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Immunoglobulin A nephropathy: a pathophysiology view

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Abstract

Background and aim

IgA nephropathy is one of the leading causes of primary glomerulonephritis worldwide and an important etiology of renal disease in young adults. IgA nephropathy is considered an immune complex-mediated disease.

Methods

This review article summarizes recent evidence on the pathophysiology of IgA nephropathy.

Results

Current studies indicate an ordered sequence of multi-hits as fundamental to disease occurrence. Altered glycan structures in the hinge region of the heavy chains of IgA1 molecules act as auto-antigens, potentially triggering the production of glycan-specific autoantibodies. Recognition of novel epitopes by IgA and IgG antibodies leads to the formation of immune complexes galactose deficient-IgA1/anti-glycan IgG or IgA. Immune complexes of IgA combined with FcαRI/CD89 have also been implicated in disease exacerbation. These nephritogenic immune complexes are formed in the circulation and deposited in renal mesangium. Deposited immune complexes ultimately induce glomerular injury, through the release of pro-inflammatory cytokines, secretion of chemokines and the resultant migration of macrophages into the kidney. The TfR1/CD71 receptor has a pivotal role in mesangial cells. New signaling intracellular mechanisms have also been described.

Conclusion

The knowledge of the whole pathophysiology of this disease could provide the rational bases for developing novel approaches for diagnosis, for monitoring disease activity, and for disease-specific treatment.

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Article 11 February 2016

Kar Neng Lai, Sydney C. W. Tang, … Richard J. Glassock

References

  1. Coppo R, Troyanov S, Bellur S, Cattran D, Cook HT, Feehally J, Roberts ISD, Morando L, Camilla R, Tesar V, Lunberg S, Gesualdo L, Emma F, Rollino C, Amore A, Praga M, Feriozzi S, Segoloni G, Pani A, Cancarini G, Durlik M, Moggia E, Mazzucco G, Giannakakis C, Honsova E, Sundelin BB, Di Palma AM, Ferrario F, Gutierrez E, Asunis AM, Barratt J, Tardanico R, Perkowska-Ptasinska A. Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments. Kidney Int. 2014;86(4):828–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mestecky J, Raska M, Julian BA, Gharavi AG, Renfrow MB, Moldoveanu Z, Novak L, Matousovic K, Novak J. IgA nephropathy: molecular mechanisms of the disease. Annu Rev Pathol. 2013;8:217–40.

    Article  CAS  PubMed  Google Scholar 

  3. Levy M, Berger J. Worldwide perspective of IgA nephropathy. Am J Kidney Dis. 1988;12(5):340–7.

    Article  CAS  PubMed  Google Scholar 

  4. Wyatt RJ, Kritchevsky SB, Woodford SY, Miller PM, Roy S, Holland NH, Jackson E, Bishof NA. IgA nephropathy: long-term prognosis for pediatric patients. J Pediatr. 1995;127(6):913–9.

    Article  CAS  PubMed  Google Scholar 

  5. Gutiérrez E, Zamora I, Ballarín JA, Arce Y, Jiménez S, Quereda C, Olea T, Martínez-Ara J, Segarra A, Bernis C, García A, Goicoechea M, García de Vinuesa S, Rojas-Rivera J, Praga M. Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol. 2012;23(10):1753–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Lv J, Shi S, Xu D, Zhang H, Troyanov S, Cattran DC, Wang H. Evaluation of the Oxford classification of IgA nephropathy: a systematic review and meta-analysis. Am J Kidney Dis. 2013;62(5):891–9.

    Article  PubMed  Google Scholar 

  7. Moriyama T, Tanaka K, Iwasaki C, Oshima Y, Ochi A, Kataoka H, Itabashi M, Takei T, Uchida K, Nitta K. Prognosis in IgA nephropathy: 30-year analysis of 1,012 patients at a single center in Japan. PLoS One. 2014;9(3):e91756.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Le W, Zeng C-H, Liu Z, Liu D, Yang Q, Lin R-X, Xia Z-K, Fan Z-M, Zhu G, Wu Y, Xu H, Zhai Y, Ding Y, Yang X, Liang S, Chen H, Xu F, Huang Q, Shen H, Wang J, Fogo AB, Liu Z-H. Validation of the Oxford classification of IgA nephropathy for pediatric patients from China. BMC Nephrol. 2012;13(1):158.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Edström Halling S, Söderberg MP, Berg UB. Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification). Nephrol Dial Transplant. 2012;27(2):715–22.

    Article  PubMed  CAS  Google Scholar 

  10. Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. Am J Kidney Dis. 2001;38(4):728–35.

    Article  CAS  PubMed  Google Scholar 

  11. Cattran DC, Coppo R, Cook HT, Feehally J, Roberts ISD, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene H-J, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li L-S, Li PKT, Liu Z-H, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76(5):534–45.

    Article  PubMed  Google Scholar 

  12. Roberts ISD, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D’Agati V, D’Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene H-J, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li L-S, Li PKT, Liu Z-H, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009;76(5):546–56.

    Article  PubMed  Google Scholar 

  13. Vangelista A, Frascà GM, Mondini S, Bonomini V. Idiopathic IgA mesangial nephropathy: immunohistological features. Contrib Nephrol. 1984;40:167–73.

    Article  CAS  PubMed  Google Scholar 

  14. Espinosa M, Ortega R, Gómez-Carrasco JM, López-Rubio F, López-Andreu M, López-Oliva MO, Aljama P. Mesangial C4d deposition: a new prognostic factor in IgA nephropathy. Nephrol Dial Transplant. 2009;24(3):886–91.

    Article  CAS  PubMed  Google Scholar 

  15. Sahin OZ, Yavas H, Taslı F, Gibyeli DG, Ersoy R, Uzum A, Cirit M. Prognostic value of glomerular C4d staining in patients with IgA nephritis. Int J Clin Exp Pathol. 2014;7(6):3299–304.

    PubMed  PubMed Central  Google Scholar 

  16. Espinosa M, Ortega R, Sánchez M, Segarra A, Salcedo MT, Gonza F, Camacho R, Espinosa M, Ortega R, Sa M, Pinedo F, Gutierrez E, Valera A, Leon M, Valdivia MA, Cabrera R, Lo K, Cobo MA, Rodriguez R, Balları J, Arce Y, Garcı B. Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2014;9(4):897–904.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rauterberg EW, Lieberknecht HM, Wingen AM, Ritz E. Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis. Kidney Int. 1987;31(3):820–9.

    Article  CAS  PubMed  Google Scholar 

  18. Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, Stahl GL, Matsushita M, Fujita T, van Kooten C, Daha MR. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17(6):1724–34.

    Article  CAS  PubMed  Google Scholar 

  19. Wyatt RJ, Julian BA. IgA Nephropathy. N Engl J Med. 2013;368(25):2402–14.

    Article  CAS  PubMed  Google Scholar 

  20. Waldherr R, Rambausek M, Duncker WD, Ritz E. Frequency of mesangial IgA deposits in a non-selected autopsy series. Nephrol Dial Transplant. 1989;4(11):943–6.

    CAS  PubMed  Google Scholar 

  21. Suzuki K, Honda K, Tanabe K, Toma H, Nihei H, Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003;63(6):2286–94.

    Article  PubMed  Google Scholar 

  22. Woof JM, Mestecky J. Mucosal immunoglobulins. Immunol Rev. 2005;206:64–82.

    Article  CAS  PubMed  Google Scholar 

  23. Brandtzaeg P, Johansen F-E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev. 2005;206:32–63.

    Article  CAS  PubMed  Google Scholar 

  24. Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal Immunol. 2011;4(6):590–7.

    Article  CAS  PubMed  Google Scholar 

  25. Robert T, Berthelot L, Cambier A, Rondeau E, Monteiro RC. Molecular insights into the pathogenesis of IgA nephropathy. Trends Mol Med. 2015;21(12):762–75.

    Article  CAS  PubMed  Google Scholar 

  26. Bonner A, Almogren A, Furtado PB, Kerr MA, Perkins SJ. The nonplanar secretory IgA2 and near planar secretory IgA1 solution structures rationalize their different mucosal immune responses. J Biol Chem. 2009;284(8):5077–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mathias A, Pais B, Favre L, Benyacoub J, Corth B. Role of secretory IgA in the mucosal sensing of commensal bacteria. Gut Microbes. 2014;5(6):688–95.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Aleyd E, Heineke MH, Van Egmond M. The era of the immunoglobulin A Fc receptor Fc a RI; its function and potential as target in disease. Immunol Rev. 2015;268(1):123–38.

    Article  CAS  PubMed  Google Scholar 

  29. Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30(1):10–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kerr MA. The structure and function of human IgA. Biochem J. 1990;271(2):285–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Novak J, Julian BA, Mestecky J, Renfrow MB. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin. Immunopathol. 2012;34(3):365–82.

    Article  CAS  PubMed  Google Scholar 

  32. Tarelli E, Smith AC, Hendry BM, Challacombe SJ. 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;13(339):2329–35.

    Article  CAS  Google Scholar 

  33. Takahashi K, Smith AD, Poulsen K, Kilian M, Julian BA, Mestecky J, Novak J, Renfrow MB. Naturally occurring structural isomers in serum IgA1 O-glycosylation. J Proteome Res. 2012;11(2):692–702.

    Article  CAS  PubMed  Google Scholar 

  34. Takahashi K, Wall SB, Suzuki H, Smith AD, Hall S, Poulsen K, Kilian M, Mobley JA, Julian BA, Mestecky J, Novak J, Renfrow MB. Clustered O-glycans of IgA1: defining macro- and microheterogeneity by use of electron capture/transfer dissociation. Mol Cell Proteom. 2010;9(11):2545–57.

    Article  CAS  Google Scholar 

  35. Yu H-H, Chu K-H, Yang Y-H, Lee J-H, Wang L-C, Lin Y-T, Chiang B-L. Genetics and immunopathogenesis of IgA nephropathy. Clin Rev Allergy Immunol. 2011;41(2):198–213.

    Article  CAS  PubMed  Google Scholar 

  36. Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, Julian BA, Tomana M, Wyatt RJ, Edberg JC, Alarcón GS, Kimberly RP, Tomino Y, Mestecky J, Novak J. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest. 2008;118(2):629–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hiki Y, Horii A, Iwase H, Tanaka A, Toda Y, Hotta K, Kobayashi Y. O-linked oligosaccharide on IgA1 hinge region in IgA nephropathy. Fundamental study for precise structure and possible role. Contrib Nephrol. 1995;111:73–84.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, Zhao M-H, Zhang Y-K, Li X-M, Wang H-Y. Binding capacity and pathophysiological effects of IgA1 from patients with IgA nephropathy on human glomerular mesangial cells. Clin Exp Immunol. 2004;136(1):168–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Novak J, Tomana M, Matousovic K, Brown R, Hall S, Novak L, Julian BA, Wyatt RJ, Mestecky J. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. 2005;67(2):504–13.

    Article  CAS  PubMed  Google Scholar 

  40. Floege J, Moura IC, Daha MR. New insights into the pathogenesis of IgA nephropathy. Semin Immunopathol. 2014;36(4):431–42.

    Article  CAS  PubMed  Google Scholar 

  41. Lai KN. Pathogenesis of IgA nephropathy. Nat Rev Nephrol. 2012;8(5):275–83.

    Article  CAS  PubMed  Google Scholar 

  42. Coppo R, Amore A, Peruzzi L, Vergano L, Camilla R. Innate immunity and IgA nephropathy. J Nephrol. 2010;23(6):626–32.

    PubMed  Google Scholar 

  43. Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, Chatham WW, Suzuki Y, Wyatt RJ, Moldoveanu Z, Lee JY, Robinson J, Tomana M, Tomino Y, Mestecky J, Novak J. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. 2009;119(6):1668–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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(1):73–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Barratt J, Eitner F, Feehally J, Floege J. Immune complex formation in IgA nephropathy: a case of the ‘right’ antibodies in the ‘wrong’ place at the ‘wrong’ time? Nephrol Dial Transplant. 2009;24(12):3620–3.

    Article  PubMed  Google Scholar 

  46. Schlöndorff D, Banas B. The mesangial cell revisited: no cell is an island. J Am Soc Nephrol. 2009;20(6):1179–87.

    Article  PubMed  CAS  Google Scholar 

  47. Levy M. Familial cases of Berger’s disease and anaphylactoid purpura: more frequent than previously thought. Am J Med. 1989;87(2):246–8.

    Article  CAS  PubMed  Google Scholar 

  48. Scolari F, Amoroso A, Savoldi S, Mazzola G, Prati E, Valzorio B, Viola BF, Nicola B, Movilli E, Sandrini M, Campanini M, Maiorca R. Familial clustering of IgA nephropathy: further evidence in an Italian population. Am J Kidney Dis. 1999;33(5):857–65.

    Article  CAS  PubMed  Google Scholar 

  49. Schena FP, Scivittaro V, Ranieri E. IgA nephropathy: pros and cons for a familial disease. Contrib Nephrol. 1993;104:36–45.

    Article  CAS  PubMed  Google Scholar 

  50. Rambausek M, Hartz G, Waldherr R, Andrassy K, Ritz E. Familial glomerulonephritis. Pediatr Nephrol. 1987;1(3):416–8.

    Article  CAS  PubMed  Google Scholar 

  51. Johnston PA, Brown JS, Braumholtz DA, Davison AM. Clinico-pathological correlations and long-term follow-up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC glomerulonephritis registry. Q J Med. 1992;84(304):619–27.

    CAS  PubMed  Google Scholar 

  52. Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet. 2012;90(1):7–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feehally J, Farrall M, Boland A, Gale DP, Gut I, Heath S, Kumar A, Peden JF, Maxwell PH, Morris DL, Padmanabhan S, Vyse TJ, Zawadzka A, Rees AJ, Lathrop M, Ratcliffe PJ. HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol. 2010;21(10):1791–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu X-Q, Li M, Zhang H, Low H-Q, Wei X, Wang J-Q, Sun L-D, Sim K-S, Li Y, Foo J-N, Wang W, Li Z-J, Yin X-Y, Tang X-Q, Fan L, Chen J, Li R-S, Wan J-X, Liu Z-S, Lou T-Q, Zhu L, Huang X-J, Zhang X-J, Liu Z-H, Liu J-J. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet. 2012;44(2):178–82.

    Article  CAS  Google Scholar 

  55. Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, Sanna-Cherchi S, Men CJ, Julian BA, Wyatt RJ, Novak J, He JC, Wang H, Lv J, Zhu L, Wang W, Wang Z, Yasuno K, Gunel M, Mane S, Umlauf S, Tikhonova I, Beerman I, Savoldi S, Magistroni R, Ghiggeri GM, Bodria M, Lugani F, Ravani P, Ponticelli C, Allegri L, Boscutti G, Frasca G, Amore A, Peruzzi L, Coppo R, Izzi C, Viola BF, Prati E, Salvadori M, Mignani R, Gesualdo L, Bertinetto F, Mesiano P, Amoroso A, Scolari F, Chen N, Zhang H, Lifton RP. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Genet N. HHS public xccess. 2015;46(11):1187–96.

  57. Magistroni R, DAgati VD, Appel GB, Kiryluk K. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int. 2015;89(1):167–75.

    Google Scholar 

  58. Kiryluk K, Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest. 2014;124(6):2325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rabb H. The T cell as a bridge between innate and adaptive immune systems: implications for the kidney. Kidney Int. 2002;61(6):1935–46.

    Article  CAS  PubMed  Google Scholar 

  60. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–84.

    Article  CAS  PubMed  Google Scholar 

  61. Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 2008;8(6):421–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. S Sharmin, Y Shimizu, M Hagiwara, K Hirayama, A Koyama. Staphylococcus aureus antigens induce IgA-type glomerulonephritis in Balb/c mice. J Nephrol. 2004;17(4):504–11.

    CAS  PubMed  Google Scholar 

  63. Yamamoto C, Suzuki S, Kimura H, Yoshida H, Gejyo F. Experimental nephropathy induced by Haemophilus parainfluenzae antigens. Nephron. 2002;90(3):320–7.

    Article  CAS  PubMed  Google Scholar 

  64. Amore A, Coppo R, Nedrud JG, Sigmund N, Lamm ME, Emancipator SN. The role of nasal tolerance in a model of IgA nephropathy induced in mice by Sendai virus. Clin Immunol. 2004;113(1):101–8.

    Article  CAS  PubMed  Google Scholar 

  65. Jessen RH, Emancipator SN, Jacobs GH, Nedrud JG. Experimental IgA-IgG nephropathy induced by a viral respiratory pathogen. Dependence on antigen form and immune status. Lab Invest. 1992;67(3):379–86.

    CAS  PubMed  Google Scholar 

  66. Coppo R, Mazzucco G, Martina G, Roccatello D, Amore A, Novara R, Bargoni A, Piccoli G, Sena LM. Gluten-induced experimental IgA glomerulopathy. Lab Invest. 1989;60(4):499–506.

    CAS  PubMed  Google Scholar 

  67. Coppo R, Camilla R, Amore A, Peruzzi L, Daprà V, Loiacono E, Vatrano S, Rollino C, Sepe V, Rampino T, Dal Canton A. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin Exp Immunol. 2010;159(1):73–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, Kanou T, Tsukaguchi H, Novak J, Horikoshi S, Tomino Y. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. 2008;19(12):2384–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Qin W, Zhong X, Fan JM, Zhang YJ, Liu XR, Ma XY. External suppression causes the low expression of the Cosmc gene in IgA nephropathy. Nephrol Dial Transplant. 2008;23(5):1608–14.

    Article  CAS  PubMed  Google Scholar 

  70. Buck KS, Smith AC, Molyneux K, El-Barbary H, Feehally J, Barratt J. B-cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy. Kidney Int. 2008;73(10):1128–36.

    Article  CAS  PubMed  Google Scholar 

  71. Kunkel EJ, Butcher EC. Plasma-cell homing. Nat Rev Immunol. 2003;3(10):822–9.

    Article  CAS  PubMed  Google Scholar 

  72. Batra A, Smith AC, Feehally J, Barratt J. T-cell homing receptor expression in IgA nephropathy. Nephrol Dial Transplant. 2007;22(9):2540–8.

    Article  CAS  PubMed  Google Scholar 

  73. Andre PM, Le Pogamp P, Chevet D. Impairment of jacalin binding to serum IgA in IgA nephropathy. J Clin Lab Anal. 1990;4(2):115–9.

    Article  CAS  PubMed  Google Scholar 

  74. 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(2):509–16.

    Article  CAS  PubMed  Google Scholar 

  75. Hiki Y, Odani H, Takahashi M, Yasuda Y, Nishimoto A, Iwase H, Shinzato T, Kobayashi Y, Maeda K. Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int. 2001;59(3):1077–85.

    Article  CAS  PubMed  Google Scholar 

  76. Coppo R, Amore A. Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int. 2004;65(5):1544–7.

    Article  CAS  PubMed  Google Scholar 

  77. Iwasaki H, Zhang Y, Tachibana K, Gotoh M, Kikuchi N, Kwon Y-D, Togayachi A, Kudo T, Kubota T, Narimatsu H. Initiation of O-glycan synthesis in IgA1 hinge region is determined by a single enzyme, UDP-N-acetyl-alpha-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2. J Biol Chem. 2003;278(8):5613–21.

    Article  CAS  PubMed  Google Scholar 

  78. Qin W, Zhou Q, Yang L-C, Li Z, Su B-H, Luo H, Fan J-M. Peripheral B lymphocyte beta1,3-galactosyltransferase and chaperone expression in immunoglobulin A nephropathy. J Intern Med. 2005;258(5):467–77.

    Article  CAS  PubMed  Google Scholar 

  79. Smith AC, de Wolff JF, Molyneux K, Feehally J, Barratt J. O-glycosylation of serum IgD in IgA nephropathy. J Am Soc Nephrol. 2006;17(4):1192–9.

    Article  CAS  PubMed  Google Scholar 

  80. Chintalacharuvu SR, Nagy NU, Sigmund N, Nedrud JG, Amm ME, Emancipator SN. T cell cytokines determine the severity of experimental IgA nephropathy by regulating IgA glycosylation. Clin Exp Immunol. 2001;126(2):326–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Serino G, Sallustio F, Cox SN, Pesce F, Schena FP. Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J Am Soc Nephrol. 2012;23(5):814–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Serino G, Sallustio F, Curci C, Cox SN, Pesce F, De Palma G. Role of let-7b in the regulation of N-acetylgalactosaminyltransferase 2 in IgA nephropathy. Nephrol Dial Transplant. 2015;30(7):1132–9.

    Article  PubMed  Google Scholar 

  83. Franc V, Řehulka P, Raus M, Stulík J, Novak J, Renfrow MB, Šebela M. Elucidating heterogeneity of IgA1 hinge-region O-glycosylation by use of MALDI-TOF/TOF mass spectrometry: role of cysteine alkylation during sample processing. J Proteom. 2013;92:299–312.

    Article  CAS  Google Scholar 

  84. Novak J, Vu HL, Novak L, Julian BA, Mestecky J, Tomana M. Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int. 2002;62(2):465–75.

    Article  CAS  PubMed  Google Scholar 

  85. Stockert RJ, Kressner MS, Collins JC, Sternlieb I, Morell AG. IgA interaction with the asialoglycoprotein receptor. Proc Natl Acad Sci USA. 1982;79(20):6229–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tomana M, Kulhavy R, Mestecky J. Receptor-mediated binding and uptake of immunoglobulin A by human liver. Gastroenterology. 1988;94(3):762–70.

    Article  CAS  PubMed  Google Scholar 

  87. Novak J, Julian BA, Tomana M, Mestecky J. IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy. Semin Nephrol. 2008;28(1):78–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nieuwhof C, Kruytzer M, Frederiks P, van Breda Vriesman PJ. Chronicity index and mesangial IgG deposition are risk factors for hypertension and renal failure in early IgA nephropathy. Am J Kidney Dis. 1998;31(6):962–70.

    Article  CAS  PubMed  Google Scholar 

  89. Berthelot L, Robert T, Vuiblet V, Tabary T, Braconnier A, Dramé M, Toupance O, Rieu P, Monteiro RC. Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes. Kidney Int. 2015;88(4):815–22.

    Article  CAS  PubMed  Google Scholar 

  90. Vuong MT, Hahn-Zoric M, Lundberg S, Gunnarsson I, van Kooten C, Wramner L, Seddighzadeh M, Fernström A, Hanson LÅ, Do LT, Jacobson SH. Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy. Kidney Int. 2010;78(12):1281–7.

    Article  CAS  PubMed  Google Scholar 

  91. Boyd JK, Barratt J. Immune complex formation in IgA nephropathy: CD89 a ‘saint’ or a ‘sinner’? Kidney Int. 2010;78(12):1211–3.

    Article  CAS  PubMed  Google Scholar 

  92. Novak J, Moldoveanu Z, Renfrow MB, Yanagihara T, Suzuki H, Raska M, Hall S, Brown R, Huang W-Q, Goepfert A, Kilian M, Poulsen K, Tomana M, Wyatt RJ, Julian BA, Mestecky J. IgA nephropathy and Henoch–Schoenlein purpura nephritis: aberrant glycosylation of IgA1, formation of IgA1-containing immune complexes, and activation of mesangial cells. Contrib Nephrol. 2007;157:134–8.

    Article  CAS  PubMed  Google Scholar 

  93. Novak J, Raskova Kafkova L, Suzuki H, Tomana M, Matousovic K, Brown R, Hall S, Sanders JT, Eison TM, Moldoveanu Z, Novak L, Novak Z, Mayne R, Julian BA, Mestecky J, Wyatt RJ. IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol Dial Transplant. 2011;26(11):3451–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Launay BP, Grossetête B, Arcos-fajardo M, Gaudin E, Torres SP, Beaudoin L, De Serre NP, Lehuen A, Monteiro RC. Fc-alpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger’ s disease): evidence for pathogenic soluble receptor—IgA complexes in patients and CD89 ransgenic mice. J Exp Med. 2000;191(11):1999–2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Berthelot L, Papista C, Maciel TT, Biarnes-Pelicot M, Tissandie E, Wang PHM, Tamouza H, Jamin A, Bex-Coudrat J, Gestin A, Boumediene A, Arcos-Fajardo M, England P, Pillebout E, Walker F, Daugas E, Vrtosvnik F, Flamant M, Benhamou M, Cogné M, Moura IC, Monteiro RC. Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. J Exp Med. 2012;209(4):793–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Leung JC, Tsang AW, Chan DT, Lai KN. Absence of CD89, polymeric immunoglobulin receptor, and asialoglycoprotein receptor on human mesangial cells. J Am Soc Nephrol. 2000;11(2):241–9.

    CAS  PubMed  Google Scholar 

  97. Kaneko Y, Otsuka T, Tsuchida Y, Gejyo F, Narita I. Integrin alpha1/beta1 and alpha2/beta1 as a receptor for IgA1 in human glomerular mesangial cells in IgA nephropathy. Int Immunol. 2012;24(4):219–32.

    Article  CAS  PubMed  Google Scholar 

  98. Moura IC, Arcos-Fajardo M, Gdoura A, Leroy V, Sadaka C, Mahlaoui N, Lepelletier Y, Vrtovsnik F, Haddad E, Benhamou M, Monteiro RC. Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy. J Am Soc Nephrol. 2005;16(9):2667–76.

    Article  CAS  PubMed  Google Scholar 

  99. Tamouza H, Chemouny JM, Raskova Kafkova L, Berthelot L, Flamant M, Demion M, Mesnard L, Paubelle E, Walker F, Julian BA, Tissandié E, Tiwari MK, Camara NOS, Vrtovsnik F, Benhamou M, Novak J, Monteiro RC, Moura IC. The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int. 2012;82(12):1284–96.

    Article  CAS  PubMed  Google Scholar 

  100. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wyatt RJ, Julian BA. Activation of complement in IgA nephropathy. Am J Kidney Dis. 1988;12(5):437–42.

    Article  CAS  PubMed  Google Scholar 

  102. Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26(7):1503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nasri H, Ahmadi A, Rafieian-Kopaei M, Bashardoust B, Nasri P, Mubarak M. Association of glomerular C4d deposition with various demographic data in IgA nephropathy patients; a preliminary study. J Nephropathol. 2015;4(1):19–23.

    PubMed  PubMed Central  Google Scholar 

  104. Espinosa M, Ortega R, Sánchez M, Segarra A, Salcedo MT, González F, Camacho R, Valdivia MA, Cabrera R, López K, Pinedo F, Gutierrez E, Valera A, Leon M, Cobo MA, Rodriguez R, Ballarín J, Arce Y, García B, Muñoz MD, Praga M. Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2014;9(5):897–904.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ohsawa I, Ishii M, Ohi H, Tomino Y. Pathological scenario with the mannose-binding lectin in patients with IgA nephropathy. J Biomed Biotechnol. 2012;2012:476739.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Liu L-L, Liu N, Chen Y, Wang L-N, Jiang Y, Wang J, Li X-L, Yao L, Fan Q-L. Glomerular mannose-binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy. Clin Exp Immunol. 2013;174(1):152–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ohsawa I, Ishii M, Ohi H, Tomino Y. Pathological scenario with the mannose-binding lectin in patients with IgA nephropathy. J Biomed Biotechnol. 2012;2012(Figure 1):476739.

    PubMed  PubMed Central  Google Scholar 

  108. Moura IC, Benhamou M, Launay P, Vrtovsnik F, Blank U, Monteiro RC. The glomerular response to IgA deposition in IgA nephropathy. Semin Nephrol. 2008;28(1):88–95.

    Article  CAS  PubMed  Google Scholar 

  109. Lai KN, Leung JCK, Chan LYY, Guo H, Tang SCW. Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state. Kidney Int. 2007;71(6):526–38.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partially supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) and FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Brazil).

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Authors and Affiliations

  1. Division of Nephrology, Clinics Hospital, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Rafaela Cabral Gonçalves Fabiano

  2. Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Sérgio Veloso Brant Pinheiro & Ana Cristina Simões e Silva

  3. Pediatric Branch, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, Room# 281, Belo Horizonte, MG, 30130-100, Brazil

    Ana Cristina Simões e Silva

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  1. Rafaela Cabral Gonçalves Fabiano
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Correspondence to Ana Cristina Simões e Silva.

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Fabiano, R.C.G., Pinheiro, S.V.B. & Simões e Silva, A.C. Immunoglobulin A nephropathy: a pathophysiology view. Inflamm. Res. 65, 757–770 (2016). https://doi.org/10.1007/s00011-016-0962-x

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  • DOI: https://doi.org/10.1007/s00011-016-0962-x

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