IgG3 donor-specific antibodies with a proinflammatory glycosylation profile may be associated with the risk of antibody-mediated rejection after kidney transplantation

Vincent Pernin, Nicole Bec, Anaïs Beyze, Alexis Bourgeois, Ilan Szwarc, Coralie Champion, Anthony Chauvin, Céline Rene, Georges Mourad, Pierre Merville, Jonathan Visentin, Helene Perrochia, Lionel Couzi, Christian Larroque, Moglie Le Quintrec, Vincent Pernin, Nicole Bec, Anaïs Beyze, Alexis Bourgeois, Ilan Szwarc, Coralie Champion, Anthony Chauvin, Céline Rene, Georges Mourad, Pierre Merville, Jonathan Visentin, Helene Perrochia, Lionel Couzi, Christian Larroque, Moglie Le Quintrec

Abstract

The pathogenicity of de novo donor-specific antibodies (dnDSA) varies according to their characteristics. While their MFI, complement-fixing ability, and IgG3 subclass are associated with ABMR occurrence and graft loss, they are not fully predictive of outcomes. We investigated the role of the Fc glycosylation of IgG3 dnDSA in ABMR occurrence using mass spectrometry after isolation by single HLA antigen beads. Between 2014 and 2018, we enrolled 54 patients who developed dnDSA (ABMR- n = 24; ABMR+ n = 30) in two French transplant centers. Fucosylation, galactosylation, GlcNAc bisection, and sialylation of IgG3 dnDSA were compared between ABMR+ and ABMR- patients. IgG3 dnDSA from ABMR+ patients exhibited significantly lower sialylation (7.5% vs. 10.5%, p < .001) and higher GlcNAc bisection (20.6% vs. 17.4%, p = .008). Fucosylation and galactosylation were similar in both groups. DSA glycosylation was not correlated with DSA MFI. In a multivariate analysis, low IgG3 sialylation, high IgG3%, time from transplantation to kidney biopsy, and tacrolimus-free regimen were independent predictive factors of ABMR. We conclude that a proinflammatory glycosylation profile of IgG3 dnDSA is associated with a risk of ABMR occurrence. Further studies are needed to confirm the clinical interest of DSA glycosylation and to clarify its role in determining the risk of ABMR and graft survival.

Trial registration: ClinicalTrials.gov NCT04026087.

Keywords: alloantibody; clinical research/practice; immunobiology; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; rejection: antibody-mediated (ABMR).

© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.

References

REFERENCES

    1. Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12(2):388-399.
    1. Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012;8(6):348-357.
    1. Valenzuela NM, Mulder A, Reed EF. HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and depending on subclass, by engaging FcγRs. J Immunol. 2013;190(12):6635-6650.
    1. Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol. 2012;8(11):670-678.
    1. Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8):1398-1406.
    1. Schinstock CA, Cosio F, Cheungpasitporn W, et al. The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant. 2017;17(6):1574-1584.
    1. Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury. J Am Soc Nephrol. 2016;27(1):293-304.
    1. Everly MJ, Rebellato LM, Haisch CE, et al. Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients. Transplantation. 2014;97(5):494-501.
    1. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226.
    1. Sicard A, Ducreux S, Rabeyrin M, et al. Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss. J Am Soc Nephrol. 2015;26(2):457-467.
    1. Bailly E, Anglicheau D, Blancho G, et al. Prognostic value of the persistence of C1q-binding anti-HLA antibodies in acute antibody-mediated rejection in kidney transplantation. Transplantation. 2018;102(4):688-698.
    1. Wuhrer M, Stam JC, van de Geijn FE, et al. Glycosylation profiling of immunoglobulin G (IgG) subclasses from human serum. Proteomics. 2007;7(22):4070-4081.
    1. Quast I, Keller CW, Maurer MA, et al. Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J Clin Invest. 2015;125(11):4160-4170.
    1. Malhotra R, Wormald MR, Rudd PM, Fischer PB, Dwek RA, Sim RB. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat Med. 1995;1(3):237-243.
    1. Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol. 2007;44(7):1524-1534.
    1. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313(5787):670-673.
    1. Parekh RB, Dwek RA, Sutton BJ, et al. Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature. 1985;316(6027):452-457.
    1. Parekh RB, Roitt IM, Isenberg DA, Dwek RA, Ansell BM, Rademacher TW. Galactosylation of IgG associated oligosaccharides: reduction in patients with adult and juvenile onset rheumatoid arthritis and relation to disease activity. Lancet. 1988;1(8592):966-969.
    1. Scherer HU, van der Woude D, Ioan-Facsinay A, et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum. 2010;62(6):1620-1629.
    1. Tomana M, Schrohenloher RE, Reveille JD, Arnett FC, Koopman WJ. Abnormal galactosylation of serum IgG in patients with systemic lupus erythematosus and members of families with high frequency of autoimmune diseases. Rheumatol Int. 1992;12(5):191-194.
    1. Vučković F, Krištić J, Gudelj I, et al. Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol. 2015;67(11):2978-2989.
    1. Holland M, Takada K, Okumoto T, et al. Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis. Clin Exp Immunol. 2002;129(1):183-190.
    1. Holland M, Yagi H, Takahashi N, et al. Differential glycosylation of polyclonal IgG, IgG-Fc and IgG-Fab isolated from the sera of patients with ANCA-associated systemic vasculitis. Biochim Biophys Acta. 2006;1760(4):669-677.
    1. Dube R, Rook GA, Steele J, et al. Agalactosyl IgG in inflammatory bowel disease: correlation with C-reactive protein. Gut. 1990;31(4):431-434.
    1. Leirisalo-Repo M, Hernandez-Munoz HE, Rook GA. Agalactosyl IgG is elevated in patients with active spondyloarthropathy. Rheumatol Int. 1999;18(5-6):171-176.
    1. Kemna MJ, Plomp R, van Paassen P, et al. Galactosylation and sialylation levels of IgG predict relapse in patients with PR3-ANCA associated vasculitis. EBioMedicine. 2017;17:108-118.
    1. Rombouts Y, Ewing E, van de Stadt LA, et al. Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis. 2015;74(1):234-241.
    1. Barba T, Harb J, Ducreux S, et al. Highly variable sialylation status of donor-specific antibodies does not impact humoral rejection outcomes. Front Immunol. 2019;10:513.
    1. Malard-Castagnet S, Dugast E, Degauque N, et al. Sialylation of antibodies in kidney recipients with de novo donor specific antibody, with or without antibody mediated rejection. Hum Immunol. 2016;77(11):1076-1083.
    1. Khovanova N, Daga S, Shaikhina T, et al. Subclass analysis of donor HLA-specific IgG in antibody-incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure. Transpl Int. 2015;28(12):1405-1415.
    1. Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 kidney meeting report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018;18(2):293-307.
    1. Pernin V, Beyze A, Szwarc I, et al. Distribution of de novo donor-specific antibody subclasses quantified by mass spectrometry: high IgG3 proportion is associated with antibody-mediated rejection occurrence and severity. Front Immunol. 2020;11:919-930.
    1. Yuan W, Sanda M, Wu J, Koomen J, Goldman R. Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease. J Proteomics. 2015;116:24-33.
    1. Zauner G, Selman MHJ, Bondt A, et al. Glycoproteomic analysis of antibodies. Mol Cell Proteomics MCP. 2013;12(4):856-865.
    1. Mahan AE, Tedesco J, Dionne K, et al. A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. J Immunol Methods. 2015;417:34-44.
    1. Ohmi Y, Ise W, Harazono A, et al. Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis. Nat Commun. 2016;7:11205.
    1. Said N, Gahoual R, Kuhn L, Beck A, François Y-N, Leize-Wagner E. Structural characterization of antibody drug conjugate by a combination of intact, middle-up and bottom-up techniques using sheathless capillary electrophoresis - Tandem mass spectrometry as nanoESI infusion platform and separation method. Anal Chim Acta. 2016;918:50-59.
    1. Selman MHJ, Derks RJE, Bondt A, et al. Fc specific IgG glycosylation profiling by robust nano-reverse phase HPLC-MS using a sheath-flow ESI sprayer interface. J Proteomics. 2012;75(4):1318-1329.
    1. Stadlmann J, Pabst M, Kolarich D, Kunert R, Altmann F. Analysis of immunoglobulin glycosylation by LC-ESI-MS of glycopeptides and oligosaccharides. Proteomics. 2008;8(14):2858-2871.
    1. Plomp R, Ruhaak LR, Uh H-W, et al. Subclass-specific IgG glycosylation is associated with markers of inflammation and metabolic health. Sci Rep. 2017;7(1):12325.
    1. Menni C, Gudelj I, Macdonald-Dunlop E, et al. Glycosylation profile of immunoglobulin G is cross-sectionally associated with cardiovascular disease risk score and subclinical atherosclerosis in two independent cohorts. Circ Res. 2018;122(11):1555-1564.
    1. Novokmet M, Lukić E, Vučković F, et al. Changes in IgG and total plasma protein glycomes in acute systemic inflammation. Sci Rep. 2014;4:4347. doi:10.1038/srep04347
    1. Jansen BC, Bondt A, Reiding KR, et al. Pregnancy-associated serum N-glycome changes studied by high-throughput MALDI-TOF-MS. Sci Rep. 2016;6:23296.
    1. Chen G, Wang Y, Qiu L, et al. Human IgG Fc-glycosylation profiling reveals associations with age, sex, female sex hormones and thyroid cancer. J Proteomics. 2012;75(10):2824-2834.
    1. Yu X, Wang Y, Kristic J, et al. Profiling IgG N-glycans as potential biomarker of chronological and biological ages: a community-based study in a Han Chinese population. Medicine. 2016;95(28):e4112.
    1. Hodoniczky J, Zheng YZ, James DC. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol Prog. 2005;21(6):1644-1652.
    1. Käsermann F, Boerema DJ, Rüegsegger M, et al. Analysis and functional consequences of increased Fab-sialylation of intravenous immunoglobulin (IVIG) after lectin fractionation. PLoS One. 2012;7(6):e37243.
    1. Tambur AR, Herrera ND, Haarberg KMK, et al. Assessing antibody strength: comparison of MFI, C1q, and titer information. Am J Transplant. 2015;15(9):2421-2430.
    1. Schinstock CA, Gandhi MJ, Stegall MD. Interpreting anti-HLA antibody testing data: a practical guide for physicians. Transplantation. 2016;100(8):1619-1628.
    1. Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol. 2017;28(6):1912-1923.
    1. Tradtrantip L, Ratelade J, Zhang H, Verkman AS. Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol. 2013;73(1):77-85.

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