Abstract
Immunoglobulin glycosylation is a pivotal mechanism that drives the diversification of antibody functions. The composition of the IgG glycome is influenced by environmental factors, genetic traits and inflammatory contexts. Differential IgG glycosylation has been shown to intricately modulate IgG effector functions and has a role in the initiation and progression of various diseases. Analysis of IgG glycosylation is therefore a promising tool for predicting disease severity. Several autoimmune and alloimmune disorders, including critical and potentially life-threatening conditions such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and antibody-mediated kidney graft rejection, are driven by immunoglobulin. In certain IgG-driven kidney diseases, including primary membranous nephropathy, IgA nephropathy and lupus nephritis, particular glycome characteristics can enhance in situ complement activation and the recruitment of innate immune cells, resulting in more severe kidney damage. Hypofucosylation, hypogalactosylation and hyposialylation are the most common IgG glycosylation traits identified in these diseases. Modulating IgG glycosylation could therefore be a promising therapeutic strategy for regulating the immune mechanisms that underlie IgG-driven kidney diseases and potentially reduce the burden of immunosuppressive drugs in affected patients.
Key points
-
Aberrant glycosylation of IgG is influenced by antibody subclass and antigen specificity and is established during B cell differentiation and maturation within germinal centres.
-
Hypogalactosylation of the fragment crystallizable (Fc) of anti-PLA2R1 is a key feature of primary membranous nephropathy.
-
Hypogalactosylation and hyposialylation of the Fc portion of anti-neutrophil cytoplasmic antibodies and total IgG in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are associated with more severe disease and disease relapse.
-
Among patients with systemic lupus erythematosus, those with lupus nephritis have reduced levels of galactosylation of the Fc portion of total IgG.
-
In patients with IgA nephropathy, hypogalactosylated IgA1 triggers the generation of anti-hypogalactosylated IgA1 autoantibodies, leading to the formation of immune complexes.
-
Aberrant hyposialylation and hypofucosylation of donor-specific antibodies are associated with antibody-mediated rejection of kidney grafts.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Leone, G. M., Mangano, K., Petralia, M. C., Nicoletti, F. & Fagone, P. Past, present and (foreseeable) future of biological anti-TNF alpha therapy. J. Clin. Med. 12, 1630 (2023).
Lu, T., Zhang, J., Xu-Monette, Z. Y. & Young, K. H. The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma. Exp. Hematol. Oncol. 12, 72 (2023).
Pegram, M. et al. Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer. Ther. Adv. Med. Oncol. 15, 17588359231187201 (2023).
Rizzetto, G., De Simoni, E., Molinelli, E., Offidani, A. & Simonetti, O. Efficacy of pembrolizumab in advanced melanoma: a narrative review. Int. J. Mol. Sci. 24, 12383 (2023).
Xiao, Z. & Murakhovskaya, I. Rituximab resistance in ITP and beyond. Front. Immunol. 14, 1215216 (2023).
Yadav, S. et al. Role of daratumumab in the frontline management of multiple myeloma: a narrative review. Expert Rev. Hematol. 16, 743–760 (2023).
Schroeder, H. W. & Cavacini, L. Structure and function of immunoglobulins. J. Allergy Clin. Immunol. 125, S41–52 (2010).
Kerr, M. A. The structure and function of human IgA. Biochem. J. 271, 285–296 (1990).
de Sousa-Pereira, P. & Woof, J. M. IgA: structure, function, and developability. Antibodies 8, 57 (2019).
Keyt, B. A., Baliga, R., Sinclair, A. M., Carroll, S. F. & Peterson, M. S. Structure, function, and therapeutic use of IgM antibodies. Antibodies 9, 53 (2020).
Sutton, B. J., Davies, A. M., Bax, H. J. & Karagiannis, S. N. IgE antibodies: from structure to function and clinical translation. Antibodies 8, 19 (2019).
Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5, 520 (2014).
Schwab, I. & Nimmerjahn, F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat. Rev. Immunol. 13, 176–189 (2013).
Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25, 21–50 (2007).
Flynn, G. C., Chen, X., Liu, Y. D., Shah, B. & Zhang, Z. Naturally occurring glycan forms of human immunoglobulins G1 and G2. Mol. Immunol. 47, 2074–2082 (2010).
Baković, M. P. et al. High-throughput IgG Fc N-glycosylation profiling by mass spectrometry of glycopeptides. J. Proteome Res. 12, 821–831 (2013).
Anumula, K. R. Quantitative glycan profiling of normal human plasma derived immunoglobulin and its fragments Fab and Fc. J. Immunol. Methods 382, 167–176 (2012).
Jefferis, R. Glycosylation of natural and recombinant antibody molecules. Adv. Exp. Med. Biol. 564, 143–148 (2005).
Koers, J. et al. Differences in IgG autoantibody Fab glycosylation across autoimmune diseases. J. Allergy Clin. Immunol. 151, 1646–1654 (2023).
Bondt, A. et al. Immunoglobulin G (IgG) Fab glycosylation analysis using a new mass spectrometric high-throughput profiling method reveals pregnancy-associated changes. Mol. Cell Proteom. 13, 3029–3039 (2014).
Beck, L. H. et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009).
Grupper, A. et al. Recurrent membranous nephropathy after kidney transplantation: treatment and long-term implications. Transplantation 100, 2710–2716 (2016).
Passerini, P., Malvica, S., Tripodi, F., Cerutti, R. & Messa, P. Membranous nephropathy (MN) recurrence after renal transplantation. Front. Immunol. 10, 1326 (2019).
Moroni, G. et al. Long-term outcome of renal transplantation in patients with idiopathic membranous glomerulonephritis (MN). Nephrol. Dial. Transpl. 25, 3408–3415 (2010).
Zhu, D. et al. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 99, 2562–2568 (2002).
Dunn-Walters, D., Boursier, L. & Spencer, J. Effect of somatic hypermutation on potential N-glycosylation sites in human immunoglobulin heavy chain variable regions. Mol. Immunol. 37, 107–113 (2000).
van de Bovenkamp, F. S. et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc. Natl Acad. Sci. USA 115, 1901–1906 (2018).
Taylor, M. E. & Drickamer, K. Introduction to Glycobiology. (Oxford University Press, 2011).
Aebi, M. N-linked protein glycosylation in the ER. Biochim. Biophys. Acta Mol. Cell Res. 1833, 2430–2437 (2013).
Aebi, M., Bernasconi, R., Clerc, S. & Molinari, M. N-glycan structures: recognition and processing in the ER. Trends Biochem. Sci. 35, 74–82 (2010).
Breitling, J. & Aebi, M. N-linked protein glycosylation in the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. 5, a013359 (2013).
Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 (1985).
Tu, L. & Banfield, D. K. Localization of Golgi-resident glycosyltransferases. Cell. Mol. Life Sci. 67, 29–41 (2010).
Jaśkiewicz, E. Retention of glycosyltransferases in the Golgi apparatus. Acta Biochim. Pol. 44, 173–179 (1997).
Hassinen, A. et al. Functional organization of Golgi N- and O-glycosylation pathways involves pH-dependent complex formation that is impaired in cancer cells. J. Biol. Chem. 286, 38329–38340 (2011).
Wuhrer, M. et al. Glycosylation profiling of immunoglobulin G (IgG) subclasses from human serum. Proteomics 7, 4070–4081 (2007).
Masuda, K. et al. Pairing of oligosaccharides in the Fc region of immunoglobulin G. FEBS Lett. 473, 349–357 (2000).
Knezević, A. et al. Variability, heritability and environmental determinants of human plasma N-glycome. J. Proteome Res. 8, 694–701 (2009).
Zauner, G. et al. Glycoproteomic analysis of antibodies. Mol. Cell Proteom. 12, 856–865 (2013).
Kobata, A. The N-linked sugar chains of human immunoglobulin G: their unique pattern, and their functional roles. Biochim. Biophys. Acta 1780, 472–478 (2008).
Gudelj, I., Lauc, G. & Pezer, M. Immunoglobulin G glycosylation in aging and diseases. Cell. Immunol. 333, 65–79 (2018).
Štambuk, J. et al. Global variability of the human IgG glycome. Aging 12, 15222–15259 (2020).
Huffman, J. E. et al. Comparative performance of four methods for high-throughput glycosylation analysis of immunoglobulin G in genetic and epidemiological research. Mol. Cell Proteom. 13, 1598–1610 (2014).
Shields, R. L. et al. 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 (2002).
Subedi, G. P. & Barb, A. W. The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor. MAbs 8, 1512–1524 (2016).
Golay, J. et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood 122, 3482–3491 (2013).
Dekkers, G. et al. Decoding the human immunoglobulin G-glycan repertoire reveals a spectrum of Fc-receptor- and complement-mediated-effector activities. Front. Immunol. 8, 877 (2017).
Ferrara, C. et al. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc. Natl Acad. Sci. USA 108, 12669–12674 (2011).
Ferrara, C., Stuart, F., Sondermann, P., Brünker, P. & Umaña, P. The carbohydrate at FcγRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J. Biol. Chem. 281, 5032–5036 (2006).
Harbison, A. & Fadda, E. An atomistic perspective on antibody-dependent cellular cytotoxicity quenching by core-fucosylation of IgG1 Fc N-glycans from enhanced sampling molecular dynamics. Glycobiology 30, 407–414 (2020).
Bruggeman, C. W. et al. Enhanced effector functions due to antibody defucosylation depend on the effector cell Fcγ receptor profile. J. Immunol. 199, 204–211 (2017).
Iida, S. et al. Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulin G on antibody-dependent cellular cytotoxicity through its high binding to FcγRIIIa. Clin. Cancer Res. 12, 2879–2887 (2006).
Kanda, Y. et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 17, 104–118 (2007).
Okazaki, A. et al. Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcγRIIIa. J. Mol. Biol. 336, 1239–1249 (2004).
Nagelkerke, S. Q. et al. Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages. Blood 124, 3709–3718 (2014).
Bologna, L. et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J. Immunol. 186, 3762–3769 (2011).
Niwa, R. et al. IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J. Immunol. Methods 306, 151–160 (2005).
Kapur, R. et al. 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, 936–945 (2014).
Sibéril, S. et al. Selection of a human anti-RhD monoclonal antibody for therapeutic use: impact of IgG glycosylation on activating and inhibitory FcγR functions. Clin. Immunol. 118, 170–179 (2006).
Sonneveld, M. E. et al. 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, 651–660 (2017).
Shrivastava, A., Joshi, S., Guttman, A. & Rathore, A. S. N-glycosylation of monoclonal antibody therapeutics: a comprehensive review on significance and characterization. Anal. Chim. Acta 1209, 339828 (2022).
McHugh, J. Glycoengineering has therapeutic potential. Nat. Rev. Rheumatol. 14, 121–121 (2018).
Pereira, N. A., Chan, K. F., Lin, P. C. & Song, Z. The ‘less-is-more’ in therapeutic antibodies: afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. MAbs 10, 693–711 (2018).
Goede, V. et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N. Engl. J. Med. 370, 1101–1110 (2014).
Jefferis, R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat. Rev. Drug. Discov. 8, 226–234 (2009).
Fokkink, W. J. R. et al. Comparison of Fc N-glycosylation of pharmaceutical products of intravenous immunoglobulin G. PLoS One 10, e0139828 (2015).
Pucić, M. et al. High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Mol. Cell Proteom. 10, M111.010090 (2011).
Schuster, M. et al. Improved effector functions of a therapeutic monoclonal Lewis Y-specific antibody by glycoform engineering. Cancer Res. 65, 7934–7941 (2005).
Benedetti, E. et al. Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway. Nat. Commun. 8, 1483 (2017).
Umaña, P., Jean-Mairet, J., Moudry, R., Amstutz, H. & Bailey, J. E. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17, 176–180 (1999).
Hodoniczky, J., Zheng, Y. Z. & James, D. C. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol. Prog. 21, 1644–1652 (2005).
Zou, G. et al. Chemoenzymatic synthesis and Fcγ receptor binding of homogeneous glycoforms of antibody Fc domain. Presence of a bisecting sugar moiety enhances the affinity of Fc to FcγIIIa receptor. J. Am. Chem. Soc. 133, 18975–18991 (2011).
Lifely, M. R., Hale, C., Boyce, S., Keen, M. J. & Phillips, J. Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and grown under different culture conditions. Glycobiology 5, 813–822 (1995).
Lu, L. L. et al. A functional role for antibodies in tuberculosis. Cell 167, 433–443.e14 (2016).
Pilkington, C., Basaran, M., Barlan, I., Costello, A. M. & Rook, G. A. Raised levels of agalactosyl IgG in childhood tuberculosis. Trans. R. Soc. Trop. Med. Hyg. 90, 167–168 (1996).
Pilkington, C., Yeung, E., Isenberg, D., Lefvert, A. K. & Rook, G. A. Agalactosyl IgG and antibody specificity in rheumatoid arthritis, tuberculosis, systemic lupus erythematosus and myasthenia gravis. Autoimmunity 22, 107–111 (1995).
Sjöwall, C. et al. Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus. Lupus 24, 569–581 (2015).
Tomana, M., Schrohenloher, R. E., Reveille, J. D., Arnett, F. C. & Koopman, W. J. Abnormal galactosylation of serum IgG in patients with systemic lupus erythematosus and members of families with high frequency of autoimmune diseases. Rheumatol. Int. 12, 191–194 (1992).
Gudelj, I. et al. Low galactosylation of IgG associates with higher risk for future diagnosis of rheumatoid arthritis during 10 years of follow-up. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 2034–2039 (2018).
Gińdzieńska-Sieśkiewicz, E. et al. Changes of glycosylation of IgG in rheumatoid arthritis patients treated with methotrexate. Adv. Med. Sci. 61, 193–197 (2016).
van de Geijn, F. E. et al. 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, R193 (2009).
Ercan, A. et al. Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis Rheum. 62, 2239–2248 (2010).
Rombouts, Y. et al. Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann. Rheum. Dis. 74, 234–241 (2015).
Dubé, R. et al. Agalactosyl IgG in inflammatory bowel disease: correlation with C-reactive protein. Gut 31, 431–434 (1990).
Šimurina, M. et al. Glycosylation of immunoglobulin G associates with clinical features of inflammatory bowel diseases. Gastroenterology 154, 1320–1333.e10 (2018).
Trbojević Akmačić, I. et al. Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome. Inflamm. Bowel Dis. 21, 1237–1247 (2015).
Nakajima, S. et al. Functional analysis of agalactosyl IgG in inflammatory bowel disease patients. Inflamm. Bowel Dis. 17, 927–936 (2011).
Bond, A. et al. A detailed lectin analysis of IgG glycosylation, demonstrating disease specific changes in terminal galactose and N-acetylglucosamine. J. Autoimmun. 10, 77–85 (1997).
Bond, A., Alavi, A., Axford, J. S., Youinou, P. & Hay, F. C. The relationship between exposed galactose and N-acetylglucosamine residues on IgG in rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and Sjögren’s syndrome (SS). Clin. Exp. Immunol. 105, 99–103 (1996).
Kemna, M. J. et al. Galactosylation and sialylation levels of IgG predict relapse in patients with PR3-ANCA associated vasculitis. EBioMedicine 17, 108–118 (2017).
Holland, M. et al. Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis. Clin. Exp. Immunol. 129, 183–190 (2002).
Holland, M. 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 1760, 669–677 (2006).
Selman, M. H. J. et al. IgG fc N-glycosylation changes in Lambert-Eaton myasthenic syndrome and myasthenia gravis. J. Proteome Res. 10, 143–152 (2011).
Fokkink, W.-J. R. et al. IgG Fc N-glycosylation in Guillain-Barré syndrome treated with immunoglobulins. J. Proteome Res. 13, 1722–1730 (2014).
Moore, J. S. et al. Increased levels of galactose-deficient IgG in sera of HIV-1-infected individuals. AIDS 19, 381–389 (2005).
Ackerman, M. E. et al. Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J. Clin. Invest. 123, 2183–2192 (2013).
Vaccari, M. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat. Med. 22, 762–770 (2016).
Ho, C.-H. et al. Aberrant serum immunoglobulin G glycosylation in chronic hepatitis B is associated with histological liver damage and reversible by antiviral therapy. J. Infect. Dis. 211, 115–124 (2015).
Mehta, A. S. et al. Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. J. Virol. 82, 1259–1270 (2008).
Boyd, P. N., Lines, A. C. & Patel, A. K. The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H. Mol. Immunol. 32, 1311–1318 (1995).
Peschke, B., Keller, C. W., Weber, P., Quast, I. & Lünemann, J. D. Fc-Galactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity. Front. Immunol. 8, 646 (2017).
Malhotra, R. et al. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat. Med. 1, 237–243 (1995).
Dekkers, G., Rispens, T. & Vidarsson, G. Novel concepts of altered immunoglobulin G galactosylation in autoimmune diseases. Front. Immunol. 9, 553 (2018).
Tsuchiya, N. et al. Effects of galactose depletion from oligosaccharide chains on immunological activities of human IgG. J. Rheumatol. 16, 285–290 (1989).
Yamaguchi, Y. et al. Glycoform-dependent conformational alteration of the Fc region of human immunoglobulin G1 as revealed by NMR spectroscopy. Biochim. Biophys. Acta Gen. Subj. 1760, 693–700 (2006).
Kiyoshi, M., Tsumoto, K., Ishii-Watabe, A. & Caaveiro, J. M. M. Glycosylation of IgG-Fc: a molecular perspective. Int. Immunol. 29, 311–317 (2017).
Nimmerjahn, F., Anthony, R. M. & Ravetch, J. V. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc. Natl Acad. Sci. USA 104, 8433–8437 (2007).
van de Geijn, F. E. et al. Mannose-binding lectin polymorphisms are not associated with rheumatoid arthritis — confirmation in two large cohorts. Rheumatology 47, 1168–1171 (2008).
van de Geijn, F. E. et al. Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis. Arthritis Res. Ther. 13, R10 (2011).
Karsten, C. M. et al. Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1. Nat. Med. 18, 1401–1406 (2012).
Heyl, K. A., Karsten, C. M. & Slevogt, H. Galectin-3 binds highly galactosylated IgG1 and is crucial for the IgG1 complex mediated inhibition of C5aReceptor induced immune responses. Biochem. Biophys. Res. Commun. 479, 86–90 (2016).
Yamada, K. et al. Galactosylation of IgG1 modulates FcγRIIB-mediated inhibition of murine autoimmune hemolytic anemia. J. Autoimmun. 47, 104–110 (2013).
Houde, D., Peng, Y., Berkowitz, S. A. & Engen, J. R. Post-translational modifications differentially affect IgG1 conformation and receptor binding. Mol. Cell Proteom. 9, 1716–1728 (2010).
Kumpel, B. M., Rademacher, T. W., Rook, G. A., Williams, P. J. & Wilson, I. B. 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 Hybrid. 5, 143–151 (1994).
Kumpel, B. M., Wang, Y., Griffiths, H. L., Hadley, A. G. & Rook, G. A. The biological activity of human monoclonal IgG anti-D is reduced by β-galactosidase treatment. Hum. Antibodies Hybrid. 6, 82–88 (1995).
Thomann, M., Reckermann, K., Reusch, D., Prasser, J. & Tejada, M. L. Fc-galactosylation modulates antibody-dependent cellular cytotoxicity of therapeutic antibodies. Mol. Immunol. 73, 69–75 (2016).
Thomann, M. et al. In vitro glycoengineering of IgG1 and its effect on Fc receptor binding and ADCC activity. PLoS One 10, e0134949 (2015).
Kaneko, Y., Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313, 670–673 (2006).
Li, T. et al. Modulating IgG effector function by Fc glycan engineering. Proc. Natl Acad. Sci. USA 114, 3485–3490 (2017).
Scallon, B. J., Tam, S. H., McCarthy, S. G., Cai, A. N. & Raju, T. S. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol. Immunol. 44, 1524–1534 (2007).
Kissel, T. et al. IgG anti-citrullinated protein antibody variable domain glycosylation increases before the onset of rheumatoid arthritis and stabilizes thereafter: a cross-sectional study encompassing ~1,500 samples. Arthritis Rheumatol. 74, 1147–1158 (2022).
Axford, J. S. et al. Changes in normal glycosylation mechanisms in autoimmune rheumatic disease. J. Clin. Invest. 89, 1021–1031 (1992).
Bondt, A. et al. Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis during pregnancy is independent of sialylation. J. Proteome Res. 12, 4522–4531 (2013).
van Timmeren, M. M. et al. IgG glycan hydrolysis attenuates ANCA-mediated glomerulonephritis. J. Am. Soc. Nephrol. 21, 1103–1114 (2010).
Wuhrer, M. et al. 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, 1657–1665 (2015).
Tingting, L. et al. Characteristics of purified Anti-β2GPI IgG N-glycosylation associate with thrombotic, obstetric, and catastrophic antiphospholipid syndrome. Rheumatology 61, 1243–1254 (2021).
Aurer, I. et al. Aberrant glycosylation of Igg heavy chain in multiple myeloma. Coll. Antropol. 31, 247–251 (2007).
Bosseboeuf, A. et al. Analysis of the targets and glycosylation of monoclonal IgAs From MGUS and myeloma patients. Front. Immunol. 11, 854 (2020).
Mittermayr, S. et al. Polyclonal immunoglobulin G N-glycosylation in the pathogenesis of plasma cell disorders. J. Proteome Res. 16, 748–762 (2017).
Chen, G. et al. Human IgG Fc-glycosylation profiling reveals associations with age, sex, female sex hormones and thyroid cancer. J. Proteom. 75, 2824–2834 (2012).
Kanoh, Y., Ohara, T., Tadano, T., Kanoh, M. & Akahoshi, T. Changes to N-linked oligosaccharide chains of human serum immunoglobulin G and matrix metalloproteinase-2 with cancer progression. Anticancer. Res. 28, 715–720 (2008).
Kanoh, Y. et al. Analysis of the oligosaccharide chain of human serum immunoglobulin G in patients with localized or metastatic cancer. Oncology 66, 365–370 (2004).
Anthony, R. M. et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320, 373–376 (2008).
Washburn, N. et al. Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. Proc. Natl Acad. Sci. USA 112, E1297–E1306 (2015).
Anthony, R. M., Wermeling, F., Karlsson, M. C. I. & Ravetch, J. V. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc. Natl Acad. Sci. USA 105, 19571–19578 (2008).
Bruhns, P., Samuelsson, A., Pollard, J. W. & Ravetch, J. V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18, 573–581 (2003).
Anthony, R. M., Kobayashi, T., Wermeling, F. & Ravetch, J. V. Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway. Nature 475, 110–113 (2011).
Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells. Nat. Med. 12, 688–692 (2006).
Guhr, T. et al. Enrichment of sialylated IgG by lectin fractionation does not enhance the efficacy of immunoglobulin G in a murine model of immune thrombocytopenia. PLoS One 6, e21246 (2011).
Campbell, I. K. et al. Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. J. Immunol. 192, 5031–5038 (2014).
Leontyev, D. et al. Sialylation-independent mechanism involved in the amelioration of murine immune thrombocytopenia using intravenous gammaglobulin. Transfusion 52, 1799–1805 (2012).
Käsermann, F. et al. Analysis and functional consequences of increased Fab-sialylation of intravenous immunoglobulin (IVIG) after lectin fractionation. PLoS One 7, e37243 (2012).
von Gunten, S. et al. IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat. Rev. Immunol. 14, 349 (2014).
Tjon, A. S. W. et al. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J. Immunol. 192, 5625–5634 (2014).
Sharma, M. et al. Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Sci. Rep. 4, 5672 (2014).
Siedlar, M. et al. Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+ CD16++ monocytes in common variable immunodeficiency (CVID) patients. Clin. Immunol. 139, 122–132 (2011).
Ichiyama, T. et al. Intravenous immunoglobulin does not increase FcγRIIB expression on monocytes/macrophages during acute Kawasaki disease. Rheumatology 44, 314–317 (2005).
Shimomura, M. et al. Intravenous immunoglobulin does not increase FcγRIIB expression levels on monocytes in children with immune thrombocytopenia. Clin. Exp. Immunol. 169, 33–37 (2012).
Temming, A. R. et al. Human DC-SIGN and CD23 do not interact with human IgG. Sci. Rep. 9, 10 (2019).
Yu, X. et al. Engineering hydrophobic protein-carbohydrate interactions to fine-tune monoclonal antibodies. J. Am. Chem. Soc. 135, 9723–9732 (2013).
Raju, T. S. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. 20, 471–478 (2008).
Crispin, M., Yu, X. & Bowden, T. A. Crystal structure of sialylated IgG Fc: implications for the mechanism of intravenous immunoglobulin therapy. Proc. Natl Acad. Sci. USA 110, E3544–3546 (2013).
Fang, J., Richardson, J., Du, Z. & Zhang, Z. Effect of Fc-glycan structure on the conformational stability of IgG revealed by hydrogen/deuterium exchange and limited proteolysis. Biochemistry 55, 860–868 (2016).
Barb, A. W. et al. NMR characterization of immunoglobulin G Fc glycan motion on enzymatic sialylation. Biochemistry 51, 4618–4626 (2012).
Zhang, Z., Shah, B. & Richardson, J. Impact of Fc N-glycan sialylation on IgG structure. MAbs 11, 1381–1390 (2019).
Powell, L. D., Sgroi, D., Sjoberg, E. R., Stamenkovic, I. & Varki, A. Natural ligands of the B cell adhesion molecule CD22β carry N-linked oligosaccharides with ɑ-2,6-linked sialic acids that are required for recognition. J. Biol. Chem. 268, 7019–7027 (1993).
Massoud, A. H. et al. Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J. Allergy Clin. Immunol. 133, 853–863.e5 (2014).
Séïté, J.-F. et al. IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood 116, 1698–1704 (2010).
Wang, T. T. et al. Anti-HA glycoforms drive B cell affinity selection and determine influenza vaccine efficacy. Cell 162, 160–169 (2015).
Quast, I. et al. Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J. Clin. Invest. 125, 4160–4170 (2015).
Wallick, S. C., Kabat, E. A. & Morrison, S. L. Glycosylation of a VH residue of a monoclonal antibody against alpha (1–6) dextran increases its affinity for antigen. J. Exp. Med. 168, 1099–1109 (1988).
Tachibana, H., Kim, J. Y. & Shirahata, S. Building high affinity human antibodies by altering the glycosylation on the light chain variable region in N-acetylglucosamine-supplemented hybridoma cultures. Cytotechnology 23, 151–159 (1997).
Leibiger, H., Wüstner, D., Stigler, R. D. & Marx, U. Variable domain-linked oligosaccharides of a human monoclonal IgG: structure and influence on antigen binding. Biochem. J. 338, 529–538 (1999).
Wright, A., Tao, M. H., Kabat, E. A. & Morrison, S. L. Antibody variable region glycosylation: position effects on antigen binding and carbohydrate structure. EMBO J. 10, 2717–2723 (1991).
Bondt, A., Wuhrer, M., Kuijper, T. M., Hazes, J. M. W. & Dolhain, R. J. E. M. Fab glycosylation of immunoglobulin G does not associate with improvement of rheumatoid arthritis during pregnancy. Arthritis Res. Ther. 18, 274 (2016).
Hafkenscheid, L. et al. N-linked glycans in the variable domain of IgG anti-citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol. 71, 1626–1633 (2019).
Lardinois, O. M. et al. Immunoglobulins G from patients with ANCA-associated vasculitis are atypically glycosylated in both the Fc and Fab regions and the relation to disease activity. PLoS One 14, e0213215 (2019).
van de Bovenkamp, F. S., Hafkenscheid, L., Rispens, T. & Rombouts, Y. The emerging importance of IgG fab glycosylation in immunity. J. Immunol. 196, 1435–1441 (2016).
Xu, P.-C. et al. Influence of variable domain glycosylation on anti-neutrophil cytoplasmic autoantibodies and anti-glomerular basement membrane autoantibodies. BMC Immunol. 13, 10 (2012).
Coelho, V. et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc. Natl Acad. Sci. USA 107, 18587–18592 (2010).
Schneider, D. et al. Lectins from opportunistic bacteria interact with acquired variable-region glycans of surface immunoglobulin in follicular lymphoma. Blood 125, 3287–3296 (2015).
Wong, K. L. et al. SM03, an znti-CD22 antibody, converts cis-to-trans ligand binding of CD22 against α2,6-linked sialic acid glycans and immunomodulates systemic autoimmune diseases. J. Immunol. 208, 2726–2737 (2022).
Chiodin, G. et al. Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior. Blood 138, 1570–1582 (2021).
Menni, C. et al. Glycosylation of immunoglobulin g: role of genetic and epigenetic influences. PLoS One 8, e82558 (2013).
Datta, A. K., Sinha, A. & Paulson, J. C. Mutation of the sialyltransferase S-sialylmotif alters the kinetics of the donor and acceptor substrates. J. Biol. Chem. 273, 9608–9614 (1998).
Lauc, G. et al. Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers. PLoS Genet. 9, e1003225 (2013).
Shadrina, A. S. et al. Multivariate genome-wide analysis of immunoglobulin G N-glycosylation identifies new loci pleiotropic with immune function. Hum. Mol. Genet. 30, 1259–1270 (2021).
Wahl, A. et al. Genome-wide association study on immunoglobulin G glycosylation patterns. Front. Immunol. 9, 277 (2018).
Whiteman, H. J. & Farrell, P. J. RUNX expression and function in human B cells. Crit. Rev. Eukaryot. Gene Expr. 16, 31–44 (2006).
Niebuhr, B. et al. Runx1 is essential at two stages of early murine B-cell development. Blood 122, 413–423 (2013).
Sellars, M., Reina-San-Martin, B., Kastner, P. & Chan, S. Ikaros controls isotype selection during immunoglobulin class switch recombination. J. Exp. Med. 206, 1073–1087 (2009).
Bondt, A. et al. ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. Ann. Rheum. Dis. 77, 1130–1136 (2018).
Pekelharing, J. M., Hepp, E., Kamerling, J. P., Gerwig, G. J. & Leijnse, B. Alterations in carbohydrate composition of serum IgG from patients with rheumatoid arthritis and from pregnant women. Ann. Rheum. Dis. 47, 91–95 (1988).
Rook, G. A. et al. Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J. Autoimmun. 4, 779–794 (1991).
Krištić, J. et al. Glycans are a novel biomarker of chronological and biological ages. J. Gerontol. A Biol. Sci. Med. Sci. 69, 779–789 (2014).
Ercan, A. et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2, e89703 (2017).
Engdahl, C. et al. 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, 84 (2018).
Du, N. et al. Phytoestrogens protect joints in collagen induced arthritis by increasing IgG glycosylation and reducing osteoclast activation. Int. Immunopharmacol. 83, 106387 (2020).
Dall’Olio, F., Malagolini, N. & Immunoglobulin, G. Glycosylation changes in aging and other inflammatory conditions. Exp. Suppl. 112, 303–340 (2021).
Dall’Olio, F. et al. N-glycomic biomarkers of biological aging and longevity: a link with inflammaging. Ageing Res. Rev. 12, 685–698 (2013).
Parekh, R., Roitt, I., Isenberg, D., Dwek, R. & Rademacher, T. Age-related galactosylation of the N-linked oligosaccharides of human serum IgG. J. Exp. Med. 167, 1731–1736 (1988).
Knezevic, A. et al. Effects of aging, body mass index, plasma lipid profiles, and smoking on human plasma N-glycans. Glycobiology 20, 959–969 (2010).
de Haan, N., Reiding, K. R., Driessen, G., van der Burg, M. & Wuhrer, M. Changes in healthy human IgG Fc-glycosylation after birth and during early childhood. J. Proteome Res. 15, 1853–1861 (2016).
Pucic, M. et al. Changes in plasma and IgG N-glycome during childhood and adolescence. Glycobiology 22, 975–982 (2012).
Yamada, E., Tsukamoto, Y., Sasaki, R., Yagyu, K. & Takahashi, N. Structural changes of immunoglobulin G oligosaccharides with age in healthy human serum. Glycoconj. J. 14, 401–405 (1997).
Vanhooren, V. et al. N-glycomic changes in serum proteins during human aging. Rejuvenation Res. 10, 521–531a (2007).
Yu, X. et al. Profiling IgG N-glycans as potential biomarker of chronological and biological ages: a community-based study in a Han Chinese population. Medicine 95, e4112 (2016).
Batten, M. et al. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 207, 2895–2906 (2010).
Bartsch, Y. C. et al. Sialylated autoantigen-reactive IgG antibodies attenuate disease development in autoimmune mouse models of lupus nephritis and rheumatoid arthritis. Front. Immunol. 9, 1183 (2018).
Hess, C. et al. T cell-independent B cell activation induces immunosuppressive sialylated IgG antibodies. J. Clin. Invest. 123, 3788–3796 (2013).
Bartsch, Y. C. et al. IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants. J. Allergy Clin. Immunol. 146, 652–666.e11 (2020).
Pfeifle, R. et al. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104–113 (2017).
Cardenas, A. et al. Plasma concentrations of per- and polyfluoroalkyl substances at baseline and associations with glycemic indicators and diabetes incidence among high-risk adults in the diabetes prevention program trial. Env. Health Perspect. 125, 107001 (2017).
Zhou, W. et al. Plasma perfluoroalkyl and polyfluoroalkyl substances concentration and menstrual cycle characteristics in preconception women. Env. Health Perspect. 125, 067012 (2017).
Fletcher, T. et al. Associations between PFOA, PFOS and changes in the expression of genes involved in cholesterol metabolism in humans. Env. Int. 57–58, 2–10 (2013).
Siebenaler, R. et al. Serum perfluoroalkyl acids (PFAAs) and associations with behavioral attributes. Chemosphere 184, 687–693 (2017).
Liu, J. et al. Associations between the serum levels of PFOS/PFOA and IgG N-glycosylation in adult or children. Environ. Pollut. 265, 114285 (2020).
Birukov, A. et al. Immunoglobulin G N-glycosylation signatures in incident type 2 diabetes and cardiovascular disease. Diabetes Care 45, 2729–2736 (2022).
Lemmers, R. F. H. et al. IgG glycan patterns are associated with type 2 diabetes in independent European populations. Biochim. Biophys. Acta Gen. Subj. 1861, 2240–2249 (2017).
Singh, S. S. et al. Association of the IgG N-glycome with the course of kidney function in type 2 diabetes. BMJ Open. Diabetes Res. Care 8, e001026 (2020).
Wang, H. et al. Leveraging IgG N-glycosylation to infer the causality between T2D and hypertension. Diabetol. Metab. Syndr. 15, 80 (2023).
Wu, Z. et al. Variation of IgG N-linked glycosylation profile in diabetic retinopathy. J. Diabetes 13, 672–680 (2021).
Nikolac Perkovic, M. et al. The association between galactosylation of immunoglobulin G and body mass index. Prog. Neuropsychopharmacol. Biol. Psychiatry 48, 20–25 (2014).
Russell, A. C. et al. Increased central adiposity is associated with pro-inflammatory immunoglobulin G N-glycans. Immunobiology 224, 110–115 (2019).
Greto, V. L. et al. Extensive weight loss reduces glycan age by altering IgG N-glycosylation. Int. J. Obes. 45, 1521–1531 (2021).
Kifer, D. et al. N-glycosylation of immunoglobulin G predicts incident hypertension. J. Hypertens. 39, 2527–2533 (2021).
Liu, J. N. et al. The association between subclass-specific IgG Fc N-glycosylation profiles and hypertension in the Uygur, Kazak, Kirgiz, and Tajik populations. J. Hum. Hypertens. 32, 555–563 (2018).
Meng, X. et al. Glycosylation of IgG associates with hypertension and type 2 diabetes mellitus comorbidity in the Chinese Muslim ethnic minorities and the Han Chinese. J. Pers. Med. 11, 614 (2021).
Wang, Y. et al. The association between glycosylation of immunoglobulin G and hypertension: a multiple ethnic cross-sectional study. Medicine 95, e3379 (2016).
Liu, D. et al. The changes of immunoglobulin G N-glycosylation in blood lipids and dyslipidaemia. J. Transl. Med. 16, 235 (2018).
Menni, C. 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. 122, 1555–1564 (2018).
Rudman, N. et al. Children at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG. Diabetologia 65, 1315–1327 (2022).
Colombo, M. et al. Quantitative levels of serum N-glycans in type 1 diabetes and their association with kidney disease. Glycobiology 31, 613–623 (2021).
Rook, G. A. et al. A longitudinal study of per cent agalactosyl IgG in tuberculosis patients receiving chemotherapy, with or without immunotherapy. Immunology 81, 149–154 (1994).
Larsen, M. D. et al. Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science 371, eabc8378 (2021).
Teo, A., Tan, H. D., Loy, T., Chia, P. Y. & Chua, C. L. L. Understanding antibody-dependent enhancement in dengue: are afucosylated IgG1s a concern? PLoS Pathog. 19, e1011223 (2023).
Trzos, S., Link-Lenczowski, P. & Pocheć, E. The role of N-glycosylation in B-cell biology and IgG activity. The aspects of autoimmunity and anti-inflammatory therapy. Front. Immunol. 14, 1188838 (2023).
Lundström, S. L. et al. IgG Fc galactosylation predicts response to methotrexate in early rheumatoid arthritis. Arthritis Res. Ther. 19, 182 (2017).
Collins, E. S. et al. Glycosylation status of serum in inflammatory arthritis in response to anti-TNF treatment. Rheumatology 52, 1572–1582 (2013).
Croce, A. et al. Effect of infliximab on the glycosylation of IgG of patients with rheumatoid arthritis. J. Clin. Lab. Anal. 21, 303–314 (2007).
Ercan, A. et al. Hypogalactosylation of serum N-glycans fails to predict clinical response to methotrexate and TNF inhibition in rheumatoid arthritis. Arthritis Res. Ther. 14, R43 (2012).
Liu, J. et al. IgG Galactosylation status combined with MYOM2-rs2294066 precisely predicts anti-TNF response in ankylosing spondylitis. Mol. Med. 25, 25 (2019).
Font, G. et al. IgG N-glycosylation from patients with pemphigus treated with rituximab. Biomedicines 10, 1774 (2022).
Schmidt, D. E. et al. IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia. Sci. Rep. 10, 3051 (2020).
Barrios, C. et al. Glycosylation profile of IgG in moderate kidney dysfunction. J. Am. Soc. Nephrol. 27, 933–941 (2016).
Haddad & G et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy. J. Clin. Invest. 131, 140453 (2021).
Oskam, N. et al. Factors affecting IgG4-mediated complement activation. Front. Immunol. 14, 1087532 (2023).
Chinello, C. et al. Definition of IgG subclass-specific glycopatterns in idiopathic membranous nephropathy: aberrant IgG glycoforms in blood. Int. J. Mol. Sci. 23, 4664 (2022).
Segelmark, M. & Wieslander, J. IgG subclasses of antineutrophil cytoplasm autoantibodies (ANCA). Nephrol. Dial. Transpl. 8, 696–702 (1993).
Espy, C. et al. Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener’s). Arthritis Rheum. 63, 2105–2115 (2011).
Shibuya, N. et al. The elderberry (Sambucus nigra L.) bark lectin recognizes the Neu5Ac(ɑ2-6)Gal/GalNAc sequence. J. Biol. Chem. 262, 1596–1601 (1987).
Stadlmann, J. et al. A close look at human IgG sialylation and subclass distribution after lectin fractionation. Proteomics 9, 4143–4153 (2009).
Dalziel, M., McFarlane, I. & Axford, J. S. Lectin analysis of human immunoglobulin G N-glycan sialylation. Glycoconj. J. 16, 801–807 (1999).
Rademacher, T. W. Network theory of glycosylation — etiologic and pathogenic implications of changes in IgG glycoform levels in autoimmunity. Semin. Cell Biol. 2, 327–337 (1991).
Magorivska, I. et al. Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells. Clin. Exp. Immunol. 184, 110–117 (2016).
Zhou, X. et al. Antibody glycosylation in autoimmune diseases. Autoimmun. Rev. 20, 102804 (2021).
Biermann, M. H. C. et al. Sweet but dangerous — the role of immunoglobulin G glycosylation in autoimmunity and inflammation. Lupus 25, 934–942 (2016).
Vučković, F. et al. Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol. 67, 2978–2989 (2015).
Han, J. et al. Fucosylation of anti-dsDNA IgG1 correlates with disease activity of treatment-naïve systemic lupus erythematosus patients. eBioMedicine 77, 103883 (2022).
Bhargava, R. et al. Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis. JCI Insight 6, e147789 (2021).
Clarke, J. Glycosylation influences IgG effects in LN. Nat. Rev. Rheumatol. 17, 310–310 (2021).
Lu, X. et al. Association between immunoglobulin G N-glycosylation and lupus nephritis in female patients with systemic lupus erythematosus: a case-control study. Front. Immunol. 14, 1257906 (2023).
van Egmond, M. et al. IgA and the IgA Fc receptor. Trends Immunol. 22, 205–211 (2001).
Novak, J., Julian, B. A., Mestecky, J. & Renfrow, M. B. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin. Immunopathol. 34, 365–382 (2012).
Ding, L., Chen, X., Cheng, H., Zhang, T. & Li, Z. Advances in IgA glycosylation and its correlation with diseases. Front. Chem. 10, 974854 (2022).
Ohyama, Y., Renfrow, M. B., Novak, J. & Takahashi, K. Aberrantly glycosylated IgA1 in IgA nephropathy: what we know and what we don’t know. J. Clin. Med. 10, 3467 (2021).
Posgai, M. T. et al. FcαRI binding at the IgA1 CH2-CH3 interface induces long-range conformational changes that are transmitted to the hinge region. Proc. Natl Acad. Sci. USA 115, E8882–E8891 (2018).
Novak, J., Barratt, J., Julian, B. A. & Renfrow, M. B. Aberrant glycosylation of the IgA1 Molecule in IgA nephropathy. Semin. Nephrol. 38, 461–476 (2018).
Suzuki, H. & Novak, J. IgA glycosylation and immune complex formation in IgAN. Semin. Immunopathol. 43, 669–678 (2021).
Moldoveanu, Z. et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 71, 1148–1154 (2007).
Berthoux, F. et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J. Am. Soc. Nephrol. 23, 1579–1587 (2012).
Zhao, N. et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 82, 790–796 (2012).
Suzuki, H. et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Invest. 119, 1668–1677 (2009).
Pattrapornpisut, P., Avila-Casado, C. & Reich, H. N. IgA nephropathy: core curriculum 2021. Am. J. Kidney Dis. 78, 429–441 (2021).
Knoppova, B. et al. Pathogenesis of IgA nephropathy: current understanding and implications for development of disease-specific treatment. J. Clin. Med. 10, 4501 (2021).
Zhang, X. et al. Poly-IgA complexes and disease severity in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 16, 1652–1664 (2021).
Placzek, W. J. et al. Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy. PLoS One 13, e0190967 (2018).
Maixnerova, D. et al. Galactose-deficient IgA1 and the corresponding IgG autoantibodies predict IgA nephropathy progression. PLoS One 14, e0212254 (2019).
Medrano, A. S. et al. Relationship between immunoglobulin A1 lectin-binding specificities, mesangial C4d deposits and clinical phenotypes in immunoglobulin A nephropathy. Nephrol. Dial. Transpl. 37, 318–325 (2022).
Chen, P. et al. Plasma galactose-deficient IgA1 and C3 and CKD progression in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 14, 1458–1465 (2019).
Liang, Y. et al. Proliferation and cytokine production of human mesangial cells stimulated by secretory IgA isolated from patients with IgA nephropathy. Cell Physiol. Biochem. 36, 1793–1808 (2015).
Zhang, J. et al. Role of human mesangial-tubular crosstalk in secretory IgA-induced IgA nephropathy. Kidney Blood Press. Res. 46, 286–297 (2021).
Amore, A. et al. Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. Am. J. Kidney Dis. 36, 1242–1252 (2000).
Person, T. et al. Cytokines and production of aberrantly O-glycosylated IgA1, the main autoantigen in IgA nephropathy. J. Interferon Cytokine Res. 42, 301–315 (2022).
Lechner, S. M., Papista, C., Chemouny, J. M., Berthelot, L. & Monteiro, R. C. Role of IgA receptors in the pathogenesis of IgA nephropathy. J. Nephrol. 29, 5–11 (2016).
Jhee, J. H. et al. CD71 mesangial IgA1 receptor and the progression of IgA nephropathy. Transl. Res. 230, 34–43 (2021).
Cambier, A. et al. Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy. Kidney Int. 101, 274–287 (2022).
Wyatt, R. J. & Julian, B. A. IgA nephropathy. N. Engl. J. Med. 368, 2402–2414 (2013).
Steffen, U. et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat. Commun. 11, 120 (2020).
Pillebout, E. et al. Biomarkers of IgA vasculitis nephritis in children. PLoS One 12, e0188718 (2017).
Song, Y. et al. Pathogenesis of IgA vasculitis: an up-to-date review. Front. Immunol. 12, 771619 (2021).
Sugiyama, M. et al. A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy. PLoS One 15, e0232194 (2020).
Haniuda, K., Gommerman, J. L. & Reich, H. N. The microbiome and IgA nephropathy. Semin. Immunopathol. 43, 649–656 (2021).
Novak, J., Julian, B. A., Tomana, M. & Mestecky, J. IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy. Semin. Nephrol. 28, 78–87 (2008).
Smith, A. C., Molyneux, K., Feehally, J. & Barratt, J. O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J. Am. Soc. Nephrol. 17, 3520–3528 (2006).
Gale, D. P. et al. Galactosylation of IgA1 is associated with common variation in C1GALT1. J. Am. Soc. Nephrol. 28, 2158–2166 (2017).
Xing, Y. et al. C1GALT1 expression is associated with galactosylation of IgA1 in peripheral B lymphocyte in immunoglobulin a nephropathy. BMC Nephrol. 21, 18 (2020).
Sellarés, J. et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am. J. Transplant. 12, 388–399 (2012).
Roufosse, C. et al. A 2018 reference guide to the Banff Classification of Renal Allograft Pathology. Transplantation 102, 1795–1814 (2018).
Haas, M. 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. 18, 293–307 (2018).
Loupy, A., Hill, G. S. & Jordan, S. C. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat. Rev. Nephrol. 8, 348–357 (2012).
Lefaucheur, C. et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J. Am. Soc. Nephrol. 21, 1398–1406 (2010).
Everly, M. J. et al. Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients. Transplantation 97, 494–501 (2014).
Hamdani, G. et al. IGG3 anti-HLA donor-specific antibodies and graft function in pediatric kidney transplant recipients. Pediatr. Transpl. 22, e13219 (2018).
Lefaucheur, C. et al. IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury. J. Am. Soc. Nephrol. 27, 293–304 (2016).
Pernin, V. et al. IgG3 donor-specific antibodies with a proinflammatory glycosylation profile may be associated with the risk of antibody-mediated rejection after kidney transplantation. Am. J. Transpl. 22, 865–875 (2022).
Pernin, V. 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. 11, 919 (2020).
Valenzuela, N. M. & Schaub, S. The biology of IgG subclasses and their clinical relevance to transplantation. Transplantation 102, S7–S13 (2018).
Viglietti, D. et al. Value of donor-specific anti-HLA antibody monitoring and characterization for risk stratification of kidney allograft loss. J. Am. Soc. Nephrol. 28, 702–715 (2017).
Schinstock, C. A. et al. The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am. J. Transpl. 17, 1574–1584 (2017).
Bailly, E. et al. Prognostic value of the persistence of C1q-binding anti-HLA antibodies in acute antibody-mediated rejection in kidney transplantation. Transplantation 102, 688–698 (2018).
Cazarote, H. B. et al. Complement-fixing donor-specific anti-HLA antibodies and kidney allograft failure. Transpl. Immunol. 49, 33–38 (2018).
Loupy, A. et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N. Engl. J. Med. 369, 1215–1226 (2013).
Malheiro, J. et al. Detection of complement-binding donor-specific antibodies, not IgG-antibody strength nor C4d status, at antibody-mediated rejection diagnosis is an independent predictor of kidney graft failure. Transplantation 102, 1943–1954 (2018).
Sicard, A. et al. Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss. J. Am. Soc. Nephrol. 26, 457–467 (2015).
Thammanichanond, D. et al. Significance of C1q-fixing donor-specific antibodies after kidney transplantation. Transpl. Proc. 46, 368–371 (2014).
Thammanichanond, D. et al. Role of pretransplant complement-fixing donor-specific antibodies identified by C1q assay in kidney transplantation. Transpl. Proc. 48, 756–760 (2016).
Viglietti, D. et al. Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection. Kidney Int. 94, 773–787 (2018).
Malard-Castagnet, S. et al. Sialylation of antibodies in kidney recipients with de novo donor specific antibody, with or without antibody mediated rejection. Hum. Immunol. 77, 1076–1083 (2016).
Barba, T. et al. Highly variable sialylation status of donor-specific antibodies does not impact humoral rejection outcomes. Front. Immunol. 10, 513 (2019).
Bharadwaj, P. et al. Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation. Cell Rep. Med. 3, 100818 (2022).
Bhargava, R. et al. N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury. Am. J. Transpl. 21, 148–160 (2021).
Schofield, D. J. et al. Application of phage display to high throughput antibody generation and characterization. Genome Biol. 8, R254 (2007).
Grabarics, M. et al. Mass spectrometry-based techniques to elucidate the sugar code. Chem. Rev. 122, 7840–7908 (2022).
García-Alija, M. et al. Modulating antibody effector functions by Fc glycoengineering. Biotechnol. Adv. 67, 108201 (2023).
Golay, J., Andrea, A. E. & Cattaneo, I. Role of Fc core fucosylation in the effector function of IgG1 antibodies. Front. Immunol. 13, 929895 (2022).
Mössner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115, 4393–4402 (2010).
Ginthör, N. E., Artinger, K., Pollheimer, M. J., Stradner, M. H. & Eller, K. Membranous nephropathy associated with immunoglobulin G4-related disease successfully treated with obinutuzumab. Clin. Kidney J. 15, 564–566 (2022).
Hudson, R., Rawlings, C., Mon, S. Y., Jefferis, J. & John, G. T. Treatment resistant M-type phospholipase A2 receptor associated membranous nephropathy responds to obinutuzumab: a report of two cases. BMC Nephrol. 23, 134 (2022).
Naik, S. et al. Obinutuzumab in refractory phospholipase A2 receptor-associated membranous nephropathy with severe CKD. Kidney Int. Rep. 8, 942–943 (2023).
Hiatt, A. et al. Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy. Proc. Natl Acad. Sci. USA 111, 5992–5997 (2014).
Bardhi, A. et al. Potent in vivo NK cell-mediated elimination of HIV-1-infected cells mobilized by a gp120-bispecific and hexavalent broadly neutralizing fusion protein. J. Virol. 91, e00937–17 (2017).
Zeitlin, L. et al. Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc. Natl Acad. Sci. USA 108, 20690–20694 (2011).
Jones, A. J. S. et al. Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology 17, 529–540 (2007).
Li, M. et al. Next generation of anti-PD-L1 atezolizumab with enhanced anti-tumor efficacy in vivo. Sci. Rep. 11, 5774 (2021).
Qian, J. et al. Structural characterization of N-linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrix-assisted laser desorption/ionization hybrid quadrupole-quadrupole time-of-flight tandem mass spectrometry and sequential enzymatic digestion. Anal. Biochem. 364, 8–18 (2007).
Janin-Bussat, M.-C. et al. Cetuximab Fab and Fc N-glycan fast characterization using IdeS digestion and liquid chromatography coupled to electrospray ionization mass spectrometry. Methods Mol. Biol. 988, 93–113 (2013).
Chung, C. H. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-ɑ-1,3-galactose. N. Engl. J. Med. 358, 1109–1117 (2008).
Steinke, J. W., Platts-Mills, T. A. E. & Commins, S. P. The alpha-gal story: lessons learned from connecting the dots. J. Allergy Clin. Immunol. 135, 589–596 (2015).
Pagan, J. D., Kitaoka, M. & Anthony, R. M. Engineered sialylation of pathogenic antibodies in vivo attenuates autoimmune disease. Cell 172, 564–577.e13 (2018).
Oefner, C. M. et al. Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. J. Allergy Clin. Immunol. 129, 1647–1655.e13 (2012).
Author information
Authors and Affiliations
Contributions
All authors made a substantial contribution to discussion of the content. All authors wrote the article or reviewed/edited the manuscript before submission.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Nephrology thanks Robert Anthony and the other, anonymous, reviewers for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Beyze, A., Larroque, C. & Le Quintrec, M. The role of antibody glycosylation in autoimmune and alloimmune kidney diseases. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00850-0
Accepted:
Published:
DOI: https://doi.org/10.1038/s41581-024-00850-0