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Heterogeneity of Aberrant O-Glycosylation of IgA1 in IgA Nephropathy

  • Jan NovakEmail author
  • Kazuo Takahashi
  • Hitoshi Suzuki
  • Colin Reily
  • Tyler Stewart
  • Hiroyuki Ueda
  • Koshi Yamada
  • Zina Moldoveanu
  • M. Colleen Hastings
  • Robert J. Wyatt
  • Jiri Mestecky
  • Milan Raska
  • Bruce A. Julian
  • Matthew B. Renfrow
Chapter

Abstract

IgA nephropathy (IgAN), a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (Gd-IgA1; autoantigen) and anti-glycan autoantibodies deposit in the glomeruli and induce renal injury. Serum IgA1 has three to six clustered O-glycans, some of which may be deficient in galactose and thus expose terminal or sialylated N-acetylgalactosamine. Patients with IgAN usually have elevated serum levels of Gd-IgA1. The mechanisms involved in production of Gd-IgA1 are not fully understood.

Using IgA1-producing cell lines, we have analyzed the heterogeneity of IgA1 O-glycosylation and the corresponding biosynthetic pathways. IgA1 secreted by cells from IgAN patients vs. healthy controls had more galactose-deficient sites and overall more O-glycans. These changes were associated with differential expression/activity of key glycosyltransferases in cells from patients with IgAN vs. controls, elevated for an initiating enzyme N-acetylgalactosaminyl (GalNAc)-transferase 14 and for GalNAc-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1-associated chaperone Cosmc. Involvement of the key enzymes in the production of Gd-IgA1 was confirmed by siRNA knockdown and biochemical approaches. Moreover, expression of these enzymes is affected by some cytokines that further enhance the enzyme imbalance to increase Gd-IgA1 production.

In summary, the production of Gd-IgA1, the key autoantigen in IgAN, by IgA1-secreting cells results from dysregulation of key glycosyltransferases and is augmented by certain cytokines. These findings provide insight into possible approaches for future disease-specific therapy.

Keywords

IgA1 O-glycosylation Galactose deficiency Autoantigen 

Notes

Acknowledgments

This review is dedicated to our late colleague, Dr. Milan Tomana, a pioneer in the studies of IgA glycosylation and the abnormalities associated with IgAN. The authors also thank all coworkers and collaborators who have participated in various aspects of these studies. The authors have been supported in part by grants DK078244, DK082753, DK099228, DK105124, DK106341, DK079337, and GM098539 from the National Institutes of Health and a gift from the IGA Nephropathy Foundation of America.

References

  1. 1.
    Berger J, Hinglais N. Les dépôts intercapillaires d’IgA-IgG (intercapillary deposits of IgA-IgG). J Urol Nephrol. 1968;74:694–5.Google Scholar
  2. 2.
    D’Amico G, Colasanti G, Barbiano di Belgioioso G, Fellin G, Ragni A, Egidi F, et al. Long-term follow-up of IgA mesangial nephropathy: clinico-histological study in 374 patients. Semin Nephrol. 1987;7(4):355–8.PubMedGoogle Scholar
  3. 3.
    Julian BA, Waldo FB, Rifai A, Mestecky J. IgA nephropathy, the most common glomerulonephritis worldwide. A neglected disease in the United States? Am J Med. 1988;84:129–32.PubMedCrossRefGoogle Scholar
  4. 4.
    D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol. 2004;24(3):179–96.PubMedCrossRefGoogle Scholar
  5. 5.
    Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Beerman I, Novak J, Wyatt RJ, Julian BA, Gharavi AG. Genetics of IgA nephropathy. Nat Clin Pract Nephrol. 2007;3:325–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Kiryluk K, Julian BA, Wyatt RJ, Scolari F, Zhang H, Novak J, et al. Genetic studies of IgA nephropathy: past, present, and future. Pediatr Nephrol. 2010;25(11):2257–68.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Kiryluk K, Li Y, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, Eitner F, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet. 2012;8(6):e1002765.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kiryluk K, Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest. 2014;124(6):2325–32.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Julian BA, Quiggins PA, Thompson JS, Woodford SY, Gleason K, Wyatt RJ. Familial IgA nephropathy. Evidence of an inherited mechanism of disease. N Engl J Med. 1985;312:202–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43:321–7.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014;46(11):1187–96.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Julian BA, Suzuki H, Suzuki Y, Tomino Y, Spasovski G, Novak J. Sources of urinary proteins and their analysis by urinary proteomics for the detection of biomarkers of disease. Proteomics Clin Appl. 2009;3(9):1029–43.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Jennette JC. The immunohistology of IgA nephropathy. Am J Kidney Dis. 1988;12(5):348–52.PubMedCrossRefGoogle Scholar
  15. 15.
    Allen AC, Bailey EM, Brenchley PEC, Buck KS, Barratt J, Feehally J. Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney Int. 2001;60:969–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Hiki Y, Odani H, Takahashi M, Yasuda Y, Nishimoto A, Iwase H, et al. Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int. 2001;59:1077–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76(5):534–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Coppo R, Troyanov S, Camilla R, Hogg RJ, Cattran DC, Cook HT, et al. The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults. Kidney Int. 2010;77(10):921–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29:829–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Haas M. IgA nephropathy and Henoch-Schoenlein purpura nephritis. In: Jennette JC, Olsen JL, Scwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney. 6th ed. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 423–86.Google Scholar
  21. 21.
    Haas M, Reich HN. Morphologic markers of progressive immunoglobulin A nephropathy. Adv Chronic Kidney Dis. 2012;19(2):107–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1785–94.PubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22:1795–803.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Moura IC, Arcos-Fajardo M, Sadaka C, Leroy V, Benhamou M, Novak J, et al. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol. 2004;15:622–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Novak J, Cook WJ, Julian BA, Mestecky J, Tomana M. IgA nephropathy (IgAN): a similarity in the mechanism of IgA1 deposition in the kidney in humans and mice. J Am Soc Nephrol. 2000;11:478–9A.Google Scholar
  26. 26.
    Novak J, Moldoveanu Z, Julian BA, Raska M, Wyatt RJ, Suzuki Y, et al. Aberrant glycosylation of IgA1 and anti-glycan antibodies in IgA nephropathy: role of mucosal immune system. Adv Otorhinolaryngol. 2011;72:60–3.PubMedGoogle Scholar
  27. 27.
    Novak J, Raskova Kafkova L, Suzuki H, Tomana M, Matousovic K, Brown R, et al. IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured mesangial cells. Nephrol Dial Transplant. 2011;26:3451–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Novak J, Tomana M, Matousovic K, Brown R, Hall S, Novak L, et al. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. 2005;67:504–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Novak J, Vu HL, Novak L, Julian BA, Mestecky J, Tomana M. Interactions of human mesangial cells with IgA and IgA-containing circulating immune complexes. Kidney Int. 2002;62:465–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Tamouza H, Chemouny J, Raskova Kafkova L, Berthelot L, Flamant M, Demion M, et al. IgA1 immune complex-mediated activation of MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int. 2012;82:1284–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. 1999;104:73–81.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Yanagihara T, Brown R, Hall S, Moldoveanu Z, Goepfert A, Julian BA, et al. In vitro-formed immune complexes containing galactose-deficient IgA1 stimulate proliferation of mesangial cells. Results Immunol. 2012;2:166–72.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bene MC, Faure GC. Mesangial IgA in IgA nephropathy arises from the mucosa. Am J Kidney Dis. 1988;12:406–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Bene MC, Hurault De Ligny B, Kessler M, Faure GC. Confirmation of tonsillar anomalies in IgA nephropathy: a multicenter study. Nephron. 1991;58(4):425–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int. 2012;81(9):833–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Smith AC, Molyneux K, Feehally J, Barratt J. O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J Am Soc Nephrol. 2006;17(12):3520–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Putnam FW. Structure of the human IgA subclasses and allotypes. Protides Biol Fluids. 1989;36:27–37.Google Scholar
  38. 38.
    Frangione B, Wolfenstein-Todel C. Partial duplication in the “hinge” region of IgA1 myeloma proteins. Proc Natl Acad Sci U S A. 1972;69:3673–6.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Tarelli E, Smith AC, Hendry BM, Challacombe SJ, Pouria S. Human serum IgA1 is substituted with up to six O-glycans as shown by matrix assisted laser desorption ionisation time-of-flight mass spectrometry. Carbohydr Res. 2004;339(13):2329–35.PubMedCrossRefGoogle Scholar
  40. 40.
    Takahashi K, Smith AD, Poulsen K, Kilian M, Julian BA, Mestecky J, et al. Identification of structural isomers in IgA1 hinge-region O-glycosylation using high-resolution mass spectrometry. J Proteome Res. 2012;11:692–702.PubMedCrossRefGoogle Scholar
  41. 41.
    Takahashi K, Wall SB, Suzuki H, Smith AD, Hall S, Poulsen K, et al. Clustered O-glycans of IgA1: defining macro- and micro-heterogeneity by use of electron capture/transfer dissociation. Mol Cell Proteomics. 2010;9:2545–57.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Franc V, Rehulka P, Raus M, Stulik J, Novak J, Renfrow MB, et al. Elucidating heterogeneity of IgA1 hinge-region O-glycosylation by use of MALDI-TOF/TOF mass spectrometry: role of cysteine alkylation during sample processing. J Proteomics. 2013;92:299–312.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Tomana M, Niedermeier W, Mestecky J, Hammack WJ. The carbohydrate composition of human myeloma IgA. Immunochemistry. 1972;9:933–40.PubMedCrossRefGoogle Scholar
  44. 44.
    Tomana M, Niedermeier W, Mestecky J, Skvaril F. The differences in carbohydrate composition between the subclasses of IgA immunoglobulins. Immunochemistry. 1976;13:325–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Mattu TS, Pleass RJ, Willis AC, Kilian M, Wormald MR, Lellouch AC, et al. The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fcα receptor interactions. J Biol Chem. 1998;273:2260–72.PubMedCrossRefGoogle Scholar
  46. 46.
    Gomes MM, Wall SB, Takahashi K, Novak J, Renfrow MB, Herr AB. Analysis of IgA1 N-glycosylation and its contribution to Fc Renfrow MB, Herr AB. Analysis of IgA1. A1 sylatiGoogle Scholar
  47. 47.
    Field MC, Amatayakul-Chantler S, Rademacher TW, Rudd PM, Dwek RA. Structural analysis of the N-glycans from human immunoglobulin A1: comparison of normal human serum immunoglobulin A1 with that isolated from patients with rheumatoid arthritis. Biochem J. 1994;299(Pt 1):261–75.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Niedermeier W, Tomana M, Mestecky J. The carbohydrate composition of J chain from human serum and secretory IgA. Biochim Biophys Acta. 1972;257(2):527–30.PubMedCrossRefGoogle Scholar
  49. 49.
    Mestecky J, Schrohenloher RE, Kulhavy R, Wright GP, Tomana M. Site of J chain attachment to human polymeric IgA. Proc Natl Acad Sci U S A. 1974;71(2):544–8.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Zikan J, Mestecky J, Kulhavy R, Bennett JC. The stoichiometry of J chain in human secretory dimeric IgA. Mol Immunol. 1986;23(5):541–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Novak J, Mestecky J. IgA immune-complex. In: Lai KN, editor. Recent advances in IgA nephropathy. Hong Kong: Imperial College Press/The World Scientific Publisher; 2009. p. 177–91.CrossRefGoogle Scholar
  52. 52.
    Mestecky J, Moro I, Kerr MA, Woof JM. Mucosal immunoglobulins. In: Mestecky J, Bienenstock J, Lamm ME, Mayer L, McGhee JR, Strober W, editors. Mucosal immunology. 3rd ed. Amsterdam: Elsevier Academic Press; 2005. p. 153–81.CrossRefGoogle Scholar
  53. 53.
    Field MC, Dwek RA, Edge CJ, Rademacher TW. O-linked oligosaccharides from human serum immunoglobulin A1. Biochem Soc Trans. 1989;17:1034–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Moore JS, Kulhavy R, Tomana M, Moldoveanu Z, Suzuki H, Brown R, et al. Reactivities of N-acetylgalactosamine-specific lectins with human IgA1 proteins. Mol Immunol. 2007;44:2598–604.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Novak J, Tomana M, Kilian M, Coward L, Kulhavy R, Barnes S, et al. Heterogeneity of O-glycosylation in the hinge region of human IgA1. Mol Immunol. 2000;37:1047–56.PubMedCrossRefGoogle Scholar
  56. 56.
    Renfrow MB, Cooper HJ, Tomana M, Kulhavy R, Hiki Y, Toma K, et al. Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation Fourier transform-ion cyclotron resonance mass spectrometry. J Biol Chem. 2005;280:19136–45.PubMedCrossRefGoogle Scholar
  57. 57.
    Renfrow MB, MacKay CL, Chalmers MJ, Julian BA, Mestecky J, Kilian M, et al. Analysis of O-glycan heterogeneity in IgA1 myeloma proteins by fourier transform ion cyclotron resonance mass spectrometry: implications for IgA nephropathy. Anal Bioanal Chem. 2007;389:1397–407.PubMedCrossRefGoogle Scholar
  58. 58.
    Iwasaki H, Zhang Y, Tachibana K, Gotoh M, Kikuchi N, Kwon YD, et al. Initiation of O-glycan synthesis in IgA1 hinge region is determined by a single enzyme, UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 2. J Biol Chem. 2003;278(8):5613–21.PubMedCrossRefGoogle Scholar
  59. 59.
    Horynova M, Takahashi K, Hall S, Renfrow MB, Novak J, Raska M. Production of N-acetylgalactosaminyl-transferase 2 (GalNAc-T2) fused with secretory signal Igκ in insect cells. Protein Expr Purif. 2012;81(2):175–80.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wandall HH, Irazoqui F, Tarp MA, Bennett EP, Mandel U, Takeuchi H, et al. The lectin domains of polypeptide GalNAc-transferases exhibit carbohydrate-binding specificity for GalNAc: lectin binding to GalNAc-glycopeptide substrates is required for high density GalNAc-O-glycosylation. Glycobiology. 2007;17(4):374–87.PubMedCrossRefGoogle Scholar
  61. 61.
    Stuchlova Horynova M, Raska M, Clausen H, Novak J. Aberrant O-glycosylation and anti-glycan antibodies in an autoimmune disease IgA nephropathy and breast adenocarcinoma. Cell Mol Life Sci. 2013;70:829–39.PubMedCrossRefGoogle Scholar
  62. 62.
    Ju T, Brewer K, D’Souza A, Cummings RD, Canfield WM. Cloning and expression of human core 1 β1,3-galactosyltransferase. J Biol Chem. 2002;277(1):178–86.PubMedCrossRefGoogle Scholar
  63. 63.
    Ju T, Cummings RD. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 β3-galactosyltransferase. Proc Natl Acad Sci U S A. 2002;99(26):16613–8.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Ju T, Cummings RD. Protein glycosylation: chaperone mutation in Tn syndrome. Nature. 2005;437(7063):1252.PubMedCrossRefGoogle Scholar
  65. 65.
    Ju T, Otto VI, Cummings RD. The Tn antigen-structural simplicity and biological complexity. Angew Chem Int Ed Engl. 2011;50(8):1770–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Raska M, Moldoveanu Z, Suzuki H, Brown R, Kulhavy R, Hall S, et al. Identification and characterization of CMP-NeuAc: GalNAc-IgA1 α2,6-sialyltransferase in IgA1-producing cells. J Mol Biol. 2007;369:69–78.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Stuchlova Horynova M, Vrablikova A, Stewart TJ, Takahashi K, Czernekova L, Yamada K, et al. N-Acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy. Nephrol Dial Transplant. 2015;30(2):234–8.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Andre PM, Le Pogamp P, Chevet D. Impairment of jacalin binding to serum IgA in IgA nephropathy. J Clin Lab Anal. 1990;4:115–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Mestecky J, Tomana M, Crowley-Nowick PA, Moldoveanu Z, Julian BA, Jackson S. Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib Nephrol. 1993;104:172–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Allen AC, Harper SJ, Feehally J. Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy. Clin Exp Immunol. 1995;100:470–4.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Moldoveanu Z, Wyatt RJ, Lee J, Tomana M, Julian BA, Mestecky J, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007;71:1148–54.PubMedCrossRefGoogle Scholar
  72. 72.
    Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J. Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int. 1997;52:509–16.PubMedCrossRefGoogle Scholar
  73. 73.
    Shimozato S, Hiki Y, Odani H, Takahashi K, Yamamoto K, Sugiyama S. Serum under-galactosylated IgA1 is increased in Japanese patients with IgA nephropathy. Nephrol Dial Transplant. 2008;23:1931–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Wada Y, Tajiri M, Ohshima S. Quantitation of saccharide compositions of O-glycans by mass spectrometry of glycopeptides and its application to rheumatoid arthritis. J Proteome Res. 2010;9(3):1367–73.PubMedCrossRefGoogle Scholar
  75. 75.
    Conley ME, Delacroix DL. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defence? Ann Intern Med. 1987;106:892–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Mestecky J, Russell MW, Jackson S, Brown TA. The human IgA system: a reassessment. Clin Immunol Immunopathol. 1986;40(1):105–14.PubMedCrossRefGoogle Scholar
  77. 77.
    Mestecky J, Lue C, Tarkowski A, Ladjeva I, Peterman JH, Moldoveanu Z, et al. Comparative studies of the biological properties of human IgA subclasses. Protides Biol Fluids. 1989;36:173–82.Google Scholar
  78. 78.
    Bene MC, de Ligny BH, Kessler M, Foliguet B, Faure GC. Tonsils in IgA nephropathy. Contrib Nephrol. 1993;104:153–61.PubMedCrossRefGoogle Scholar
  79. 79.
    Harper SJ, Allen AC, Bene MC, Pringle JH, Faure G, Lauder I, et al. Increased dimeric IgA-producing B cells in tonsils in IgA nephropathy determined by in situ hybridization for J chain mRNA. Clin Exp Immunol. 1995;101(3):442–8.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Horie A, Hiki Y, Odani H, Yasuda Y, Takahashi M, Kato M, et al. IgA1 molecules produced by tonsillar lymphocytes are under-O-glycosylated in IgA nephropathy. Am J Kidney Dis. 2003;42(3):486–96.PubMedCrossRefGoogle Scholar
  81. 81.
    Itoh A, Iwase H, Takatani T, Nakamura I, Hayashi M, Oba K, et al. Tonsillar IgA1 as a possible source of hypoglycosylated IgA1 in the serum of IgA nephropathy patients. Nephrol Dial Transplant. 2003;18(6):1108–14.PubMedCrossRefGoogle Scholar
  82. 82.
    Miura N, Imai H, Kikuchi S, Hayashi S, Endoh M, Kawamura T, et al. Tonsillectomy and steroid pulse (TSP) therapy for patients with IgA nephropathy: a nationwide survey of TSP therapy in Japan and an analysis of the predictive factors for resistance to TSP therapy. Clin Exp Nephrol. 2009;13(5):460–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Nakata J, Suzuki Y, Suzuki H, Sato D, Kano T, Yanagawa H, et al. Changes in nephritogenic serum galactose-deficient IgA1 in IgA nephropathy following tonsillectomy and steroid therapy. PLoS One. 2014;9(2):e89707.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Baenziger JU, Fiete D. Galactose and N-acetylgalactosamine-specific endocytosis of glycopeptides by isolated rat hepatocytes. Cell. 1980;22:611–20.PubMedCrossRefGoogle Scholar
  85. 85.
    Baenziger JU, Maynard Y. Human hepatic lectin. Physicochemical properties and specificity. J Biol Chem. 1980;255:4607–13.PubMedGoogle Scholar
  86. 86.
    Baenziger JU, Fiete D. Recycling of hepatocyte asialoglycoprotein receptor does not require delivery of ligand to lysosomes. J Biol Chem. 1982;257:6007–9.PubMedGoogle Scholar
  87. 87.
    Moldoveanu Z, Epps JM, Thorpe SR, Mestecky J. The sites of catabolism of murine monomeric IgA. J Immunol. 1988;141:208–13.PubMedGoogle Scholar
  88. 88.
    Moldoveanu Z, Moro I, Radl J, Thorpe SR, Komiyama K, Mestecky J. Site of catabolism of autologous and heterologous IgA in non-human primates. Scand J Immunol. 1990;32:577–83.PubMedCrossRefGoogle Scholar
  89. 89.
    Phillips JO, Russell MW, Brown TA, Mestecky J. Selective hepatobiliary transport of human polymeric IgA in mice. Mol Immunol. 1984;21:907–14.PubMedCrossRefGoogle Scholar
  90. 90.
    Phillips JO, Komiyama K, Epps JM, Russell MW, Mestecky J. Role of hepatocytes in the uptake of IgA and IgA-containing immune complexes in mice. Mol Immunol. 1988;25:873–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Tomana M, Phillips JO, Kulhavy R, Mestecky J. Carbohydrate-mediated clearance of secretory IgA from the circulation. Mol Immunol. 1985;22:887–92.PubMedCrossRefGoogle Scholar
  92. 92.
    Tomana M, Kulhavy R, Mestecky J. Receptor-mediated binding and uptake of immunoglobulin A by human liver. Gastroenterology. 1988;94:887–92.Google Scholar
  93. 93.
    Kiryluk K, Gharavi AG, Izzi C, Scolari F. IgA nephropathy – the case for a genetic basis becomes stronger. Nephrol Dial Transplant. 2010;25(2):336–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Kiryluk K, Novak J, Gharavi AG. Pathogenesis of immunoglobulin a nephropathy: recent insight from genetic studies. Annu Rev Med. 2013;64:339–56.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. 2008;19(5):1008–14.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hastings MC, Moldoveanu Z, Julian BA, Novak J, Sanders JT, McGlothan KR, et al. Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol. 2010;5(11):2069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kiryluk K, Moldoveanu Z, Sanders JT, Eison TM, Suzuki H, Julian BA, et al. Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis. Kidney Int. 2011;80:79–87.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 2012;82(7):790–6.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Mestecky J, Hashim OH, Tomana M. Alterations in the IgA carbohydrate chains influence the cellular distribution of IgA1. Contrib Nephrol. 1995;111:66–72.PubMedCrossRefGoogle Scholar
  100. 100.
    Mestecky J, Tomana M, Czerkinsky C, Tarkowski A, Matsuda S, Waldo FB, et al. IgA-associated renal diseases: immunochemical studies of IgA1 proteins, circulating immune complexes, and cellular interactions. Semin Nephrol. 1987;7:332–5.PubMedGoogle Scholar
  101. 101.
    Lau KK, Gaber LW, Delos Santos NM, Fisher KA, Grimes SJ, Wyatt RJ. Pediatric IgA nephropathy: clinical features at presentation and outcome for African-Americans and Caucasians. Clin Nephrol. 2004;62(3):167–72.PubMedCrossRefGoogle Scholar
  102. 102.
    Leung JCK, Poon PYK, Lai KN. Increased sialylation of polymeric immunoglobulin A1: mechanism of selective glomerular deposition in immunoglobulin A nephropathy? J Lab Clin Med. 1999;133:152–60.PubMedCrossRefGoogle Scholar
  103. 103.
    Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest. 2008;118:629–39.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C, et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol. 2012;23:1579–87.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Camilla R, Suzuki H, Dapra V, Loiacono E, Peruzzi L, Amore A, et al. Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol. 2011;6(8):1903–11.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Hiki Y, Horii A, Iwase H, Tanaka A, Toda Y, Hotta K, et al. O-linked oligosaccharide on IgA1 hinge region in IgA nephropathy. Fundamental study for precise structure and possible role. Contrib Nephrol. 1995;111:73–84.PubMedCrossRefGoogle Scholar
  107. 107.
    Iwase H, Tanaka A, Hiki Y, Kokubo T, Ishii-Karakasa I, Nishikido J, et al. Application of matrix-assisted laser desorption ionization time-of-flight mass spectrometry to the analysis of glycopeptide-containing multiple O-linked oligosaccharides. J Chromatogr Biomed Sci Appl. 1998;709(1):145–9.CrossRefGoogle Scholar
  108. 108.
    Iwase H, Tanaka A, Hiki Y, Kokubo T, Karakasa-Ishii I, Kobayashi Y, et al. Estimation of the number of O-linked oligosaccharides per heavy chain of human IgA1 by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis of the hinge glycopeptide. J Biochem. 1996;120:393–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Odani H, Hiki Y, Takahashi M, Nishimoto A, Yasuda Y, Iwase H, et al. Direct evidence for decreased sialylation and galactosylation of human serum IgA1 Fc O-glycosylated hinge peptides in IgA nephropathy by mass spectrometry. Biochem Biophys Res Commun. 2000;271:268–74.PubMedCrossRefGoogle Scholar
  110. 110.
    Odani H, Yamamoto K, Iwayama S, Iwase H, Takasaki A, Takahashi K, et al. Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry. J Nephrol. 2010;23(1):70–6.PubMedGoogle Scholar
  111. 111.
    Takahashi K, Hiki Y, Odani H, Shimozato S, Iwase H, Sugiyama S, et al. Structural analyses of O-glycan sugar chains on IgA1 hinge region using SELDI-TOFMS with various lectins. Biochem Biophys Res Commun. 2006;350(3):580–7.PubMedCrossRefGoogle Scholar
  112. 112.
    Wada Y, Dell A, Haslam SM, Tissot B, Canis K, Azadi P, et al. Comparison of methods for profiling O-glycosylation: human proteome organisation human disease glycomics/proteome initiative multi-institutional study of IgA1. Mol Cell Proteomics. 2010;9(4):719–27.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Hastings MC, Moldoveanu Z, Suzuki H, Berthoux F, Julian BA, Sanders JT, et al. Biomarkers in IgA nephropathy: relationship to pathogenetic hits. Expert Opin Med Diagn. 2013;7(6):615–27.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Mestecky J, Raska M, Julian BA, Gharavi AG, Renfrow MB, Moldoveanu Z, et al. IgA nephropathy: molecular mechanisms of the disease. Annu Rev Pathol. 2013;8:217–40.PubMedCrossRefGoogle Scholar
  115. 115.
    Mestecky J, Tomana M, Moldoveanu Z, Julian BA, Suzuki H, Matousovic K, et al. The role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy. Kidney Blood Press Res. 2008;31:29–37.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Novak J, Julian BA, Mestecky J, Renfrow MB. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin Immunopathol. 2012;34(3):365–82.PubMedCrossRefGoogle Scholar
  117. 117.
    Suzuki H, Raska M, Yamada K, Moldoveanu Z, Julian BA, Wyatt RJ, et al. Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes. J Biol Chem. 2014;289(8):5330–9.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Takahashi K, Raska M, Stuchlova Horynova M, Hall SD, Poulsen K, Kilian M, et al. Enzymatic sialylation of IgA1 O-glycans: implications for studies of IgA nephropathy. PLoS One. 2014;9(2):e99026.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Takahashi K, Suzuki H, Yamada K, Hall S, Moldoveanu Z, Poulsen K, et al. Molecular characterization of IgA1 secreted by IgA1-producing cell lines from patients with IgA nephropathy. J Am Soc Nephrol. 2012;23:853A.Google Scholar
  120. 120.
    Raska M, Yamada K, Horynova M, Takahashi K, Suzuki H, Moldoveanu Z, et al. Role of GalNAc-transferases in the synthesis of aberrant IgA1 O-glycans in IgA nephropathy. J Am Soc Nephrol. 2011;22:625A.Google Scholar
  121. 121.
    Yamada K, Huang ZQ, Suzuki H, Raska M, Moldoveanu Z, Suzuki Y, et al. IL-6 increases production of galactose-deficient IgA1 by IgA1-secreting cells from IgA nephropathy patients through STAT3 signaling pathways. J Am Soc Nephrol. 2012;23:389A.Google Scholar
  122. 122.
    Reily C, Ueda H, Huang ZQ, Mestecky J, Julian BA, Willey CD, et al. Cellular signaling and production of galactose-deficient IgA1 in IgA nephropathy, an autoimmune disease. J Immunol Res. 2014;2014:197548.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    McCarthy DD, Kujawa J, Wilson C, Papandile A, Poreci U, Porfilio EA, et al. Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J Clin Invest. 2011;121(10):3991–4002.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V et al. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26(7):1503–12.Google Scholar
  125. 125.
    Boehm MK, Woof JM, Kerr MA, Perkins SJ. The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: a study by X-ray and neutron solution scattering and homology modelling. J Mol Biol. 1999;286(5):1421–47.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Jan Novak
    • 1
    Email author
  • Kazuo Takahashi
    • 1
    • 2
  • Hitoshi Suzuki
    • 1
    • 3
  • Colin Reily
    • 1
  • Tyler Stewart
    • 1
  • Hiroyuki Ueda
    • 1
  • Koshi Yamada
    • 1
    • 3
  • Zina Moldoveanu
    • 1
  • M. Colleen Hastings
    • 4
  • Robert J. Wyatt
    • 4
  • Jiri Mestecky
    • 1
  • Milan Raska
    • 1
    • 5
  • Bruce A. Julian
    • 1
  • Matthew B. Renfrow
    • 1
  1. 1.Department of MicrobiologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.School of MedicineFujita Health UniversityToyoakeJapan
  3. 3.Juntendo University Faculty of MedicineTokyoJapan
  4. 4.University of Tennessee Health Science CenterMemphisUSA
  5. 5.Faculty of Medicine and DentistryPalacky University in OlomoucOlomoucCzech Republic

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