Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of autoantibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gammareceptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive armsand is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as agalactosylatedG0, monogalactosylated G1, and digalactosylated G2, which are further modified by core-fucosylation (F) and bisecting N-acetylglucosamine (B) moieties such as G0F and G0FB. Interestingly, proinflammatory G0F is shown to be regulated by estrogen in vivo. Here,it is hypothesized that the regulation of G0F by estrogen contributes to sex dichotomy in RA by setting up the level of IgG-dependentinflammation and therefore, RA disease activity (Das28-CRP3). To investigate this hypothesis, IgG glycosylation was characterized inserum samples from active RA patients (n = 232) and healthy controls (n = 232) by serum N-glycan analysis using the high performanceliquid chromatography. According to the results, the IgG Fc glycan phenotype originates predominantly from the structure of G0F, andboth G0F and G0FB correlate with Das28-CRP3 in females, but not in males. In conclusion, IgG G0F-dependent inflammation differsin males and females, and these differences point to the differential regulation of inflammation by sex hormone estrogen via IgG glycosylation.

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Adamczyk B, Stockmann H, O’Flaherty R, Karlsson NG, Rudd PM (2017). High-throughput analysis of the plasma N-glycome by UHPLC. Methods in Molecular Biology 1503: 97-108. doi: 10.1007/978-1-4939-6493-2_8.
Adamczyk B, Struwe WB, Ercan A, Nigrovic PA, Rudd PM (2013). Characterization of fibrinogen glycosylation and its importance for serum/plasma N-glycome analysis. Journal of Proteome Research 12 (1): 444-454. doi: 10.1021/pr300813h.
Ahmed AA, Giddens J, Pincetic A, Lomino JV, Ravetch JV et al. (2014). Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. Journal of Molecular Biology 426 (18): 3166-3179. doi: 10.1016/j.jmb.2014.07.006.
Allen CD, Okada T, Cyster JG (2007). Germinal-center organization and cellular dynamics. Immunity 27 (2): 190-202. doi: 10.1016/j.immuni.2007.07.009.
Allhorn M, Briceno JG, Baudino L, Lood C, Olsson ML et al. (2010). The IgG-specific endoglycosidase EndoS inhibits both cellular and complement-mediated autoimmune hemolysis. Blood 115 (24): 5080-5088. doi: 10.1182/blood-2009-08-239020.
Anthony RM, Kobayashi T, Wermeling F, Ravetch JV (2011). Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475 (7354): 110-113. doi: 10.1038/nature10134.
Anthony RM, Nimmerjahn F, Ashline DJ, Reinhold VN, Paulson JC et al. (2008). Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320 (5874): 373-376. doi: 10.1126/science.1154315.
Anthony RM, Ravetch JV (2010). A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs. Journal of Clinical Immunology 30 (Suppl. 1): S9-S14. doi: 10.1007/ s10875-010-9405-6.
Apweiler R, Hermjakob H, Sharon N (1999). On the frequency of protein glycosylation, as deduced from analysis of the SWISSPROT database. Biochimica et Biophysica Acta 1473 (1): 4-8. doi: 10.1016/s0304-4165(99)00165-8.
Arnold JN, Dwek RA, Rudd PM, Sim RB (2006). Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunology Letters 106 (2): 103-110. doi: 10.1016/j.imlet.2006.05.007.
Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA (2007). The impact of glycosylation on the biological function and structure of human immunoglobulins. Annual Review of Immunology 25: 21-50. doi: 10.1146/annurev.immunol.25.022106.141702.
Atzeni F, Talotta R, Masala IF, Bongiovanni S, Boccassini L et al. (2017). Biomarkers in rheumatoid arthritis. Israel Medical Association Journal 19: 512-516.
Axford JS (1999). Glycosylation and rheumatic disease. Biochimica et Biophysica Acta 1455 (2-3): 219-229. doi: 10.1016/s0925- 4439(99)00057-5.
Biram A, Davidzohn N, Shulman Z (2019). T cell interactions with B cells during germinal center formation, a three-step model. Immunological Reviews 288 (1): 37-48. doi: 10.1111/ imr.12737.
Bondt A, Hafkenscheid L, Falck D, Kuijper TM, Rombouts Y et al. (2018). ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 77 (8): 1130-1136. doi: 10.1136/ annrheumdis-2018-212946.
Bondt A, Selman MH, Deelder AM, Hazes JM, Willemsen SP et al. (2013). Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis during pregnancy is independent of sialylation. Journal of Proteome Research 12 (10): 4522-4531. doi: 10.1021/pr400589m.
Bournazos S (2019). IgG Fc receptors: evolutionary considerations. In: Ravetch J, Nimmerjahn F (editors). Fc Mediated Activity of Antibodies. Current Topics in Microbiology and Immunology, Vol. 423. Cham, Switzerland: Springer, 1-11. doi: 10.1007/82_2019_149.
Bournazos S, Ravetch JV (2017). Diversification of IgG effector functions. International Immunology 29 (7): 303-310. doi: 10.1093/intimm/dxx025.
De Silva NS, Klein U (2015). Dynamics of B cells in germinal centres. Nature Reviews Immunology 15 (3): 137-148. doi: 10.1038/ nri3804.
Ditzel HJ (2004). The K/BxN mouse: a model of human inflammatory arthritis. Trends in Molecular Medicine10 (1): 40-45. doi: 10.1016/j.molmed.2003.11.004.
Dolsen MR, Crosswell AD, Prather AA (2019). Links between stress, sleep, and inflammation: are there sex differences? Current Psychiatry Reports 21 (2): 8. doi: 10.1007/s11920-019-0993-4.
Engdahl C, Bondt A, Harre U, Raufer J, Pfeifle R et al. (2018). Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Research & Therapy 20 (1): 84. doi: 10.1186/s13075-018-1586-z.
Ercan A, Cui J, Chatterton DE, Deane KD, Hazen MM et al. (2010). Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis & Rheumatology 62 (8): 2239- 2248. doi: 10.1002/art.27533.
Ercan A, Kohrt WM, Cui J, Deane KD, Pezer M et al. (2017). Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2 (4): e89703. doi: 10.1172/jci.insight.89703.
Ferrara C, Grau S, Jager C, Sondermann P, Brunker P et al. (2011). Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proceedings of the National Academy of Sciences of the United States of America108 (31): 12669- 12674. doi: 10.1073/pnas.1108455108.
Gagneux P, Varki A (1999). Evolutionary considerations in relating oligosaccharide diversity to biological function. Glycobiology 9 (8): 747-755. doi: 10.1093/glycob/9.8.747.
Golay J, Da Roit F, Bologna L, Ferrara C, Leusen JH et al. (2013). Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood 122 (20): 3482-3491. doi: 10.1182/blood-2013-05-504043.
Harris LJ, Larson SB, Hasel KW, McPherson A (1997). Refined structure of an intact IgG2a monoclonal antibody. Biochemistry 36 (7): 1581-1597. doi: 10.1021/bi962514+.
Hassfeld W, Steiner G, Hartmuth K, Kolarz G, Scherak O et al. (1989). Demonstration of a new antinuclear antibody (anti-RA33) that is highly specific for rheumatoid arthritis. Arthritis & Rheumatology 32 (12): 1515-1520. doi: 10.1002/ anr.1780321204.
Holers VM (2007). Antibodies to citrullinated proteins: pathogenic and diagnostic significance. Current Rheumatology Reports 9 (5): 396-400. doi: 10.1007/s11926-007-0063-5.
Holland M, Yagi H, Takahashi N, Kato K, Savage CO et al. (2006). Differential glycosylation of polyclonal IgG, IgG-Fc and IgGFab isolated from the sera of patients with ANCA-associated systemic vasculitis. Biochimica et Biophysica Acta 1760 (4): 669-677. doi: 10.1016/j.bbagen.2005.11.021.
Hueber W, Tomooka BH, Batliwalla F, Li W, Monach PA et al. (2009). Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Research & Therapy 11 (3): R76. doi: 10.1186/ar2706.
Jay JW, Bray B, Qi Y, Igbinigie E, Wu H et al. (2018). IgG antibody 3D structures and dynamics. Antibodies (Basel) 7 (2): 18. doi: 10.3390/antib7020018.
Jefferis R (2012). Isotype and glycoform selection for antibody therapeutics. Archives of Biochemistry and Biophysics 526 (2): 159-166. doi: 10.1016/j.abb.2012.03.021.
Kaneko Y, Nimmerjahn F, Ravetch JV (2006). Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313 (5787): 670-673. doi: 10.1126/science.1129594.
Klein SL (2012a). Immune cells have sex and so should journal articles. Endocrinology 153 (6): 2544-2550. doi: 10.1210/ en.2011-2120.
Klein SL (2012b). Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. Bioessays 34 (12): 1050-1059. doi: 10.1002/bies.201200099.
Korganow AS, Ji H, Mangialaio S, Duchatelle V, Pelanda R et al. (1999). From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10 (4): 451-461. doi: 10.1016/s1074-7613(00)80045-x.
Lood C, Allhorn M, Lood R, Gullstrand B, Olin AI et al. (2012). IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: a possible new treatment? Arthritis & Rheumatology 64 (8): 2698-2706. doi: 10.1002/art.34454.
Lund J, Tanaka T, Takahashi N, Sarmay G, Arata Y et al. (1990). A protein structural change in aglycosylated IgG3 correlates with loss of huFc gamma R1 and huFc gamma R111 binding and/ or activation. Molecular Immunology 27 (11): 1145-1153. doi: 10.1016/0161-5890(90)90103-7.
Maccioni M, Zeder-Lutz G, Huang H, Ebel C, Gerber P et al. (2002). Arthritogenic monoclonal antibodies from K/BxN mice. Journal of Experimental Medicine 195 (8): 1071-1077. doi: 10.1084/jem.20011941.
Malhotra R, Wormald MR, Rudd PM, Fischer PB, Dwek RA et al. (1995). Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nature Medicine 1 (3): 237-243. doi: 10.1038/nm0395-237.
Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C et al. (2001). The major synovial targets of the rheumatoid arthritis-specificantifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. Journal of Immunology 166 (6): 4177-4184. doi: 10.4049/ jimmunol.166.6.4177.
Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B et al. (2002). How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nature Immunology 3 (4): 360-365. doi: 10.1038/ni772.
Matsuo K, Xiang Y, Nakamura H, Masuko K, Yudoh K et al. (2006). Identification of novel citrullinated autoantigens of synovium in rheumatoid arthritis using a proteomic approach. Arthritis Research & Therapy 8 (6): R175. doi: 10.1186/ar2085.
Monach PA, Benoist C, Mathis D (2004). The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Advances in Immunology 82: 217-248. doi: 10.1016/ S0065-2776(04)82005-4.
Monach PA, Mathis D, Benoist C (2008). The K/BxN arthritis model. Current Protocols in Immunology 81 (1): 1-12. doi: 10.1002/0471142735.im1522s81.
Nandakumar KS (2018). Targeting IgG in arthritis: disease pathways and therapeutic avenues. International Journal of Molecular Sciences 19 (3): 677. doi: 10.3390/ijms19030677.
Nandakumar KS, Collin M, Happonen KE, Lundstrom SL, Croxford AM et al. (2018). Streptococcal Endo-beta-NAcetylglucosaminidase suppresses antibody-mediated inflammation in vivo. Frontiers in Immunology 9: 1623. doi: 10.3389/fimmu.2018.01623.
Nandakumar KS, Collin M, Olsen A, Nimmerjahn F, Blom AM et al. (2007). Endoglycosidase treatment abrogates IgG arthritogenicity: importanceof IgG glycosylation in arthritis. European Journal of Immunology 37 (10): 2973-2982. doi: 10.1002/eji.200737581.
Ngo ST, Steyn FJ, McCombe PA (2014). Gender differences in autoimmune disease. Frontiers in Neuroendocrinology 35 (3): 347-369. doi: 10.1016/j.yfrne.2014.04.004.
Nicholson LB (2016). The immune system. Essays in Biochemistry 60 (3): 275-301. doi: 10.1042/EBC20160017.
Pagan JD, Kitaoka M, Anthony RM (2018). Engineered sialylation of pathogenic antibodies in vivo attenuates autoimmune disease. Cell 172 (3): 564-577. doi: 10.1016/j.cell.2017.11.041.
Peschke B, Keller CW, Weber P, Quast I, Lunemann JD (2017). Fcgalactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity. Frontiers in Immunology 8: 646. doi: 10.3389/ fimmu.2017.00646.
Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT et al. (2014). Type I and type II Fc receptors regulate innate and adaptiveimmunity. Nature Immunology 15 (8): 707-716. doi: 10.1038/ni.2939.
Quast I, Peschke B, Lunemann JD (2017). Regulation of antibody effector functions through IgG Fc N-glycosylation. Cellular and Molecular Life Sciences 74 (5): 837-847. doi: 10.1007/ s00018-016-2366-z.
Rainville JR, Tsyglakova M, Hodes GE (2018). Deciphering sex differences in the immune system and depression. Frontiers in Neuroendocrinology 50: 67-90. doi: 10.1016/j. yfrne.2017.12.004.
Raju TS, Lang SE (2014). Diversity in structure and functions of antibody sialylation in the Fc. Current Opinion in Biotechnology 30: 147-152. doi: 10.1016/j.copbio.2014.06.014.
Reiding KR, Vreeker GCM, Bondt A, Bladergroen MR, Hazes JMW et al. (2017). Serum protein N-glycosylation changes with rheumatoid arthritis disease activity during and after pregnancy. Frontiers in Medicine 4: 241. doi: 10.3389/ fmed.2017.00241.
Royle L, Campbell MP, Radcliffe CM, White DM, Harvey DJ et al. (2008). HPLC-based analysis of serum N-glycans on a 96-well plate platform with dedicated database software. Analytical Biochemistry 376 (1): 1-12. doi: 10.1016/j.ab.2007.12.012.
Royle L, Radcliffe CM, Dwek RA, Rudd PM (2006). Detailed structural analysis of N-glycans released from glycoproteins in SDS-PAGE gel bands using HPLC combined with exoglycosidase array digestions. Methods in Molecular Biology 347: 125-143. doi: 10.1385/1-59745-167-3:125.
Schroeder HW Jr., Cavacini L (2010). Structure and function of immunoglobulins. Journal of Allergy and Clinical Immunology 125 (2-Suppl. 2): S41-S52. doi: 10.1016/j.jaci.2009.09.046.
Silman AJ, Pearson JE (2002). Epidemiology and genetics of rheumatoid arthritis. Arthritis Research & Therapy 4 (Suppl. 3): S265-S272. doi: 10.1186/ar578.
Skriner K, Adolph K, Jungblut PR, Burmester GR (2006). Association of citrullinated proteins with synovial exosomes. Arthritis & Rheumatology 54 (12): 3809-3814. doi: 10.1002/art.22276.
Smolen JS, Aletaha D, McInnes IB (2016). Rheumatoid arthritis. The Lancet 388 (10055): 2023-2038. doi: 10.1016/S0140- 6736(16)30173-8.
Suan D, Sundling C, Brink R (2017). Plasma cell and memory B cell differentiation from the germinal center. Current Opinion in Immunology 45: 97-102. doi: 10.1016/j.coi.2017.03.006.
Subedi GP, Hanson QM, Barb AW (2014). Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient FcgammaRIIIa binding. Structure 22 (10): 1478-1488. doi: 10.1016/j.str.2014.08.002.
Tanaka-Watanabe Y, Matsumoto I, Iwanami K, Inoue A, Goto D et al. (2009). B cells play a crucial role as antigen-presenting cells andcollaborate with inflammatory cytokines in glucose-6-phosphate isomerase-induced arthritis. Clinical and Experimental Immunology 155 (2): 285-294. doi: 10.1111/j.1365-2249.2008.03816.x.
Taylor AI, Fabiane SM, Sutton BJ, Calvert RA (2009). The crystal structure of an avian IgY-Fc fragment reveals conservation with both mammalian IgG and IgE†‡. Biochemistry 48 (3): 558-562. doi: 10.1021/bi8019993.
Uysal H, Bockermann R, Nandakumar KS, Sehnert B, Bajtner E et al. (2009). Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. Journal of Experimental Medicine 206 (2): 449-462. doi: 10.1084/ jem.20081862.
Van Boekel MA, Vossenaar ER, Van den Hoogen FH, Van Venrooij WJ (2002). Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Research & Therapy 4 (2): 87-93. doi: 10.1186/ar395.
Van de Geijn FE, Wuhrer M, Selman MH, Willemsen SP, De Man YA 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 Research & Therapy 11 (6): R193. doi: 10.1186/ar2892.
Verpoort KN, Cheung K, Ioan-Facsinay A, Van der Helm-van Mil AHM, De Vries-Bouwstra JK et al. (2007). Fine specificity of the anti-citrullinated protein antibody response is influenced by the shared epitope alleles. Arthritis & Rheumatology 56 (12): 3949-3952. doi: 10.1002/art.23127.
Victora GD, Nussenzweig MC (2012). Germinal centers. Annual Review of Immunology 30: 429-457. doi: 10.1146/annurevimmunol-020711-075032.
Vidarsson G, Dekkers G, Rispens T (2014). IgG subclasses and allotypes: from structure to effector functions. Frontiers in Immunology 5: 520. doi: 10.3389/fimmu.2014.00520.
Vossenaar ER, Despres N, Lapointe E, Van der Heijden A, Lora M et al. (2004). Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Research & Therapy 6 (2): R142-R150. doi: 10.1186/ar1149.
Wang J, Balog CI, Stavenhagen K, Koeleman CA, Scherer HU et al. (2011). Fc-glycosylation of IgG1 is modulated by B-cell stimuli. Molecular & Cellular Proteomics 10 (5): M110.004655. doi: 10.1074/mcp.M110.004655.
Watson M, Rudd PM, Bland M, Dwek RA, Axford JS (1999). Sugar printing rheumatic diseases: a potential method for disease differentiation using immunoglobulin G oligosaccharides. Arthritis & Rheumatology 42 (8): 1682- 1690. doi: 10.1002/1529-0131(199908)42:8<1682::AIDANR17>3.0.CO;2-X.
Wozniczko-Orlowska G, Milgrom F (1982). Collagen-anti-collagen complexes in rheumatoid arthritis sera. International Archives of Allergy and Immunology 68 (1): 28-34. doi: 10.1159/000233063.
Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ (1979). Antikeratin antibodies in rheumatoid arthritis. British Medical Journal 2 (6182): 97-99. doi: 10.1136/bmj.2.6182.97.