Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Antibody glycosylation as a potential biomarker for chronic inflammatory autoimmune diseases

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Glycosylation of immunoglobulins (Ig) is known to influence their effector functions in physiological and pathological conditions. Changes in the glycosylation pattern of immunoglobulin G and autoantibodies in various inflammatory autoimmune diseases have been studied for many years. However, despite extensive research, many questions are still elusive regarding the formation of such differentially glycosylated antibodies and alterations of glycosylation patterns in other immunoglobulin classes for example. Nevertheless, knowledge has been deepened greatly, especially in the field of rheumatoid arthritis. Changes of Ig glycosylation patterns have been shown to appear before onset of the disease and moreover can subject to treatment. In this review, we discuss the potential of detecting Ig glycosylation changes as biomarkers for disease activity or monitoring of patients with chronic inflammatory autoimmune diseases such as antiphospholipid syndrome, rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis and Henoch-Schönlein purpura.
  Article Metrics


1. Munoz LE, Lauber K, Schiller M, et al. (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6: 280-289.    

2. Bohm S, Kao D, Nimmerjahn F (2014) Sweet and sour: the role of glycosylation for the anti-inflammatory activity of immunoglobulin G. Curr Top Microbiol Immunol 382: 393-417.

3. 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.    

4. Arnold JN, Wormald MR, Sim RB, et al. (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25: 21-50.    

5. Catera M, Borelli V, Malagolini N, et al. (2016) Identification of novel plasma glycosylation-associated markers of aging. Oncotarget 7: 7455-7468.

6. Parekh RB, Roitt IM, Isenberg DA, et al. (1988) Galactosylation of IgG associated oligosaccharides: reduction in patients with adult and juvenile onset rheumatoid arthritis and relation to disease activity. Lancet 1: 966-969.

7. Saulsbury FT (1997) Alterations in the O-linked glycosylation of IgA1 in children with Henoch-Schonlein purpura. J Rheumatol 24: 2246-2249.

8. Allen AC, Willis FR, Beattie TJ, et al. (1998) Abnormal IgA glycosylation in Henoch-Schonlein purpura restricted to patients with clinical nephritis. Nephrol Dial Transplant 13: 930-934.    

9. Schur PH (1988) IgG subclasses. A historical perspective. Monogr Allergy 23: 1-11.

10. Lund J, Takahashi N, Nakagawa H, et al. (1993) Control of IgG/Fc glycosylation: a comparison of oligosaccharides from chimeric human/mouse and mouse subclass immunoglobulin Gs. Mol Immunol 30: 741-748.    

11. Potter M (1983) Structural correlates of immunoglobulin diversity. Surv Immunol Res 2: 27-42.

12. Stanley P, Schachter H, Taniguchi N (2009) N-Glycans. In: Varki A, Cummings RD, Esko JD et al., editors. Essentials of Glycobiology. 2nd ed. Cold Spring Harbor (NY).

13. Wright A, Tao MH, Kabat EA, et al. (1991) Antibody variable region glycosylation: position effects on antigen binding and carbohydrate structure. EMBO J 10: 2717-2723.

14. Guhr T, Bloem J, Derksen NI, et al. (2011) 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.    

15. Radcliffe CM, Arnold JN, Suter DM, et al. (2007) Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J Biol Chem 282: 7405-7415.

16. Bruhns P, Iannascoli B, England P, et al. (2009) Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 113: 3716-3725.    

17. Boesch AW, Brown EP, Cheng HD, et al. (2014) Highly parallel characterization of IgG Fc binding interactions. MAbs 6: 915-927.    

18. Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7: 715-725.    

19. Einarsdottir HK, Selman MH, Kapur R, et al. (2013) Comparison of the Fc glycosylation of fetal and maternal immunoglobulin G. Glycoconj J 30: 147-157.    

20. Vidarsson G, Dekkers G, Rispens T (2014) IgG subclasses and allotypes: from structure to effector functions. Front Immunol 5: 520.

21. Carroll MC (1998) The role of complement and complement receptors in induction and regulation of immunity. Annu Rev Immunol 16: 545-568.    

22. van de Geijn FE, Wuhrer M, Selman MH, 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: R193.    

23. Nimmerjahn F, Ravetch JV (2012) Translating basic mechanisms of IgG effector activity into next generation cancer therapies. Cancer Immun 12: 13.

24. Negrini S, Pappalardo F, Murdaca G, et al. (2016) The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med, 1-11.

25. Elkon K, Casali P (2008) Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 4: 491-498.    

26. Krapp S, Mimura Y, Jefferis R, et al. (2003) Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity. J Mol Biol 325: 979-989.    

27. Fickentscher C, Magorivska I, Janko C, et al. (2015) The Pathogenicity of Anti-beta2GP1-IgG Autoantibodies Depends on Fc Glycosylation. J Immunol Res 2015: 638129.

28. Schur PH, Rosen F, Norman ME (1979) Immunoglobulin subclasses in normal children. Pediatr Res 13: 181-183.    

29. French MA, Harrison G (1984) Serum IgG subclass concentrations in healthy adults: a study using monoclonal antisera. Clin Exp Immunol 56: 473-475.

30. Arvieux J, Roussel B, Ponard D, et al. (1994) IgG2 subclass restriction of anti-beta 2 glycoprotein 1 antibodies in autoimmune patients. Clin Exp Immunol 95: 310-315.

31. Samarkos M, Davies KA, Gordon C, et al. (2001) IgG subclass distribution of antibodies against beta(2)-GP1 and cardiolipin in patients with systemic lupus erythematosus and primary antiphospholipid syndrome, and their clinical associations. Rheumatology (Oxford) 40: 1026-1032.    

32. Guerin J, Casey E, Feighery C, et al. (1999) Anti-Beta 2-glycoprotein I antibody isotype and IgG subclass in antiphospholipid syndrome patients. Autoimmunity 31: 109-116.    

33. Ambrozic A, Avicin T, Ichikawa K, et al. (2002) Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis. Int Immunol 14: 823-830.    

34. 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: 452-457.    

35. Matsumoto A, Shikata K, Takeuchi F, et al. (2000) Autoantibody activity of IgG rheumatoid factor increases with decreasing levels of galactosylation and sialylation. J Biochem 128: 621-628.    

36. Rombouts Y, Ewing E, van de Stadt LA, et al. (2015) Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis 74: 234-241.

37. Malhotra R, Wormald MR, Rudd PM, et al. (1995) Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat Med 1: 237-243.    

38. Gindzienska-Sieskiewicz E, Radziejewska I, Domyslawska I, et al. (2016) Changes of glycosylation of IgG in rheumatoid arthritis patients treated with methotrexate. Adv Med Sci 61: 193-197.    

39. Harre U, Lang SC, Pfeifle R, et al. (2015) Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 6: 6651.    

40. Tomana M, Schrohenloher RE, Reveille JD, et al. (1992) 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.    

41. Sjowall C, Zapf J, von Lohneysen S, et al. (2015) Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus. Lupus 24: 569-581.    

42. Vuckovic F, Kristic J, Gudelj I, et al. (2015) Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome. Arthritis Rheumatol 67: 2978-2989.    

43. Karsten CM, Pandey MK, Figge J, et al. (2012) Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcgammaRIIB and dectin-1. Nat Med 18: 1401-1406.    

44. Quast I, Keller CW, Maurer MA, et al. (2015) Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J Clin Invest 125: 4160-4170.    

45. Magorivska I, Munoz 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: 110-117.    

46. Elenitsas R, Abell E, Lee YY, et al. (1990) Comparison of IgG subclass autoantibodies in patients with systemic lupus erythematosus and subacute cutaneous lupus erythematosus. J Dermatol Sci 1: 207-215.    

47. Bijl M, Dijstelbloem HM, Oost WW, et al. (2002) IgG subclass distribution of autoantibodies differs between renal and extra-renal relapses in patients with systemic lupus erythematosus. Rheumatology (Oxford) 41: 62-67.

48. Harper L, Savage CO (2000) Pathogenesis of ANCA-associated systemic vasculitis. J Pathol 190: 349-359.

49. Porges AJ, Redecha PB, Kimberly WT, et al. (1994) Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol 153: 1271-1280.

50. Kocher M, Edberg JC, Fleit HB, et al. (1998) Antineutrophil cytoplasmic antibodies preferentially engage Fc gammaRIIIb on human neutrophils. J Immunol 161: 6909-6914.

51. Holland M, Takada K, Okumoto T, et al. (2002) Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis. Clin Exp Immunol 129: 183-190.    

52. Jayne DRW, Weetman AP, Lockwood CM (1991) Igg Subclass Distribution of Autoantibodies to Neutrophil Cytoplasmic Antigens in Systemic Vasculitis. Clin Exp Immunol 84: 476-481.

53. Arnold JN, Wormald MR, Suter DM, et al. (2005) Human serum IgM glycosylation: identification of glycoforms that can bind to mannan-binding lectin. J Biol Chem 280: 29080-29087.    

54. Hiatt A (2014) Designed IgM from glycoengineering. Proc Natl Acad Sci U S A 111: 6124-6125.    

55. Breen LD, Pucic-Bakovic M, Vuckovic F, et al. (2016) IgG and IgM glycosylation patterns in patients undergoing image-guided tumor ablation. Biochim Biophys Acta 1860: 1786-1794.    

56. Colucci M, Stockmann H, Butera A, et al. (2015) Sialylation of N-linked glycans influences the immunomodulatory effects of IgM on T cells. J Immunol 194: 151-157.    

57. Mestecky J, Moro B, Underdown BJ (1999) Mucosal immunoglobulins. Mucosal Immunology. 2nd ed. San Diego: Academic Press. pp. 133-152

58. Mattu TS, Pleass RJ, Willis AC, et al. (1998) The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fcalpha receptor interactions. J Biol Chem 273: 2260-2272.    

59. Pierce-Cretel A, Pamblanco M, Strecker G, et al. (1981) Heterogeneity of the glycans O-glycosidically linked to the hinge region of secretory immunoglobulins from human milk. Eur J Biochem 114: 169-178.

60. Pierce-Cretel A, Decottignies JP, Wieruszeski JM, et al. (1989) Primary structure of twenty three neutral and monosialylated oligosaccharides O-glycosidically linked to the human secretory immunoglobulin A hinge region determined by a combination of permethylation analysis and 400-MHz 1H-NMR spectroscopy. Eur J Biochem 182: 457-476.    

61. Kraft DM, McKee D, Scott C (1998) Henoch-Schonlein purpura: a review. Am Fam Physician 58: 405-408, 411.

62. Audemard-Verger A, Pillebout E, Guillevin L, et al. (2015) IgA vasculitis (Henoch-Shonlein purpura) in adults: Diagnostic and therapeutic aspects. Autoimmun Rev 14: 579-585.    

63. Kerr MA (1990) The structure and function of human IgA. Biochem J 271: 285-296.    

64. Davin JC, Coppo R (2014) Henoch-Schonlein purpura nephritis in children. Nat Rev Nephrol 10: 563-573.    

65. Zickerman AM, Allen AC, Talwar V, et al. (2000) IgA myeloma presenting as Henoch-Schonlein purpura with nephritis. Am J Kidney Dis 36: E19.

66. Van Der Helm-Van Mil AH, Smith AC, Pouria S, et al. (2003) Immunoglobulin A multiple myeloma presenting with Henoch-Schonlein purpura associated with reduced sialylation of IgA1. Br J Haematol 122: 915-917.    

67. Shihabi ZK (2006) Cryoglobulins: an important but neglected clinical test. Ann Clin Lab Sci 36: 395-408.

68. Muller RB, Vogt B, Winkler S, et al. (2012) Detection of low level cryoglobulins by flow cytometry. Cytometry A 81: 883-887.

69. Kuroki A, Kuroda Y, Kikuchi S, et al. (2002) Level of galactosylation determines cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor. Blood 99: 2922-2928.    

70. Otani M, Kuroki A, Kikuchi S, et al. (2012) Sialylation determines the nephritogenicity of IgG3 cryoglobulins. J Am Soc Nephrol 23: 1869-1878.    

71. Brouet JC, Clauvel JP, Danon F, et al. (1974) Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 57: 775-788.

72. Zinneman HH, Levi D, Seal US (1968) On the nature of cryoglobulins. J Immunol 100: 594-603.

Copyright Info: © 2016, Martin Herrmann, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved