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IgA glycosylation and immune complex formation in IgAN

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Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. This disease, discovered in 1968, is characterized by IgA-IgG glomerular immunodeposits with a mesangial pattern. It is thought that these immunodeposits originate from the immune complexes formed in the circulation. It is hypothesized that the pathogenesis of IgAN is driven by aberrant glycoforms of IgA1 (galactose-deficient IgA1, Gd-IgA1). Gd-IgA1, in genetically susceptible individuals, represents the initiating factor for the formation of circulating immune complexes due to its recognition by IgG autoantibodies and the subsequent formation of pathogenic IgA1-IgG immune complexes. Complement activation through alternative and/or lectin pathways is likely playing an important role in the pathogenic properties of these complexes and may further upregulate local inflammatory responses and glomerular injury.

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References

  1. Chauveau D, Droz D (1993) Follow-up evaluation of the first patients with IgA nephropathy described at Necker Hospital. Contrib Nephrol 104:1–5

    Article  CAS  PubMed  Google Scholar 

  2. D’Amico G (2004) Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol 24:179–196

    Article  PubMed  Google Scholar 

  3. Imai H, Miura N (2012) A treatment dilemma in adult immunoglobulin A nephropathy: what is the appropriate target, preservation of kidney function or induction of clinical remission? Clin Exp Nephrol 16:195–201

    Article  CAS  PubMed  Google Scholar 

  4. Chen A, Yang SS, Lin TJ, Ka SM (2018) IgA nephropathy: clearance kinetics of IgA-containing immune complexes. Semin Immunopathology 40:539–543

    Article  Google Scholar 

  5. Kiryluk K, Novak J (2014) The genetics and immunobiology of IgA nephropathy. J Clin Invest 124:2325–2332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Magistroni R, D’Agati VD, Appel GB, Kiryluk K (2015) New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int 88:974–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanfilippo F, Croker BP, Bollinger RR (1982) Fate of four cadaveric donor renal allografts with mesangial IgA deposits. Transplantation 33:370–376

    Article  CAS  PubMed  Google Scholar 

  8. van der Boog PJ, de Fijter JW, Bruijn JA, van Es LA (1999) Recurrence of IgA nephropathy after renal transplantation. Ann Med Interne 150:137–142

    Google Scholar 

  9. Hiki Y, Odani H, Takahashi M, Yasuda Y, Nishimoto A, Iwase H, Shinzato T, Kobayashi Y, Maeda K (2001) Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int 259:1077–1085

    Article  Google Scholar 

  10. Allen AC, Bailey EM, Brenchley PE, Buck KS, Barratt J, Feehally J (2001) Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney Int 60:969–973

    Article  CAS  PubMed  Google Scholar 

  11. Coppo R, Basolo B, Martina G, Rollino C, De Marchi M, Giacchino F, Mazzucco G, Messina M, Piccoli G (1982) Circulating immune complexes containing IgA, IgG and IgM in patients with primary IgA nephropathy and with Henoch-Schoenlein nephritis. Correlation with clinical and histologic signs of activity. Clin Nephrol 18:230–239

    CAS  PubMed  Google Scholar 

  12. Coppo R, Basolo B, Piccoli G, Mazzucco G, Bulzomi MR, Roccatello D, De Marchi M, CarbonaraAO B, di Belgiojoso G (1984) IgA1 and IgA2 immune complexes in primary IgA nephropathy and Henoch-Schonlein nephritis. Clin Exp Iimmunol 57:583–590

    CAS  Google Scholar 

  13. Czerkinsky C, Koopman WJ, Jackson S, Collins JE, Crago SS, Schrohenloher RE, Julian BA, Galla JH, Mestecky J (1986) Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies. J Clin Invest 77:1931–1938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Novak J, Vu HL, Novak L, Julian BA, Mestecky J, Tomana M (2002) Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int 62:465–475

    Article  CAS  PubMed  Google Scholar 

  15. Novak J, Tomana M, Matousovic K, Brown R, Hall S, Novak L, Julian BA, Wyatt RJ, Mestecky J (2005) IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int 67:504–513

    Article  CAS  PubMed  Google Scholar 

  16. Tamouza H, Chemouny JM, Raskova Kafkova L, Berthelot L, Flamant M, Demion M, Mesnard L, Paubelle E, Walker F, Julian BA, Tissandie E, Tiwari MK, Camara NO, Vrtovsnik F, BenhamouM NJ, Monteiro RC, Moura IC (2012) 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 82:1284–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Suzuki Y, Matsuzaki K, Suzuki H, Okazaki K, Yanagawa H, Ieiri N, Sato M, Sato T, Taguma Y, Matsuoka J, Horikoshi S, Novak J, Hotta O, Tomino Y (2014) Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy. Clin Exp Nephrol 18:770–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bene MC, Faure G, Hurault de Ligny B, Kessler M, Duheille J (1983) Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance. J Clin Invest 71:1342–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Roberts IS (2014) Pathology of IgA nephropathy. Nat Rev Nephrol 10:445–454

    Article  CAS  PubMed  Google Scholar 

  20. Bellur SS, Troyanov S, Cook HT, Roberts ID, Working Group of International IgA Nephropathy Network and Renal Pathology Society (2011) Immunostaining findings in IgA nephropathy: correlation with histology and clinical outcome in the Oxford classification patient cohort. Nephrol Dial Transplant 26:2533–2536

    Article  PubMed  Google Scholar 

  21. Suzuki K, Honda K, Tanabe K, Toma H, Nihei H, Yamaguchi Y (2003) Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int 63:2286–2294

    Article  PubMed  Google Scholar 

  22. Nakazawa S, Imamura R, Kawamura M, Kato T, Abe T, Namba T, Iwatani H, Yamanaka K, Uemura M, Kishikawa H, Nishimura K, Oka K, Tajiri M, Wada Y, Nonomura N (2019) Difference in IgA1 O-glycosylation between IgA deposition donors and IgA nephropathy recipients. Biochem Biophys Res Commun 508:1106–1112

    Article  CAS  PubMed  Google Scholar 

  23. Gaber LW, Khan FN, Graviss EA, Nguyen DT, Moore LW, Truong LD, Barrios RJ, Suki WN (2020) Prevalence, characteristics, and outcomes of incidental IgA glomerular deposits in donor kidneys. Kidney Int Rep 5:1914–1924

    Article  PubMed  PubMed Central  Google Scholar 

  24. Conley ME, Cooper MD, Michael AF (1980) Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest 66:1432–1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tomino Y, Endoh M, Nomoto Y, Sakai H (1981) Immunoglobulin A1 and IgA nephropathy. N Engl J Med 305:1159–1160

    Article  CAS  PubMed  Google Scholar 

  26. Barratt J, Feehally J, Smith AC (2004) Pathogenesis of IgA nephropathy. Semin Nephrol 24:197–217

    Article  CAS  PubMed  Google Scholar 

  27. Papista C, Berthelot L, Monteiro RC (2011) Dysfunctions of the Iga system: a common link between intestinal and renal diseases. Cell Mol Immunol 8:126–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Perse M, Veceric-Haler Z (2019) The role of IgA in the pathogenesis of IgA nephropathy. Int J Mol Sci 20:6199

    Article  CAS  PubMed Central  Google Scholar 

  29. Reily C, Stewart TJ, Renfrow MB, Novak J (2019) Glycosylation in health and disease. Nat Rev Nephrol 15:346–366

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Renfrow MB, Cooper HJ, Tomana M, Kulhavy R, Hiki Y, Toma K, Emmett MR, Mestecky J, Marshall AG (2005) Novak J (2005) Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation Fourier transform-ion cyclotron resonance mass spectrometry. J Biol Chem 280:19136–19145

    Article  CAS  PubMed  Google Scholar 

  32. Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, Huang WQ, Anreddy SR, Hall S, Hastings MC, Lau KK, Cook WJ, Novak J (2007) Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int 71:1148–1154

    Article  CAS  PubMed  Google Scholar 

  33. 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 (2008) IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118:629–639

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kiryluk K, Li Y, Moldoveanu Z, Suzuki H, Reily C, Hou P, Xie J, Mladkova N, Prakash S, Fischman C, Shapiro S, LeDesma RA, Bradbury D, Ionita-Laza I, Eitner F, Rauen T, Maillard N, Berthoux F, Floege J, Chen N, Zhang H, Scolari F, Wyatt RJ, Julian BA, Gharavi AG, Novak J (2017) GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet 10:e1006609

  35. Barratt J, Eitner F (2009) Glomerular disease: sugars and immune complex formation in IgA nephropathy. Nat Rev Nephrol 5:612–614

    Article  CAS  PubMed  Google Scholar 

  36. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J (1999) Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest 104:73–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Suzuki H, Allegri L, Suzuki Y, Hall S, Moldoveanu Z, Wyatt RJ, Novak J, Julian BA (2016) Galactose-deficient IgA1 as a candidate urinary polypeptide marker of IgA nephropathy? Dis Markers 2016:7806438

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Yasutake J, Suzuki Y, Suzuki H, Hiura N, Yanagawa H, Makita Y, Kaneko E, Tomino Y (2015) Novel lectin-independent approach to detect galactose-deficient IgA1 in IgA nephropathy. Nephrol Dial Transplant 30:1315–1321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, Mestecky J, Novak J, Julian BA (2008) Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol 19:1008–1014

    Article  PubMed  PubMed Central  Google Scholar 

  40. Matousovic K, Novak J, Yanagihara T, Tomana M, Moldoveanu Z, Kulhavy R, Julian BA, Konecny K, Mestecky J (2006) IgA-containing immune complexes in the urine of IgA nephropathy patients. Nephrol Dial Transplant 21:2478–2484

    Article  CAS  PubMed  Google Scholar 

  41. Novak J, Julian BA, Mestecky J, Renfrow MB (2012) Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin Immunopathol 34:365–382

    Article  CAS  PubMed  Google Scholar 

  42. Mestecky J, Raska M, Julian BA, Gharavi AG, Renfrow MB, Moldoveanu Z, Novak L, Matousovic K, Novak J (2013) IgA nephropathy: molecular mechanisms of the disease. Annu Rev Pathol 8:217–240

    Article  CAS  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 (2009) Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest 119:1668–1677

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, Wyatt RJ, Scolari F, Mestecky J, Gharavi AG, Julian BA (2011) The pathophysiology of IgA nephropathy. J Am Soc Nephrol 22:1795–1803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, Gharavi AG, Novak J, Zhang H (2012) The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int 82:790–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Camilla R, Suzuki H, Daprà V, Loiacono E, Peruzzi L, Amore A, Ghiggeri GM, Mazzucco G, Scolari F, Gharavi AG, Appel GB, Troyanov S, Novak J, Julian BA, Coppo R (2011) Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol 6:1903–1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C, Tomino Y, Julian BA, Novak J (2012) Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol 23:1579–1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maixnerova D, Ling C, Hall S, Reily C, Brown R, Neprasova M, Suchanek M, Honsova E, Zima T, Novak J, Tesar V (2019) Correction: Galactose-deficient IgA1 and the corresponding IgG autoantibodies predict IgA nephropathy progression. PLoS ONE 12:e0219947

    Article  Google Scholar 

  49. Yanagawa H, Suzuki H, Suzuki Y, Kiryluk K, Gharavi AG, Matsuoka K, Makita Y, Julian BA, Novak J, Tomino Y (2014) A panel of serum biomarkers differentiates IgA nephropathy from other renal diseases. PLoS ONE 9:e98081

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Aucouturier P, Monteiro RC, Noël LH, Preud’homme JL, Lesavre P (1989) Glomerular and serum immunoglobulin G subclasses in IgA nephropathy. Clin Immunol Immunopathol 51:338–347

    Article  CAS  PubMed  Google Scholar 

  51. Rizk DV, Saha MK, Hall S, Novak L, Brown R, Huang ZQ, Fatima H, Julian BA, Novak J (2019) Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1. J Am Soc Nephrol 30:2017–2026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moldoveanu Z, Suzuki H, Reily C, Satake K, Novak L, Xu N, Huang ZQ, Knoppova B, Khan A, Hall S, Yanagawa H, Brown R, Winstead CJ, O'Quinn DB, Weinmann A, Gharavi AG, Kiryluk K, Julian BA, Weaver CT, Suzuki Y, Novak J (2021) Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy. J Autoimmun. 118:102593. https://doi.org/10.1016/j.jaut.2021.102593. Jan 25. PMID: 33508637; PMCID: PMC7997636.

  53. Yamaji K, Suzuki Y, Suzuki H, Satake K, Horikoshi S, Novak J, Tomino Y (2014) The kinetics of glomerular deposition of nephritogenic IgA. PLoS ONE 9:e113005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Sofue T, Inui M, Hara T, Moritoki M, Nishioka S, Nishijima Y, Moriwaki K, Hayashida Y, Ueda N, Kushida Y, Haba R, Nishiyama A, Kakehi Y, Kohno M (2013) Latent IgA deposition from donor kidneys does not affect transplant prognosis, irrespective of mesangial expansion. Clin Transplant 27(Suppl 26):14–21

    Article  PubMed  Google Scholar 

  55. Yel L (2010) Selective IgA deficiency. J Clin Immunol 30:10–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Feehally J, Beattie TJ, Brenchley PE, Coupes BM, Mallick NP, Postlethwaite RJ (1986) Sequential study of the IgA system in relapsing IgA nephropathy. Kidney Int 30:924–931

    Article  CAS  PubMed  Google Scholar 

  57. Macpherson AJ, Yilmaz B, Limenitakis JP, Ganal-Vonarburg SC (2018) IgA function in relation to the intestinal microbiota. Annu Rev Immunol 36:359–381

    Article  CAS  PubMed  Google Scholar 

  58. Bunker JJ, Bendelac A (2018) IgA responses to microbiota. Immunity 49:211–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rollino C, Vischini G, Coppo R (2016) IgA nephropathy and infections. J Nephrol 29:463–468

    Article  CAS  PubMed  Google Scholar 

  60. Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M, Heikenwalder M, Cahenzli J, Velykoredko Y, Balmer ML, Endt K, Geuking MB, Curtiss R 3rd, McCoy KD, Macpherson AJ (2010) Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328:1705–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Allen AC, Feehally J (2000) IgA1 glycosylation and the pathogenesis of IgA nephropathy. Am J Kidney Dis 35:551–556

    Article  CAS  PubMed  Google Scholar 

  62. Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, Kanou T, Tsukaguchi H, Novak J, Horikoshi S, Tomino Y (2008) Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 19:2384–2395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Novak J, Moldoveanu Z, Julian BA, Raska M, Wyatt RJ, Suzuki Y, Tomino Y, Gharavi AG, Mestecky J, Suzuki H (2011) Aberrant glycosylation of IgA1 and anti-glycan antibodies in IgA nephropathy: role of mucosal immune system. Adv Otorhinolaryngol 72:60–63

    PubMed  Google Scholar 

  64. Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Makita Y, Suzuki H, Kano T, Takahata A, Julian BA, Novak J, Suzuki Y (2020) TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy. Kidney Int 97:340–349

    Article  CAS  PubMed  Google Scholar 

  66. Harper SJ, Allen AC, Pringle JH, Feehally J (1996) Increased dimeric IgA producing B cells in the bone marrow in IgA nephropathy determined by in situ hybridisation for J chain mRNA. J Clin Pathol 49:38–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bene MC, Faure G, Duheille J (1982) IgA nephropathy: characterization of the polymeric nature of mesangial deposits by in vitro binding of free secretory component. Clin Exp Immunol 47:527–534

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kunkel EJ, Butcher EC (2003) Plasma-cell homing. Nat Rev Immunol 3:822–829

    Article  CAS  PubMed  Google Scholar 

  69. Suzuki Y, Suzuki H, Nakata J, Sato D, Kajiyama T, Watanabe T, Tomino Y (2011) Pathological role of tonsillar B cells in IgA nephropathy. Clin Dev Immunol 2011:639074

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Floege J, Feehally J (2016) The mucosa-kidney axis in IgA nephropathy. Nat Rev Nephrol 12:147–156

    Article  CAS  PubMed  Google Scholar 

  71. Horie A, Hiki Y, Odani H, Yasuda Y, Takahashi M, Kato M, Iwase H, Kobayashi Y, Nakashima I, Maeda K (2003) IgA1 molecules produced by tonsillar lymphocytes are under-O-glycosylated in IgA nephropathy. Am J Kidney Dis 42:486–496

    Article  CAS  PubMed  Google Scholar 

  72. Nakata J, Suzuki Y, Suzuki H, Sato D, Kano T, Yanagawa H, Matsuzaki K, Horikoshi S, Novak J, Tomino Y (2014) Changes in nephritogenic serum galactose-deficient IgA1 in IgA nephropathy following tonsillectomy and steroid therapy. PLoS ONE 9:e89707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Inoue T, Sugiyama H, Hiki Y, Takiue K, Morinaga H, Kitagawa M, Maeshima Y, Fukushima K, Nishizaki K, Akagi H, Narimatsu Y, Narimatsu H, Makino H (2010) Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy. Clin Immunol 136:447–455

    Article  CAS  PubMed  Google Scholar 

  74. Bene MC, Hurault De Ligny B, Kessler M, Faure GC (1991) Confirmation of tonsillar anomalies in IgA nephropathy: a multicenter study. Nephron 58:425–428

    Article  CAS  PubMed  Google Scholar 

  75. Khodadadi L, Cheng Q, Radbruch A, Hiepe F (2019) The maintenance of memory plasma cells. Front Immunol 10:721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Komatsu H, Fujimoto S, Hara S, Sato Y, Yamada K, Kitamura K (2008) Effect of tonsillectomy plus steroid pulse therapy on clinical remission of IgA nephropathy: a controlled study. Clin J Am Soc Nephrol 3:1301–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Xie Y, Nishi S, Ueno M, Imai N, Sakatsume M, Narita I, Suzuki Y, Akazawa K, Shimada H, Arakawa M, Gejyo F (2003) The efficacy of tonsillectomy on long-term renal survival in patients with IgA nephropathy. Kidney Int 63:1861–1867

    Article  PubMed  Google Scholar 

  78. Hirano K, Matsuzaki K, Yasuda T, Nishikawa M, Yasuda Y, Koike K, Maruyama S, Yokoo T, Matsuo S, Kawamura T, Suzuki Y (2019) Association between tonsillectomy and outcomes in patients with immunoglobulin A nephropathy. JAMA Netw Open 2:e194772

    Article  PubMed  PubMed Central  Google Scholar 

  79. Maruyama S, Gohda T, Suzuki Y, Suzuki H, Sonoda Y, Ichikawa S, Li Z, Murakoshi M, Horikoshi S, Tomino Y (2016) Beneficial effects of tonsillectomy plus steroid pulse therapy on inflammatory and tubular markers in patients with IgA nephropathy. Kidney Res Clin Pract 35:233–236

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wyatt RJ, Julian BA (2013) IgA nephropathy. N Engl J Med 368:2402–2414

    Article  CAS  PubMed  Google Scholar 

  81. Wang M, Lv J, Zhang X, Chen P, Zhao M, Zhang H (2020) Secondary IgA nephropathy shares the same immune features with primary IgA nephropathy. Kidney Int Rep 5:165–172

    Article  PubMed  Google Scholar 

  82. Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tesar V, Del Vecchio L, NEFIGAN Trial Investigators (2017) Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 389:2117–2127

    Article  PubMed  Google Scholar 

  83. Kano T, Suzuki H, Makita Y, Fukao Y, Suzuki Y (2021) Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy. Kidney Int in press

  84. Miyazaki T, Hirokami Y, Matsuhashi N, Takatsuka H, Naito M (1999) Increased susceptibility of thymocytes to apoptosis in mice lacking AIM, a novel murine macrophage-derived soluble factor belonging to the scavenger receptor cysteine-rich domain superfamily. J Exp Med 189:413–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Irabu H, Shimizu M, Kaneko S, Inoue N, Mizuta M, Tasaki Y, Ohta K, Yachie A, Wada T (2021) Apoptosis inhibitor of macrophage as a biomarker for disease activity in Japanese children with IgA nephropathy and Henoch-Schonlein purpura nephritis. Pediatr Res 89:667–672

    Article  CAS  PubMed  Google Scholar 

  86. Takahata A, Arai S, Hiramoto E, Kitada K, Kato R, Makita Y, Suzuki H, Nakata J, Araki K, Miyazaki T, Suzuki Y (2020) Crucial role of AIM/CD5L in the development of glomerular inflammation in IgA nephropathy. J Am Soc Nephrol 31:2013–2024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hastings MC, Moldoveanu Z, Julian BA, Novak J, Sanders JT, McGlothan KR, Gharavi AG, Wyatt RJ (2010) Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol 5:2069–2074

    Article  PubMed  PubMed Central  Google Scholar 

  88. Huang ZQ, Raska M, Stewart TJ, Reily C, King RG, Crossman DK, Crowley MR, Hargett A, Zhang Z, Suzuki H, Hall S, Wyatt RJ, Julian BA, Renfrow MB, Gharavi AG, Novak J (2016) Somatic mutations modulate autoantibodies against galactose-deficient IgA1 in IgA nephropathy. J Am Soc Nephrol 27:3278–3284

    Article  PubMed  PubMed Central  Google Scholar 

  89. Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, Glassock RJ (2016) IgA nephropathy Nat Rev Dis Primers 2:16001

    Article  PubMed  Google Scholar 

  90. Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J (2015) Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol 26:1503–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. van den Wall Bake AW, Daha MR, van Es LA (1989) Immunopathogenetic aspects of IgA nephropathy. Nephrologie 10:141–145

    PubMed  Google Scholar 

  92. Kennel-De March A, Bene MC, Hurault de Ligny B, Kessler M, Faure GC (1997) Enhanced expression of CD31 and CD54 on tonsillar high endothelial venules in IgA nephropathy. Clin Immunol Immunopathol 84:158–165

    Article  CAS  PubMed  Google Scholar 

  93. Buren M, Yamashita M, Suzuki Y, Tomino Y, Emancipator SN (2007) Altered expression of lymphocyte homing chemokines in the pathogenesis of IgA nephropathy. Contrib Nephrol 157:50–55

    CAS  PubMed  Google Scholar 

  94. Novak J, Moldoveanu Z, Renfrow MB et al (2007) IgA nephropathy and Henoch-Schoenlein purpura nephritis: aberrant glycosylation of IgA1, formation of IgA1-containing immune complexes, and activation of mesangial cells. Contrib Nephrol 157:134–138

    Article  CAS  PubMed  Google Scholar 

  95. Saha MK, Julian BA, Novak J, Rizk DV (2018) Secondary IgA nephropathy. Kidney Int 94:674–681

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to our colleagues and collaborators who have worked with us on the studies concerning the pathogenesis of IgAN as well as to all volunteers and patients with IgAN who provided biospecimens.

Funding

This study was supported in part by NIH grants DK078244, AI149431, DK082753, and GM098539; by JSPS KAKENHI Grant Number 21K08285; and by a gift from the IGA Nephropathy Foundation of America.

Author information

Authors and Affiliations

  1. Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan

    Hitoshi Suzuki

  2. Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, BBRB 761A, AL, 35294, Birmingham, USA

    Jan Novak

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  1. Hitoshi Suzuki
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  2. Jan Novak
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Correspondence to Hitoshi Suzuki or Jan Novak.

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Competing interests

HS and JN are co-inventors on US patent application 14/318,082 (assigned to UAB Research Foundation). JN is a co-founder and co-owner of and consultant for Reliant Glycosciences, LLC.

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This article is a contribution to the Special issue on: The IgA system, IgA nephropathy and IgA vasculitis - Guest Editors: Jürgen Floege & Jonathan Barratt

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Suzuki, H., Novak, J. IgA glycosylation and immune complex formation in IgAN. Semin Immunopathol 43, 669–678 (2021). https://doi.org/10.1007/s00281-021-00883-8

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