Abstract
Autoimmune diseases are accompanied by changes in protein glycosylation, in both the immune system and target tissues. The best-studied alteration in autoimmunity is agalactosylation of immunoglobulin G (IgG), characterized primarily in rheumatoid arthritis (RA), and then detected also in systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and multiple sclerosis (MS). The rebuilding of IgG N-glycans in RA correlates with the relapses and remissions of the disease, is associated with physiological states such as pregnancy but also depends on applied anti-inflammatory therapy. In turn, a decreased core fucosylation of the whole pool of IgG N-glycans is a serum glycomarker in autoimmune thyroid diseases (AITD) encompassing Hashimoto’s thyroiditis (HT) and Grave’s disease (GD). However, fucosylation of anti-thyroglobulin IgG (an immunological marker of HT) was elevated in HT serum. Core fucosylation of IgG oligosaccharides was also lowered in MS and SLE. In AITD and IBD, chronic inflammation T lymphocytes showed the reduced expression of MGAT5 gene encoding β1,6-N-acetylglucosaminyltransferase V (GnT-V) responsible for β1,6-branching of N-glycans, which is important for T cell receptor activation. Structural changes of glycans have a profound effect on the pro-inflammatory activity of immune cells and serum immune proteins, including IgG in autoimmunity.
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References
Alavi A, Axford JS (2008) Sweet and sour: the impact of sugars on disease. Rheumatology (Oxford) 47(6):760–770. https://doi.org/10.1093/rheumatology/ken081
Anderson NL, Anderson NG (2002) The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1(11):845–867. https://doi.org/10.1074/mcp.r200007-mcp200
Antonelli A, Ferrari SM, Corrado A et al (2015) Autoimmune thyroid disorders. Autoimmun Rev 14(2):174–180. https://doi.org/10.1016/j.autrev.2014.10.016
Bond A, Kerr MA, Hay FC (1995) Distinct oligosaccharide content of rheumatoid arthritis-derived immune complexes. Arthritis Rheum 38(6):744–749. https://doi.org/10.1002/art.1780380605
Bond A, Alavi A, Axford JS et al (1997) A detailed lectin analysis of IgG glycosylation, demonstrating disease specific changes in terminal galactose and N-acetylglucosamine. J Autoimmun 10(1):77–85. https://doi.org/10.1006/jaut.1996.0104
Bondt A, Selman MHJ, Deelder AM et al (2013) Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis during pregnancy is independent of sialylation. J Proteome Res 12(10):4522–4531. https://doi.org/10.1021/pr400589m
Carvalho DP, Ferreira AC, Coelho SM et al (2000) Thyroid peroxidase activity is inhibited by amino acids. Braz J Med Biol Res 33(3):355–361. https://doi.org/10.1590/s0100-879x2000000300015
Cavallo S (2020) Immune-mediated genesis of multiple sclerosis. J Transl Autoimmun 3:100039. https://doi.org/10.1016/j.jtauto.2020.100039
Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125(2 Suppl 2):S3–S23. https://doi.org/10.1016/j.jaci.2009.12.980
Chazenbalk GD, Pichurin PN, Guo J et al (2005) Interactions between the mannose receptor and thyroid autoantigens. Clin Exp Immunol 139(2):216–224. https://doi.org/10.1111/j.1365-2249.2004.02689.x
Chien M-W, Fu S-H, Hsu C-Y et al (2018) The modulatory roles of N-glycans in T-cell-mediated autoimmune diseases. Int J Mol Sci 19(3):780. https://doi.org/10.3390/ijms19030780
Chui D, Sellakumar G, Green R et al (2001) Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc Natl Acad Sci U S A 98(3):1142–1147. https://doi.org/10.1073/pnas.98.3.1142
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7
Croce A, Firuzi O, Altieri F et al (2007) Effect of infliximab on the glycosylation of IgG of patients with rheumatoid arthritis. J Clin Lab Anal 21(5):303–314. https://doi.org/10.1002/jcla.20191
Cvetko A, Kifer D, Gornik O et al (2020) Glycosylation alterations in multiple sclerosis show increased proinflammatory potential. Biomedicines 8(10):410. https://doi.org/10.3390/biomedicines8100410
D’Cruz DP, Khamashta MA, Hughes GR (2007) Systemic lupus erythematosus. Lancet 369(9561):587–396. https://doi.org/10.1016/S0140-6736(07)60279-7
Delves PJ (1998) The role of glycosylation in autoimmune disease. Autoimmunity 27(4):239–253. https://doi.org/10.3109/08916939808993836
Dema B, Charles N (2014) Advances in mechanisms of systemic lupus erythematosus. Discov Med 17(95):247–255
Dema B, Charles N (2016) Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies 5(1):2. https://doi.org/10.3390/antib5010002
Demetriou M, Granovsky M, Quaggin S et al (2001) Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409(6821):733–739. https://doi.org/10.1038/35055582
Dennis JW, Nabi IR, Demetriou M (2009) Metabolism, cell surface organization, and disease. Cell 139(7):1229–1241. https://doi.org/10.1016/j.cell.2009.12.008
Di Jeso B, Arvan P (2016) Thyroglobulin from molecular and cellular biology to clinical endocrinology. Endocr Rev 37(1):2–36. https://doi.org/10.1210/er.2015-1090
Dias AM, Dourado J, Lago P et al (2014) Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis. Hum Mol Genet 23(9):2416–2127. https://doi.org/10.1093/hmg/ddt632
Dias AM, Correia A, Pereira MS et al (2018) Metabolic control of T cell immune response through glycans in inflammatory bowel disease. Proc Natl Acad Sci U S A 115(20):E4651–E4660. https://doi.org/10.1073/pnas.1720409115
Elkon K, Casali P (2008) Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 4(9):491–498. https://doi.org/10.1038/ncprheum0895
Fang Q, Ou J, Nandakumar KS (2019) Autoantibodies as diagnostic markers and mediator of joint inflammation in arthritis. Mediat Inflamm 2019:6363086. https://doi.org/10.1155/2019/6363086
Field JJ, Okeley NM, Zeng W et al (2016) Understanding the mechanism of 2FF-induced immune modulation. Cancer Res 76(14 Suppl):4005
Fröhlich E, Wahl R (2017) Thyroid autoimmunity: role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases. Front Immunol 8:521. https://doi.org/10.3389/fimmu.2017.00521
Fujii H, Shinzaki S, Iijima H et al (2016) Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease. Gastroenterology 150(7):1620–1632. https://doi.org/10.1053/j.gastro.2016.03.002
Gindzienska-Sieskiewicz E, Klimiuk PA, Kisiel DG et al (2007) The changes in monosaccharide composition of immunoglobulin G in the course of rheumatoid arthritis. Clin Rheumatol 26(5):685–690. https://doi.org/10.1007/s10067-006-0370-7
Gińdzieńska-Sieśkiewicz E, Radziejewska I, Domysławska I et al (2016) Changes of glycosylation of IgG in rheumatoid arthritis patients treated with methotrexate. Adv Med Sci 61(2):193–197. https://doi.org/10.1016/j.advms.2015.12.009
Goodarzi MT, Axford JS, Varanasi SS et al (1998) Sialyl Lewis(x) expression on IgG in rheumatoid arthritis and other arthritic conditions: a preliminary study. Glycoconj J 15(2):1149–1154. https://doi.org/10.1023/A:1006920007227
Gornik I, Maravić G, Dumić J et al (1999) Fucosylation of IgG heavy chains is increased in rheumatoid arthritis. Clin Biochem 32(8):605–608. https://doi.org/10.1016/S0009-9120(99)00060-0
Green RS, Stone EL, Tenno M et al (2007) Mammalian N-glycan branching protects against innate immune self-recognition and inflammation in autoimmune disease pathogenesis. Immunity 27(2):308–320. https://doi.org/10.1016/j.immuni.2007.06.008
Guan Q (2019) A comprehensive review and update on the pathogenesis of inflammatory bowel disease. J Immunol Res 2019:7247238. https://doi.org/10.1155/2019/7247238
Gudelj I, Salo PP, Trbojević-Akmačić I et al (2018) 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(6 Pt A):2034–2039. https://doi.org/10.1016/j.bbadis.2018.03.018
Hafkenscheid L, De Moel E, Smolik I et al (2019) N-linked glycans in the variable domain of IgG anti-citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol 71(10):1626–1633. https://doi.org/10.1002/art.40920
Huang C, Liu Y, Wu H et al (2017) Characterization of IgG glycosylation in rheumatoid arthritis patients by MALDI-TOF-MSn and capillary electrophoresis. Anal Bioanal Chem 409(15):3731–3739. https://doi.org/10.1007/s00216-017-0302-1
Isozaki T, Ruth JH, Amin MA et al (2014) Fucosyltransferase 1 mediates angiogenesis, cell adhesion and rheumatoid arthritis synovial tissue fibroblast proliferation. Arthritis Res Ther 16(1):R28. https://doi.org/10.1186/ar4456
Kappler K, Hennet T (2020) Emergence and significance of carbohydrate-specific antibodies. Genes Immun 21(4):224–239. https://doi.org/10.1038/s41435-020-0105-9
Katsorida ME, Moutsopoulos HM (2001) Autoimmunity and autoimmune disease. Nephrol Dial Transplant 16(Suppl 6):48–51. https://doi.org/10.1093/ndt/16.suppl_6.48
Kempers AC, Hafkenscheid L, Scherer HU et al (2018) Variable domain glycosylation of ACPA-IgG: a missing link in the maturation of the ACPA response? Clin Immunol 186:34–37. https://doi.org/10.1016/j.clim.2017.09.001
Kohno Y, Yamaguchi F, Saito K et al (1991) Anti-thyroid peroxidase antibodies in sera from healthy subjects and from patients with chronic thyroiditis: differences in the ability to inhibit thyroid peroxidase activities. Clin Exp Immunol 85(3):459–463. https://doi.org/10.1111/j.1365-2249.1991.tb05749.x.
Korta P, Pocheć E (2019) Glycosylation of thyroid-stimulating hormone receptor. Endokrynol Pol 70(1):86–100. https://doi.org/10.5603/EP.a2018.0077
Korta P, Ząbczyńska M, Bajgier N et al (2019) The expression of glycosyltransferases is changed in CD4+ T cells in Hashimoto’s thyroiditis. 44th FEBS Congress, Krakow, July 2019
Kozłowska K, Rydlewska M, Ząbczyńska M et al (2018) IgG glycosylation in autoimmune diseases. Postepy Hig Med Dosw 72:975–990. https://doi.org/10.5604/01.3001.0012.7351
Lacki JK, Porawska W, Mackiewicz U et al (1996) Changes in agalactosyl IgG levels correlate with radiological progression in early rheumatoid arthritis. Ann Med 28(3):265–269. https://doi.org/10.3109/07853899609033129
Lauc G, Pezer M, Rudan I et al (2016) Mechanisms of disease: the human N-glycome. Biochim Biophys Acta 1860(8):1574–1582. https://doi.org/10.1016/j.bbagen.2015.10.016
Le SN, Porebski BT, McCoey J et al (2015) Modelling of thyroid peroxidase reveals insights into its enzyme function and autoantigenicity. PLoS One 10(12):e0142615. https://doi.org/10.1371/journal.pone.0142615
Liang W, Mao S, Sun S et al (2018) Core fucosylation of the T cell receptor is required for T cell activation. Front Immunol 9:78. https://doi.org/10.3389/fimmu.2018.00078
Magorivska I, Muñoz LE, Janko C et al (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
Malhotra R, Wormald MR, Rudd PM et al (1995) Glycosylation changes of IgG associated with rheumatooid arthritis can activate complement via the mannose-binding protein. Nat Med 1(3):237–243. https://doi.org/10.1038/nm0395-237
Marti Fernandez I, Macrini C, Krumbholz M et al (2019) The glycosylation site of myelin oligodendrocyte glycoprotein affects autoantibody recognition in a large proportion of patients. Front Immunol 10:1189. https://doi.org/10.3389/fimmu.2019.01189
Martin K, Talukder R, Hay FC et al (2001) Characterization of changes in IgG associated oligosaccharide profiles in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis using fluorophore linked carbohydrate electrophoresis. J Rheumatol 28(7):1531–1536
Martin TC, Šimurina M, Ząbczyńska M et al (2020) Decreased immunoglobulin G Core Fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases. Mol Cell Proteomics 19(5):774–792. https://doi.org/10.1074/mcp.RA119.001860
Maverakis E, Kim K, Shimoda M et al (2015) Glycans in the immune system and the altered Glycan theory of autoimmunity: a critical review. J Autoimmun 57:1–13. https://doi.org/10.1016/j.jaut.2014.12.002
McLachlan SM, Alpi K, Rapoport B (2011) Review and hypothesis: does Graves’ disease develop in non-human great apes? Thyroid 21(12):1359–1366. https://doi.org/10.1089/thy.2011.0209
Mirshafiey A, Kianiaslani M (2013) Autoantigens and autoantibodies in multiple sclerosis. Iran J Allergy Asthma Immunol 12(4):292–303
Moremen KW, Ramiah A, Stuart M et al (2018) Expression system for structural and functional studies of human glycosylation enzymes. Nat Chem Biol 14(2):156–162. https://doi.org/10.1038/nchembio.2539
Naito N, Saito K, Hosoya T et al (1990) Anti-thyroglobulin autoantibodies in sera from patients with chronic thyroiditis and from healthy subjects: differences in cross-reactivity with thyroid peroxidase. Clin Exp Immunol 80(1):4–10. https://doi.org/10.1111/j.1365-2249.1990.tb06433.x.
Parekh RB, Dwek RA, Sutton BJ et al (1985) Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316(6027):452–457. https://doi.org/10.1038/316452a0
Pasek M, Duk M, Podbielska M et al (2006) Galactosylation of IgG from rheumatoid arthritis (RA) patients – changes during therapy. Glycoconj J 23(7–8):463–471. https://doi.org/10.1007/s10719-006-5409-0
Rademacher TW, Williams P, Dwek RA (1994) Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc Natl Acad Sci U S A 91(13):6123–6127. https://doi.org/10.1073/pnas.91.13.6123
Rebuffat SA, Nguyen B, Robert B et al (2008) Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease. J Clin Endocrinol Metab 93(3):929–934. https://doi.org/10.1210/jc.2007-2042
Rombouts Y, Ewing E, Van De Stadt LA et al (2019) N-linked glycans in the variable domain of IgG anti-citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol 71(10):1626–1633. https://doi.org/10.1002/art.40920
Rydén I, Påhlsson P, Lundblad A et al (2002) Fucosylation of α1-acid glycoprotein (orosomucoid) compared with traditional biochemical markers of inflammation in recent onset rheumatoid arthritis. Clin Chim Acta 317(1–2):221–229. https://doi.org/10.1016/S0009-8981(01)00803-8
Shade K-TC, Anthony RM (2013) Antibody glycosylation and inflammation. Antibodies 2:392–414. https://doi.org/10.3390/antib2030392
Shinzaki S, Iijima H, Nakagawa T et al (2008) IgG oligosaccharide alterations are a novel diagnostic marker for disease activity and the clinical course of inflammatory bowel disease. Am J Gastroenterol 103(5):1173–1181. https://doi.org/10.1111/j.1572-0241.2007.01699.x
Sjöwall C, Zapf J, Von Löhneysen S et al (2015) Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus. Lupus 24(6):569–581. https://doi.org/10.1177/0961203314558861
Su Z, Xie Q, Wang Y et al (2020) Abberant immunoglobulin g glycosylation in rheumatoid arthritis by LTQ-ESI-MS. Int J Mol Sci 21(6):2045. https://doi.org/10.3390/ijms21062045
Sun D, Hu F, Gao H et al (2019) Distribution of abnormal IgG glycosylation patterns from rheumatoid arthritis and osteoarthritis patients by MALDI-TOF-MSn. Analyst 144(6):2042–2051. https://doi.org/10.1039/c8an02014k
Szabó E, Hornung Á, Monostori É et al (2019) Altered cell surface N-glycosylation of resting and activated T cells in systemic lupus erythematosus. Int J Mol Sci 20(18):pii: E4455. https://doi.org/10.3390/ijms20184455
Theodoratou E, Campbell H, Ventham NT et al (2014) The role of glycosylation in IBD. Nat Rev Gastroenterol Hepatol 11(10):588–600. https://doi.org/10.1038/nrgastro.2014.78
Trbojevic Akmacic I, Ventham NT, Theodoratou E et al (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
Van de Geijn FE, Wuhrer M, Selman MHJ et al (2009) Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther 11(6):R193. https://doi.org/10.1186/ar2892
Vermeulen N, de Béeck KO, Vermeire S et al (2011) Identification of a novel autoantigen in inflammatory bowel disease by protein microarray. Inflamm Bowel Dis 17(6):1291–1300. https://doi.org/10.1002/ibd.21508
Vučkovïc F, Krištïc J, Gudelj I et al (2015) Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol 67(11):2978–2989. https://doi.org/10.1002/art.39273
Watson M, Rudd PM, Bland M et al (1999) Sugar printing rheumatic diseases: a potential method for disease differentiation using immunoglobulin G oligosaccharides. Arthritis Rheum 42(8):1682–1690. https://doi.org/10.1002/1529-0131(199908)42:8<1682::AID-ANR17>3.0.CO;2-X
Wu CY, Yang HY, Lai JH (2020) Anti-citrullinated protein antibodies in patients with rheumatoid arthritis: biological effects and mechanisms of immunopathogenesis. Int J Mol Sci 21(11):4015. https://doi.org/10.3390/ijms21114015
Wuhrer M, Selman MHJ, McDonnell LA et al (2015) 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
Yuan S, Li Q, Zhang Y et al (2015) Changes in anti-thyroglobulin IgG glycosylation patterns in Hashimoto’s thyroiditis patients. J Clin Endocrinol Metab 100(2):717–724. https://doi.org/10.1210/jc.2014-2921
Ząbczyńska M, Kozłowska K, Pocheć E (2018) Glycosylation in the thyroid gland: vital aspects of glycoprotein function in thyrocyte physiology and thyroid disorders. Int J Mol Sci 19(9):2792. https://doi.org/10.3390/ijms19092792
Ząbczyńska M, Korta P, Chojnacka A et al (2019) Altered expression of T cell glycosyltransferases in Graves’ disease. 44th FEBS congress, Krakow, July 2019. FEBS Open Bio 9(Suppl. 1):395. https://doi.org/10.1002/2211-5463.12675
Ząbczyńska M, Link-Lenczowski P, Novokmet M et al (2020a) Altered N-glycan profile of IgG-depleted serum proteins in Hashimoto's thyroiditis. Biochim Biophys Acta Gen Subj 1864(3):129464. https://doi.org/10.1016/j.bbagen.2019.129464
Ząbczyńska M, Polak K, Kozłowska K et al (2020b) The contribution of IgG glycosylation to antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in Hashimoto’s thyroiditis: an in vitro model of thyroid autoimmunity. Biomolecules 10(2):171. https://doi.org/10.3390/biom10020171
Zhao L, Liu M, Gao Y et al (2013) Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. Eur J Endocrinol 168(4):585–592. https://doi.org/10.1530/EJE-12-0964
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Ząbczyńska, M., Link-Lenczowski, P., Pocheć, E. (2021). Glycosylation in Autoimmune Diseases. In: Lauc, G., Trbojević-Akmačić, I. (eds) The Role of Glycosylation in Health and Disease. Advances in Experimental Medicine and Biology, vol 1325. Springer, Cham. https://doi.org/10.1007/978-3-030-70115-4_10
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