–3490. https://doi.org/10.1073/pnas.1702173114
Lood C, Allhorn M, Lood R, Gullstrand B, Olin AI, Ronnblom L, Truedsson L, Collin M, Bengtsson AA (2012) IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: a possible new treatment? Arthritis Rheum 64(8):2698–2706. https://doi.org/10.1002/art.34454
Maamary J, Wang TT, Tan GS, Palese P, Ravetch JV (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 114(38):10172–10177
Maddur MS, Stephen-Victor E, Das M, Prakhar P, Sharma VK, Singh V, Rabin M, Trinath J, Balaji KN, Bolgert F, Vallat JM, Magy L, Kaveri SV, Bayry J (2017) Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy. J Neuroinflammation 14(1):58. https://doi.org/10.1186/s12974-017-0818-5
Magorivska I, Munoz LE, Janko C, Dumych T, Rech J, Schett G, Nimmerjahn F, Bilyy R, Herrmann M (2016) Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells. Clin Exp Immunol 184(1):110–117. https://doi.org/10.1111/cei.12744
Massoud AH, Guay J, Shalaby KH, Bjur E, Ablona A, Chan D, Nouhi Y, McCusker CT, Mourad MW, Piccirillo CA, Mazer BD (2012) Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3-positive regulatory T cells. J Allergy Clin Immunol 129(6):1656–1665 e1653. https://doi.org/10.1016/j.jaci.2012.02.050
Massoud AH, Yona M, Xue D, Chouiali F, Alturaihi H, Ablona A, Mourad W, Piccirillo CA, Mazer BD (2014) Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 133(3):853–863 e855. https://doi.org/10.1016/j.jaci.2013.09.029
Mekhaiel DN, Czajkowsky DM, Andersen JT, Shi J, El-Faham M, Doenhoff M, McIntosh RS, Sandlie I, He J, Hu J, Shao Z, Pleass RJ (2011) Polymeric human Fc-fusion proteins with modified effector functions. Sci Rep 1:124. https://doi.org/10.1038/srep00124
Mimura Y, Church S, Ghirlando R, Ashton PR, Dong S, Goodall M, Lund J, Jefferis R (2000) The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms. Mol Immunol 37(12):697–706
Mimura Y, Sondermann P, Ghirlando R, Lund J, Young SP, Goodall M, Jefferis R (2001) Role of oligosaccharide residues of IgG1-Fc in FcγRIIb binding. J Biol Chem 276(49):45539–45547. https://doi.org/10.1074/jbc.M107478200
Mogensen TH, Melchjorsen J, Larsen CS, Paludan SR (2010) Innate immune recognition and activation during HIV infection. Retrovirology 7:54. https://doi.org/10.1186/1742-4690-7-54
Nechansky A, Schuster M, Jost W, Siegl P, Wiederkum S, Gorr G, Kircheis R (2007) Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies. Mol Immunol 44(7):1815–1817. https://doi.org/10.1016/j.molimm.2006.08.013
Niknami M, Wang MX, Nguyen T, Pollard JD (2013) Beneficial effect of a multimerized immunoglobulin Fc in an animal model of inflammatory neuropathy (experimental autoimmune neuritis). J Peripher Nerv Syst 18(2):141–152
Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science 310(5759):1510–1512
Nimmerjahn F, Ravetch JV (2006) Fcγ receptors: old friends and new family members. Immunity 24(1):19–28. https://doi.org/10.1016/j.immuni.2005.11.010
Nose M, Wigzell H (1983) Biological significance of carbohydrate chains on monoclonal antibodies. Proc Natl Acad Sci U S A 80(21):6632–6636
Oefner CM, Winkler A, Hess C, Lorenz AK, Holecska V, Huxdorf M, Schommartz T, Petzold D, Bitterling J, Schoen AL, Stoehr AD, Vu Van D, Darcan-Nikolaisen Y, Blanchard V, Schmudde I, Laumonnier Y, Strover HA, Hegazy AN, Eiglmeier S, Schoen CT, Mertes MM, Loddenkemper C, Lohning M, Konig P, Petersen A, Luger EO, Collin M, Kohl J, Hutloff A, Hamelmann E, Berger M, Wardemann H, Ehlers M (2012) Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. J Allergy Clin Immunol 129(6):1647–1655 e1613. https://doi.org/10.1016/j.jaci.2012.02.037
Ogata S, Shimizu C, Franco A, Touma R, Kanegaye JT, Choudhury BP, Naidu NN, Kanda Y, Hoang LT, Hibberd ML, Tremoulet AH, Varki A, Burns JC (2013) Treatment response in Kawasaki disease is associated with sialylation levels of endogenous but not therapeutic intravenous immunoglobulin G. PLoS ONE 8(12):e81448. https://doi.org/10.1371/journal.pone.0081448
Ohkuma K, Sasaki T, Kamei S, Okuda S, Nakano H, Hamamoto T, Fujihara K, Nakashima I, Misu T, Itoyama Y (2007) Modulation of dendritic cell development by immunoglobulin G in control subjects and multiple sclerosis patients. Clin Exp Immunol 150(3):397–406. https://doi.org/10.1111/j.1365-2249.2007.03496.x
Ohmi Y, Ise W, Harazono A, Takakura D, Fukuyama H, Baba Y, Narazaki M, Shoda H, Takahashi N, Ohkawa Y, Ji S, Sugiyama F, Fujio K, Kumanogoh A, Yamamoto K, Kawasaki N, Kurosaki T, Takahashi Y, Furukawa K (2016) Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis. Nat Commun 7:11205. https://doi.org/10.1038/ncomms11205
Ono M, Okada H, Bolland S, Yanagi S, Tomohiro K, Ravetch JV (1997) Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90(2):293–301
Ortiz DF, Lansing JC, Rutitzky L, E. K, Prod’homme T, Choudhury A, Washburn N, Bhatnagar N, Beneduce C, K. H, Prenovitz R, Child M, Killough J, Tyler S, Brown J, Nguyen S, Schwab I, Hains M, Meccariello R, Markowitz L, Wang J, Zouaoui R, Simpson A, Schultes B, Capila I, Ling L, Nimmerjahn F, Manning AM, Bosques CJ (2016) Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors. Sci Transl Med 8(365):ra158
Pagan JD, Kitaoka M, Anthony RM (2018) Engineered sialylation of pathogenic antibodies in vivo attenuates autoimmune disease. Cell 172(3):564–577 e513. https://doi.org/10.1016/j.cell.2017.11.041
Parekh RB, Dwek RA, Sutton BJ, Fernandes DL, Leung A, Stanworth D, Rademacher T, Mizouchi T, Takahashi N, Matsuta K (1985) Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316
Pasek M, Duk M, Podbielska M, Sokolik R, Szechinski J, Lisowska E, Krotkiewski H (2006) Galactosylation of IgG from rheumatoid arthritis (RA) patients—changes during therapy. Glycoconjugate J 23(7–8):463–471. https://doi.org/10.1007/s10719-006-5409-0
Qian J, Zhu J, Wang M, Wu S, Chen T (2011) Suppressive effects of intravenous immunoglobulin (IVIG) on human umbilical cord blood immune cells. Pediatr Allergy Immunol 22(2):211–220. https://doi.org/10.1111/j.1399-3038.2010.01049.x
Qureshi OS, Rowley TF, Junker F, Peters SJ, Crilly S, Compson J, Eddleston A, Bjorkelund H, Greenslade K, Parkinson M, Davies NL, Griffin R, Pither TL, Cain K, Christodoulou L, Staelens L, Ward E, Tibbitts J, Kiessling A, Smith B, Brennan FR, Malmqvist M, Fallah-Arani F, Humphreys DP (2017) Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions. Sci Rep 7(1):17049. https://doi.org/10.1038/s41598-017-17255-8
Raju TS (2008) Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr Opin Immunol 20(4):471–478. https://doi.org/10.1016/j.coi.2008.06.007
Ramakrishna C, Newo AN, Shen YW, Cantin E (2011) Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis. PLoS Pathog 7(6):e1002071. https://doi.org/10.1371/journal.ppat.1002071
Ravetch JV, Clynes RA (1998) Divergent roles for Fc receptors and complement in vivo. Ann Rev Immunol 16:421–432
Rombouts Y, Ewing E, van de Stadt LA, Selman MH, Trouw LA, Deelder AM, Huizinga TW, Wuhrer M, van Schaardenburg D, Toes RE, Scherer HU (2015) Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis 74(1):234–241. https://doi.org/10.1136/annrheumdis-2013-203565
Rook GA, Steele J, Brealey R, Whyte A, Isenberg D, Sumar N, Nelson JL, Bodman KB, Young A, Roitt IM (1991) Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J Autoimmun 4(5):779–794
Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291(5503):484–486
Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS (2007) Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44(7):1524–1534. https://doi.org/10.1016/j.molimm.2006.09.005
Scherer HU, van der Woude D, Ioan-Facsinay A, el Bannoudi H, Trouw LA, Wang J, Haupl T, Burmester GR, Deelder AM, Huizinga TW, Wuhrer M, Toes RE (2010) Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum 62(6):1620–1629. https://doi.org/10.1002/art.27414
Schwab I, Nimmerjahn F (2013) Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol 13(3):176–189. https://doi.org/10.1038/nri3401
Schwab I, Biburger M, Kronke G, Schett G, Nimmerjahn F (2012) IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1. Eur J Immunol 42(4):826–830. https://doi.org/10.1002/eji.201142260
Schwab I, Mihai S, Seeling M, Kasperkiewicz M, Ludwig RJ, Nimmerjahn F (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. https://doi.org/10.1002/eji.201344230
Selman MH, Niks EH, Titulaer MJ, Verschuuren JJ, Wuhrer M, Deelder AM (2011) IgG fc N-glycosylation changes in Lambert-Eaton myasthenic syndrome and myasthenia gravis. J Proteome Res 10(1):143–152
Shields RL, Lai J, Keck R, O’Connell LY, Hong K, Meng YG, Weikert SH, Presta LG (2002) Lack of fucose on human IgG1N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chem 277(30):26733–26740. https://doi.org/10.1074/jbc.M202069200
Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki M, Hanai N, Shitara K (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. https://doi.org/10.1074/jbc.M210665200
Siragam V, Brinc D, Crow AR, Song S, Freedman J, Lazarus AH (2005) Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease. J Clin Invest 115(1):155–160. https://doi.org/10.1172/jci200522753ds1
Siragam V, Crow AR, Brinc D, Song S, Freedman J, Lazarus AH (2006) Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells. Nat Med 12(6):688–692. https://doi.org/10.1038/nm1416
Sjowall C, Zapf J, von Lohneysen S, Magorivska I, Biermann M, Janko C, Winkler S, Bilyy R, Schett G, Herrmann M, Munoz LE (2015) Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus. Lupus 24(6):569–581
Sondermann P, Kaiser J, Jacob U (2001) Molecular basis for immune complex recognition: a comparison of Fc-receptor structures. J Mol Biol 309(3):737–749
Sondermann P, Pincetic A, Maamary J, Lammens K, Ravetch JV (2013) General mechanism for modulating immunoglobulin effector function. Proc Natl Acad Sci U S A 110(24):9868–9872
Sonneveld ME, Natunen S, Sainio S, Koeleman CA, Holst S, Dekkers G, Koelewijn J, Partanen J, van der Schoot CE, Wuhrer M, Vidarsson G (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. https://doi.org/10.1111/bjh.14053
Sonneveld ME, Koelewijn J, de Haas M, Admiraal J, Plomp R, Koeleman CA, Hipgrave Ederveen AL, Ligthart P, Wuhrer M, van der Schoot CE, Vidarsson G (2017) Antigen specificity determines anti-red blood cell IgG-Fc alloantibody glycosylation and thereby severity of haemolytic disease of the fetus and newborn. Br J Haematol 176(4):651–660. https://doi.org/10.1111/bjh.14438
Spirig R, Campbell IK, Koernig S, Chen CG, Lewis BJB, Butcher R, Muir I, Taylor S, Chia J, Leong D, Simmonds J, Scotney P, Schmidt P, Fabri L, Hofmann A, Jordi M, Spycher MO, Cattepoel S, Brasseit J, Panousis C, Rowe T, Branch DR, Baz Morelli A, Kasermann F, Zuercher AW (2018) rIgG1 Fc Hexamer inhibits antibody-mediated autoimmune disease via effects on complement and FcγRs. J Immunol 200(8):2542–2553. https://doi.org/10.4049/jimmunol.1701171
Steiniger B, Barth P, Herbst B, Hartnell A, Crocker PR (1997) The species-specific structure of microanatomical compartments in the human spleen: strongly sialoadhesin-positive macrophages occur in the perifollicular zone, but not in the marginal zone. Immunology 92(2):307–316
Strait RT, Morris SC, Finkelman FD (2006) IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcγRIIb cross-linking. J Clin Invest 116(3):833–841. https://doi.org/10.1172/JCI25575
Subedi GP, Barb AW (2016) The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fcγ receptor. mAbs 8(8):1512–1524. https://doi.org/10.1080/19420862.2016.1218586
Tackenberg B, Jelcic I, Baerenwaldt A, Oertel WH, Sommer N, Nimmerjahn F, Lunemann JD (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. https://doi.org/10.1073/pnas.0807319106
Teeling JL, Jansen-Hendriks T, Juijpers TW, de Haas M, van de Winkel JG, Hack CE, Bleeker WK (2001) Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 98(4):1095–1099
Thiruppathi M, Sheng JR, Li L, Prabhakar BS, Meriggioli MN (2014) Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis. J Autoimmun 52:64–73. https://doi.org/10.1016/j.jaut.2013.12.014
Tjon AS, van Gent R, Jaadar H, Martin van Hagen P, Mancham S, van der Laan LJ, te Boekhorst PA, Metselaar HJ, Kwekkeboom J (2014) Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J Immunol 192(12):5625–5634. https://doi.org/10.4049/jimmunol.1301260
Trbojevic Akmacic I, Ventham NT, Theodoratou E, Vuckovic F, Kennedy NA, Kristic J, Nimmo ER, Kalla R, Drummond H, Stambuk J, Dunlop MG, Novokmet M, Aulchenko Y, Gornik O, Campbell H, Pucic Bakovic M, Satsangi J, Lauc G, Consortium I-B (2015) Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome. Inflamm Bowel Dis 21(6):1237–1247. https://doi.org/10.1097/MIB.0000000000000372
Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K (2012) High-dose intravenous immunoglobulin treatment increases regulatory T cells in patients with eosinophilic granulomatosis with polyangiitis. J Rheumatol 39(5):1019–1025. https://doi.org/10.3899/jrheum.110981
Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K (2014) High-dose intravenous immunoglobulin therapy for eosinophilic granulomatosis with polyangiitis. Clin Transl Allergy 4(38)
Vaccaro C, Zhou J, Ober RJ, Ward ES (2005) Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23(10):1283–1288. https://doi.org/10.1038/nbt1143
van de Geijn FE, Wuhrer M, Selman MH, Willemsen SP, de Man YA, Deelder AM, Hazes JM, Dolhain RJ (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(6):R193. https://doi.org/10.1186/ar2892
Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282(5388):490–493
Vidarsson G, Dekkers G, Rispens T (2014) IgG subclasses and allotypes: from structure to effector functions. Front Immunol 5:520. https://doi.org/10.3389/fimmu.2014.00520
Vuckovic F, Kristic J, Gudelj I, Teruel M, Keser T, Pezer M, Pucic-Bakovic M, Stambuk J, Trbojevic Akmacic I, Barrios C, Pavic T, Menni C, Wang Y, Zhou Y, Cui L, Song H, Zeng Q, Guo X, Pns-Estel BA, Mckeigue P, Leslie Patrick A, Gornik O, Spector TD, Harjacek M, Alarcon-Riquelme M, Molokhia M, Wang W, Luac G (2015) Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol 67(11):2798–3789
Washburn N, Schwab I, Ortiz D, Bhatnagar N, Lansing JC, Medeiros A, Tyler S, Mekala D, Cochran E, Sarvaiya H, Garofalo K, Meccariello R, Meador JW 3rd, Rutitzky L, Schultes BC, Ling L, Avery W, Nimmerjahn F, Manning AM, Kaundinya GV, Bosques CJ (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 112(11):E1297–E1306. https://doi.org/10.1073/pnas.1422481112
Watson M, Rudd PM, Bland M, Dwek RA, Axford JS (1999) Sugar printing rheumatic diseases: a potential method for disease differentiation using immunoglobulin G oligosaccharides. Arthritis Rheum 42(8):1682–1690
Wong AH, Fukami Y, Sudo M, Kokubun N, Hamada S, Yuki N (2016) Sialylated IgG-Fc: a novel biomarker of chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 87(3):257–259. https://doi.org/10.1136/jnnp2014-309964
Wuhrer M, Porcelijn L, Kapur R, Koeleman CA, Deelder AM, De Haas M, Vidarsson G (2009) Regulated glycosylation patterns of IgG during alloimmune responses against human platelet antigens. J Proteome Res 8(2):450–456
Wuhrer M, Selman MH, McDonnell LA, Kumpfel T, Derfuss T, Khademi M, Olsson T, Hohlfeld R, Meinl E, Krumbholz M (2015a) Pro-inflammatory pattern of IgG1 Fc glycosylation in multiple sclerosis cerebrospinal fluid. J Neuroinflammation 12:235. https://doi.org/10.1186/s12974-015-0450-1
Wuhrer M, Stavenhagen K, Koeleman CA, Selman MH, Harper L, Jacobs BC, Savage CO, Jefferis R, Deelder AM, Morgan M (2015b) 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. https://doi.org/10.1021/pr500780a
Zhang G, Massaad CA, Gao T, Pillai L, Bogdanova N, Ghauri S, Sheikh KA (2016) Sialylated intravenous immunoglobulin suppress anti-ganglioside antibody mediated nerve injury. Exp Neurol 282:49–55. https://doi.org/10.1016/j.expneurol.2016.05.020
Zuercher AW, Spirig R, Baz Morelli A, Kasermann F (2016) IVIG in autoimmune disease—potential next generation biologics. Autoimmun Rev 15(8):781–785. https://doi.org/10.1016/j.autrev.2016.03.018
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Beneduce, C., Kurtagic, E., Bosques, C.J. (2019). Anti-inflammatory Activity of IgG-Fc. 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_148
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