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Published in:

01-11-2007 | Review

Immunopathogenesis of IgAN

Authors: Jonathan Barratt, Alice C. Smith, Karen Molyneux, John Feehally

Published in: Seminars in Immunopathology | Issue 4/2007

Abstract

The defining hallmark of IgA nephropathy (IgAN) is deposition of polymeric IgA1 in the glomerular mesangium accompanied by a mesangial proliferative glomerulonephritis. The mechanisms involved in mesangial polymeric IgA1 deposition and the initiation of inflammatory glomerular injury remain unclear. This lack of a complete understanding of the pathogenesis of IgAN has meant that there is still no treatment known to modify mesangial deposition of IgA. Increasing evidence, however, supports the importance of IgA-containing immune complex formation as a pivotal factor driving mesangial IgA deposition and triggering of glomerular injury. A number of potentially important changes to the IgA1 molecule have been identified in IgAN, which may contribute to immune complex formation. These changes suggest that the polymeric IgA1 that deposits in IgA nephropathy is derived from mucosally primed plasma cells. The presence of this IgA in the circulation reflects displacement of mucosal B lineage cells to systemic sites and may be the result of mishoming of lymphocytes trafficking along the mucosa–bone marrow axis.

Abe K, Miyazaki M, Koji T, Furusu A, Ozono Y, Harada T, Sakai H, Nakane PK, Kohno S (1998) Expression of decay accelerating factor mRNA and complement C3 mRNA in human diseased kidney. Kidney Int 54(1):120–130PubMed

Abe K, Miyazaki M, Koji T, Furusu A, Shioshita K, Tsukasaki S, Ozono Y, Harada T, Sakai H, Kohno S (2001) Intraglomerular synthesis of complement C3 and its activation products in IgA nephropathy. Nephron 87(3):231–239PubMed

Abreu-Martin MT, Targan SR (1996) Regulation of immune responses of the intestinal mucosa. Crit Rev Immunol 16(3):277–309PubMed

Alexander WS, Viney EM, Zhang JG, Metcalf D, Kauppi M, Hyland CD, Carpinelli MR, Stevenson W, Croker BA, Hilton AA, Ellis S, Selan C, Nandurkar HH, Goodnow CC, Kile BT, Nicola NA, Roberts AW, Hilton DJ (2006) Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene. Proc Natl Acad Sci USA 103(44):16442–16447PubMed

Allen AC, Bailey EM, Barratt J, Buck KS, Feehally J (1999) Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis. J Am Soc Nephrol 10(8):1763–1771PubMed

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(3):969–973PubMed

Allen AC, Harper SJ, Feehally J (1995) Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy. Clin Exp Immunol 100(3):470–474PubMedCrossRef

Allen AC, Topham PS, Harper SJ, Feehally J (1997) Leucocyte beta 1,3 galactosyltransferase activity in IgA nephropathy. Nephrol Dial Transplant 12(4):701–706PubMed

Allen AC, Willis FR, Beattie TJ, Feehally J (1998) Abnormal IgA glycosylation in Henoch–Schonlein purpura restricted to patients with clinical nephritis. Nephrol Dial Transplant 13(4):930–934PubMed

10.

Amore A, Cirina P, Conti G, Brusa P, Peruzzi L, Coppo R (2001) Glycosylation of circulating iga in patients with iga nephropathy modulates proliferation and apoptosis of mesangial cells. J Am Soc Nephrol 12(9):1862–1871PubMed

11.

Amore A, Conti G, Cirina P, Peruzzi L, Alpa M, Bussolino F, Coppo R (2000) Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. Am J Kidney Dis 36(6):1242–1252PubMed

12.

Appel GB, Waldman M (2006) The IgA nephropathy treatment dilemma. Kidney Int 69(11):1939–1944PubMed

13.

Arima S, Nakayama M, Naito M, Sato T, Takahashi K (1991) Significance of mononuclear phagocytes in IgA nephropathy. Kidney Int 39(4):684–692PubMed

14.

Baharaki D, Dueymes M, Perrichot R, Basset C, Le Corre R, Cledes J, Youinou P (1996) Aberrant glycosylation of IgA from patients with IgA nephropathy. Glycoconj J 13(4):505–511PubMed

15.

Barratt J, Bailey EM, Buck KS, Mailley J, Moayyedi P, Feehally J, Turney JH, Crabtree JE, Allen AC (1999) Exaggerated systemic antibody response to mucosal Helicobacter pylori infection in IgA nephropathy. Am J Kidney Dis 33(6):1049–1057PubMed

16.

Barratt J, Feehally J (2005) IgA nephropathy. J Am Soc Nephrol 16(7):2088–2097PubMed

17.

Barratt J, Feehally J (2006) Treatment of IgA nephropathy. Kidney Int 69(11):1934–1938PubMed

18.

Barratt J, Feehally J, Smith AC (2004) Pathogenesis of IgA nephropathy. Semin Nephrol 24(3):197–217PubMed

19.

Barratt J, Greer MR, Pawluczyk IZ, Allen AC, Bailey EM, Buck KS, Feehally J (2000) Identification of a novel Fcalpha receptor expressed by human mesangial cells. Kidney Int 57(5):1936–1948PubMed

20.

Barratt J, Smith AC, Feehally J (2007) The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy. Nephrology (Carlton) 12(3):275–284

21.

Batra A, Smith AC, Feehally J, Barratt J (2007) T-cell homing receptor expression in IgA nephropathy. Nephrol Dial Transplant 22:2540–2548PubMed

22.

Beerman I, Novak J, Wyatt RJ, Julian BA, Gharavi AG (2007) The genetics of IgA nephropathy. Nat Clin Pract Nephrol 3(6):325–338PubMed

23.

Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, Butcher EC (1995) alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80(3):413–422PubMed

24.

Bisceglia L, Cerullo G, Forabosco P, Torres DD, Scolari F, Di Perna M, Foramitti M, Amoroso A, Bertok S, Floege J, Mertens PR, Zerres K, Alexopoulos E, Kirmizis D, Ermelinda M, Zelante L, Schena FP (2006) Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci. Am J Hum Genet 79(6):1130–1134PubMed

25.

Breitfeld PP, Simmons CF Jr, Strous GJ, Geuze HJ, Schwartz AL (1985) Cell biology of the asialoglycoprotein receptor system: a model of receptor-mediated endocytosis. Int Rev Cytol 97:47–95PubMed

26.

Buck KS, Barratt J, Feehally J, Smith AC (2003) Beta-1-3-galactosyltransferase activity in IgA nephropathy. J Am Soc Nephrol 14:632A

27.

Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272(5258):60–66PubMed

28.

Chao CC, Sandor M, Dailey MO (1994) Expression and regulation of adhesion molecules by gamma delta T cells from lymphoid tissues and intestinal epithelium. Eur J Immunol 24(12):3180–3187PubMed

29.

Chen A, Chen WP, Sheu LF, Lin CY (1994) Pathogenesis of IgA nephropathy: in vitro activation of human mesangial cells by IgA immune complex leads to cytokine secretion. J Pathol 173(2):119–126PubMed

30.

Chintalacharuvu SR, Emancipator SN (1997) The glycosylation of IgA produced by murine B cells is altered by Th2 cytokines. J Immunol 159(5):2327–2333PubMed

31.

Coppo R, Amore A (2004) Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int 65(5):1544–1547PubMed

32.

Coppo R, Amore A, Gianoglio B, Porcellini MG, Peruzzi L, Gusmano R, Giani M, Sereni F, Gianviti A, Rizzoni G et al (1995) Macromolecular IgA and abnormal IgA reactivity in sera from children with IgA nephropathy. Italian collaborative paediatric IgA nephropathy study. Clin Nephrol 43(1):1–13PubMed

33.

Coppo R, Amore A, Gianoglio B, Reyna A, Peruzzi L, Roccatello D, Alessi D, Sena LM (1993) Serum IgA and macromolecular IgA reacting with mesangial matrix components. Contrib Nephrol 104:162–171PubMed

34.

Cuevas X, Lloveras J, Mir M, Aubia J, Masramon J (1987) Disappearance of mesangial IgA deposits from the kidneys of two donors after transplantation. Transplant Proc 19(1 Pt 3):2208–2209PubMed

35.

D'Amico G (2004) Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol 24(3):179–196PubMed

36.

Davin JC, Ten Berge IJ, Weening JJ (2001) What is the difference between IgA nephropathy and Henoch–Schonlein purpura nephritis? Kidney Int 59(3):823–834PubMed

37.

de Fijter JW, Eijgenraam JW, Braam CA, Holmgren J, Daha MR, van Es LA, van den Wall Bake AW (1996) Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy. Kidney Int 50(3):952–961PubMed

38.

Defrance T, Vanbervliet B, Briere F, Durand I, Rousset F, Banchereau J (1992) Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med 175(3):671–682PubMed

39.

Elangbam CS, Qualls CW Jr, Dahlgren RR (1997) Cell adhesion molecules—update. Vet Pathol 34(1):61–73PubMedCrossRef

40.

Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M (1998) Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant 13(8):1984–1990PubMed

41.

Feehally J (1988) Immune mechanisms in glomerular IgA deposition. Nephrol Dial Transplant 3(4):361–78PubMed

42.

Fortune F, Courteau M, Williams DG, Lehner T (1992) T and B cell responses following immunization with tetanus toxoid in IgA nephropathy. Clin Exp Immunol 88(1):62–67PubMedCrossRef

43.

Fujihashi K, Kweon MN, Kiyono H, VanCott JL, van Ginkel FW, Yamamoto M, McGhee JR (1997) A T cell/B cell/epithelial cell internet for mucosal inflammation and immunity. Springer Semin Immunopathol 18(4):477–494PubMed

44.

Fujihashi K, McGhee JR, Kweon MN, Cooper MD, Tonegawa S, Takahashi I, Hiroi T, Mestecky J, Kiyono H (1996) gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A responses. J Exp Med 183(4):1929–1935PubMed

45.

Fujii K, Muller KD, Clarkson AR, Woodroffe AJ (1990) The effect of IgA immune complexes on the proliferation of cultured human mesangial cells. Am J Kidney Dis 16(3):207–210PubMed

46.

Gharavi AG, Yan Y, Scolari F, Schena FP, Frasca GM, Ghiggeri GM, Cooper K, Amoroso A, Viola BF, Battini G, Caridi G, Canova C, Farhi A, Subramanian V, Nelson-Williams C, Woodford S, Julian BA, Wyatt RJ, Lifton RP (2000) IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet 26(3):354–357PubMed

47.

Gomez-Guerrero C, Duque N, Egido J (1998) Mesangial cells possess an asialoglycoprotein receptor with affinity for human immunoglobulin A. J Am Soc Nephrol 9(4):568–576PubMed

48.

Gomez-Guerrero C, Lopez-Armada MJ, Gonzalez E, Egido J (1994) Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial cells and induce production of TNF-alpha and IL-6, and proliferation. J Immunol 153(11):5247–5255PubMed

49.

Grossetete B, Launay P, Lehuen A, Jungers P, Bach JF, Monteiro RC (1998) Down-regulation of Fc alpha receptors on blood cells of IgA nephropathy patients: evidence for a negative regulatory role of serum IgA. Kidney Int 53(5):1321–1335PubMed

50.

Grossetete B, Viard JP, Lehuen A, Bach JF, Monteiro RC (1995) Impaired Fc alpha receptor expression is linked to increased immunoglobulin A levels and disease progression in HIV-1-infected patients. Aids 9(3):229–234PubMed

51.

Harada T, Hobby P, Courteau M, Knight JF, Williams DG (1989) Charge distribution of plasma IgA in IgA nephropathy. Clin Exp Immunol 77(2):211–214PubMed

52.

Harper SJ, Allen AC, Bene MC, Pringle JH, Faure G, Lauder I, Feehally J (1995) Increased dimeric IgA-producing B cells in tonsils in IgA nephropathy determined by in situ hybridization for J chain mRNA. Clin Exp Immunol 101(3):442–448PubMedCrossRef

53.

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(1):38–42PubMed

54.

Harper SJ, Pringle JH, Wicks AC, Hattersley J, Layward L, Allen A, Gillies A, Lauder I, Feehally J (1994) Expression of J chain mRNA in duodenal IgA plasma cells in IgA nephropathy. Kidney International 45(3):836–844PubMed

55.

Hashim OH, Shuib AS, Chua CT (2001) The interaction of selective plant lectins with neuraminidase-treated and untreated IgA1 from the sera of IgA nephropathy patients. Immunol Invest 30(1):21–31PubMed

56.

Hiemstra PS, Biewenga J, Gorter A, Stuurman ME, Faber A, van Es LA, Daha MR (1988) Activation of complement by human serum IgA, secretory IgA and IgA1 fragments. Mol Immunol 25(6):527–533PubMed

57.

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 59(3):1077–1085PubMed

58.

Hiki Y, Saitoh M, Kobayashi Y (1991) Serum IgA class anti-IgA antibody in IgA nephropathy. Nephron 59(4):552–560PubMedCrossRef

59.

Hiki Y, Tanaka A, Kokubo T, Iwase H, Nishikido J, Hotta K, Kobayashi Y (1998) Analyses of IgA1 hinge glycopeptides in IgA nephropathy by matrix- assisted laser desorption/ionization time-of-flight mass spectrometry. J Am Soc Nephrol 9(4):577–582PubMed

60.

Hisano S, Matsushita M, Fujita T, Endo Y, Takebayashi S (2001) Mesangial IgA2 deposits and lectin pathway-mediated complement activation in IgA glomerulonephritis. Am J Kidney Dis 38(5):1082–1088PubMed

61.

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(3):486–496PubMed

62.

Hotta O, Furuta T, Chiba S, Tomioka S, Taguma Y (2002) Regression of IgA nephropathy: a repeat biopsy study. Am J Kidney Dis 39(3):493–502PubMed

63.

Itoh A, Iwase H, Takatani T, Nakamura I, Hayashi M, Oba K, Hiki Y, Kobayashi Y, Okamoto M (2003) Tonsillar IgA1 as a possible source of hypoglycosylated IgA1 in the serum of IgA nephropathy patients. Nephrol Dial Transplant 18(6):1108–1114PubMed

64.

Iwasaki H, Zhang Y, Tachibana K, Gotoh M, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Kubota T, Narimatsu H (2003) 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 278(8):5613–5621PubMed

65.

Iwase H, Tanaka A, Hiki Y, Kokubo T, Sano T, Ishii-Karakasa I, Toma K, Kobayashi Y, Hotta K (1999) Aggregated human serum immunoglobulin A1 induced by neuraminidase treatment had a lower number of O-linked sugar chains on the hinge portion. J Chromatogr B Biomed Sci Appl 724(1):1–7PubMed

66.

Iwase H, Yokozeki Y, Hiki Y, Tanaka A, Kokubo T, Sano T, Ishii-Karakasa I, Hisatani K, Kobayashi Y, Hotta K (1999) Human serum immunoglobulin G3 subclass bound preferentially to asialo-, agalactoimmunoglobulin A1/Sepharose. Biochem Biophys Res Commun 264(2):424–429PubMed

67.

Ju T, Brewer K, D’Souza A, Cummings RD, Canfield WM (2002) Cloning and expression of human core 1 beta1,3-galactosyltransferase. J Biol Chem 277(1):178–186PubMed

68.

Ju T, Cummings RD (2005) Protein glycosylation: chaperone mutation in Tn syndrome. Nature 437(7063):1252PubMed

69.

Ju T, Cummings RD (2002) A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc Natl Acad Sci USA 99(26):16613–16618PubMed

70.

Kennel-de March A, Bene MC, Renoult E, Kessler M, Faure GC, Kolopp-Sarda MN (1999) Enhanced expression of L-selectin on peripheral blood lymphocytes from patients with IgA nephropathy. Clin Exp Immunol 115(3):542–546PubMed

71.

Kerr MA (1990) The structure and function of human IgA. Biochem J 271(2):285–296PubMed

72.

Kobayashi I, Nogaki F, Kusano H, Ono T, Miyawaki S, Yoshida H, Muso E (2002) Interleukin-12 alters the physicochemical characteristics of serum and glomerular IgA and modifies glycosylation in a ddY mouse strain having high IgA levels. Nephrol Dial Transplant 17(12):2108–2116PubMed

73.

Kokubo T, Hashizume K, Iwase H, Arai K, Tanaka A, Toma K, Hotta K, Kobayashi Y (2000) Humoral immunity against the proline-rich peptide epitope of the IgA1 hinge region in IgA nephropathy. Nephrol Dial Transplant 15(1):28–33PubMed

74.

Kokubo T, Hiki Y, Iwase H, Horii A, Tanaka A, Nishikido J, Hotta K, Kobayashi Y (1997) Evidence for involvement of IgA1 hinge glycopeptide in the IgA1-IgA1 interaction in IgA nephropathy. J Am Soc Nephrol 8(6):915–919PubMed

75.

Kokubo T, Hiki Y, Iwase H, Tanaka A, Toma K, Hotta K, Kobayashi Y (1998) Protective role of IgA1 glycans against IgA1 self-aggregation and adhesion to extracellular matrix proteins. J Am Soc Nephrol 9(11):2048–2054PubMed

76.

Kriz W, Gretz N, Lemley KV (1998) Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 54(3):687–697PubMed

77.

Kunkel EJ, Butcher EC (2002) Chemokines and the tissue-specific migration of lymphocytes. Immunity 16(1):1–4PubMed

78.

Lam CW, Chui SH, Leung NW, Li EK, Lai KN (1991) Light chain ratios of serum immunoglobulins in disease. Clin Biochem 24(3):283–287PubMed

79.

Layward L, Allen AC, Harper SJ, Hattersley JM, Feehally J (1992) Increased and prolonged production of specific polymeric IgA after systemic immunization with tetanus toxoid in IgA nephropathy. Clin Exp Immunol 88(3):394–398PubMedCrossRef

80.

Layward L, Allen AC, Hattersley JM, Harper SJ, Feehally J (1993) Elevation of IgA in IgA nephropathy is localized in the serum and not saliva and is restricted to the IgA1 subclass. Nephrol Dial Transplant 8(1):25–28PubMed

81.

Layward L, Allen AC, Hattersley JM, Harper SJ, Feehally J (1994) Low antibody affinity restricted to the IgA isotype in IgA nephropathy. Clin Exp Immunol 95(1):35–41PubMedCrossRef

82.

Layward L, Allen AC, Hattersley JM, Harper SJ, Feehally J (1995) Response to mucosal antigen challenge in IgA nephropathy. Exp Nephrol 3(5):300–307PubMed

83.

Leung JC, Poon PY, Lai KN (1999) Increased sialylation of polymeric immunoglobulin A1: mechanism of selective glomerular deposition in immunoglobulin A nephropathy? J Lab Clin Med 133(2):152–160PubMed

84.

Leung JC, Tang SC, Chan DT, Lui SL, Lai KN (2002) Increased sialylation of polymeric lambda-IgA1 in patients with IgA nephropathy. J Clin Lab Anal 16(1):11–19PubMed

85.

Leung JC, Tang SC, Lam MF, Chan TM, Lai KN (2001) Charge-dependent binding of polymeric IgA1 to human mesangial cells in IgA nephropathy. Kidney Int 59(1):277–285PubMed

86.

Leung JC, Tsang AW, Chan DT, Lai KN (2000) Absence of CD89, polymeric immunoglobulin receptor, and asialoglycoprotein receptor on human mesangial cells. J Am Soc Nephrol 11(2):241–249PubMed

87.

Leung JC, Tsang AW, Chan LY, Tang SC, Lam MF, Lai KN (2002) Size-dependent binding of IgA to HepG2, U937, and human mesangial cells. J Lab Clin Med 140(6):398–406PubMed

88.

Li GS, Zhang H, Lv JC, Shen Y, Wang HY (2007) Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy. Kidney Int 71:448–453PubMed

89.

Li HL, Hancock WW, Dowling JP, Atkins RC (1991) Activated (IL-2R) intraglomerular mononuclear cells in crescentic glomerulonephritis. Kidney Int 39(4):793–798PubMed

90.

Linossier MT, Palle S, Berthoux F (2003) Different glycosylation profile of serum IgA1 in IgA nephropathy according to the glomerular basement membrane thickness: normal versus thin. Am J Kidney Dis 41(3):558–564PubMed

91.

Lopez-Armada MJ, Gomez-Guerrero C, Egido J (1996) Receptors for immune complexes activate gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF-beta. J Immunol 157(5):2136–2142PubMed

92.

Lycke N (1998) T cell and cytokine regulation of the IgA response. Chem Immunol 71:209–234PubMed

93.

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(9):2478–2484PubMed

94.

Matsuda M, Shikata K, Wada J, Sugimoto H, Shikata Y, Kawasaki T, Makino H (1998) Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy. Nephron 80(4):408–413PubMed

95.

McDonald KJ, Cameron AJ, Allen JM, Jardine AG (2002) Expression of Fc alpha/mu receptor by human mesangial cells: a candidate receptor for immune complex deposition in IgA nephropathy. Biochem Biophys Res Commun 290(1):438–442PubMed

96.

Meadow SR, Scott DG (1985) Berger disease: Henoch–Schonlein syndrome without the rash. J Pediatr 106(1):27–32PubMed

97.

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 71:1148–1154PubMed

98.

Moll S, Miot S, Sadallah S, Gudat F, Mihatsch MJ, Schifferli JA (2001) No complement receptor 1 stumps on podocytes in human glomerulopathies. Kidney Int 59(1):160–168PubMed

99.

Monteiro RC, Chevailler A, Noel LH, Lesavre P (1988) Serum IgA preferentially binds to cationic polypeptides in IgA nephropathy. Clin Exp Immunol 73(2):300–306PubMed

100.

Monteiro RC, Halbwachs-Mecarelli L, Roque-Barreira MC, Noel LH, Berger J, Lesavre P (1985) Charge and size of mesangial IgA in IgA nephropathy. Kidney Int 28(4):666–671PubMed

101.

Monteiro RC, Moura IC, Launay P, Tsuge T, Haddad E, Benhamou M, Cooper MD, Arcos-Fajardo M (2002) Pathogenic significance of IgA receptor interactions in IgA nephropathy. Trends Mol Med 8(10):464–468PubMed

102.

Moura IC, Arcos-Fajardo M, Sadaka C, Leroy V, Benhamou M, Novak J, Vrtovsnik F, Haddad E, Chintalacharuvu KR, Monteiro RC (2004) Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol 15(3):622–634PubMed

103.

Moura IC, Centelles MN, Arcos-Fajardo M, Malheiros DM, Collawn JF, Cooper MD, Monteiro RC (2001) Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med 194(4):417–425PubMed

104.

Nakamura I, Iwase H, Arai K, Nagai Y, Toma K, Katsumata T, Hiki Y, Kokubo T, Sano T, Kobayashi Y (2004) Detection of gender difference and epitope specificity of IgG antibody activity against IgA1 hinge portion in IgA nephropathy patients by using synthetic hinge peptide and glycopeptide probes. Nephrology (Carlton) 9(1):26–30

105.

Nakamura I, Iwase H, Ohba Y, Hiki Y, Katsumata T, Kobayashi Y (2002) Quantitative analysis of IgA1 binding protein prepared from human serum by hypoglycosylated IgA1/Sepharose affinity chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 776(1):101–106PubMed

106.

Nishie T, Miyaishi O, Azuma H, Kameyama A, Naruse C, Hashimoto N, Yokoyama H, Narimatsu H, Wada T, Asano M (2007) Development of immunoglobulin a nephropathy- like disease in {beta}-1,4-Galactosyltransferase-I-deficient mice. Am J Pathol 170(2):447–456PubMed

107.

Novak J, Moldoveanu Z, Renfrow MB, Yanagihara T, Suzuki H, Raska M, Hall S, Brown R, Huang WQ, Goepfert A, Kilian M, Poulsen K, Tomana M, Wyatt RJ, Julian BA, Mestecky J (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 157:134–138PubMedCrossRef

108.

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(2):504–513PubMed

109.

Olive C, Allen AC, Harper SJ, Wicks AC, Feehally J, Falk MC (1997) Expression of the mucosal gamma delta T cell receptor V region repertoire in patients with IgA nephropathy. Kidney Int 52(4):1047–1053PubMed

110.

Oortwijn BD, Roos A, Royle L, van Gijlswijk-Janssen DJ, Faber-Krol MC, Eijgenraam JW, Dwek RA, Daha MR, Rudd PM, van Kooten C (2006) Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy. J Am Soc Nephrol 17(12):3529–3539PubMed

111.

Oortwijn BD, van der Boog PJ, Roos A, van der Geest RN, de Fijter JW, Daha MR, van Kooten C (2006) A pathogenic role for secretory IgA in IgA nephropathy. Kidney Int 69(7):1131–1138PubMed

112.

Osborn L (1990) Leukocyte adhesion to endothelium in inflammation. Cell 62(1):3–6PubMed

113.

Paynter HE, Banks RA (1998) Evolution of IgA nephropathy into Henoch–Schoenlein purpura in an adult. Clin Nephrol 49(2):121–123PubMed

114.

Peruzzi L, Amore A, Cirina P, Trusolino L, Basso G, Ricotti E, Emancipator SN, Marchisio PC, Coppo R (2000) Integrin expression and IgA nephropathy: in vitro modulation by IgA with altered glycosylation and macromolecular IgA. Kidney Int 58(6):2331–2340PubMed

115.

Qin W, Zhou Q, Yang LC, Li Z, Su BH, Luo H, Fan JM (2005) Peripheral B lymphocyte beta1,3-galactosyltransferase and chaperone expression in immunoglobulin A nephropathy. J Intern Med 258(5):467–477PubMed

116.

Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR (2000) The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes. J Exp Med 191(12):2171–2182PubMed

117.

Rifai A, Schena FP, Montinaro V, Mele M, D'Addabbo A, Nitti L, Pezzullo JC (1989) Clearance kinetics and fate of macromolecular IgA in patients with IgA nephropathy. Lab Invest 61(4):381–388PubMed

118.

Rigby S, Dailey MO (2000) Traffic of L-selectin-negative T cells to sites of inflammation. Eur J Immunol 30(1):98–107PubMed

119.

Roodnat JI, de Fijter JW, van Kooten C, Daha MR, van Es LA (1999) Decreased IgA1 response after primary oral immunization with live typhoid vaccine in primary IgA nephropathy. Nephrol Dial Transplant 14(2):353–359PubMed

120.

Roos A, Bouwman LH, van Gijlswijk-Janssen DJ, Faber-Krol MC, Stahl GL, Daha MR (2001) Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol 167(5):2861–2868PubMed

121.

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 (2006) Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol 17(6):1724–1734PubMed

122.

Rosen SD (2004) Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22:129–156PubMed

123.

Rott LS, Briskin MJ, Andrew DP, Berg EL, Butcher EC (1996) A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation. J Immunol 156(10):3727–3736PubMed

124.

Royle L, Roos A, Harvey DJ, Wormald MR, van Gijlswijk-Janssen D, Redwan el RM, Wilson IA, Daha MR, Dwek RA, Rudd PM (2003) Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems. J Biol Chem 278(22):20140–20153PubMed

125.

Sanfilippo F, Croker BP, Bollinger RR (1982) Fate of four cadaveric donor renal allografts with mesangial IgA deposits. Transplantation 33(4):370–376PubMed

126.

Schena FP, Scivittaro V, Ranieri E, Sinico R, Benuzzi S, Di Cillo M, Aventaggiato L (1993) Abnormalities of the IgA immune system in members of unrelated pedigrees from patients with IgA nephropathy. Clin Exp Immunol 92(1):139–144PubMedCrossRef

127.

Schietinger A, Philip M, Yoshida BA, Azadi P, Liu H, Meredith SC, Schreiber H (2006) A mutant chaperone converts a wild-type protein into a tumor-specific antigen. Science 314(5797):304–308PubMed

128.

Schweighoffer T, Tanaka Y, Tidswell M, Erle DJ, Horgan KJ, Luce GE, Lazarovits AI, Buck D, Shaw S (1993) Selective expression of integrin alpha 4 beta 7 on a subset of human CD4+memory T cells with Hallmarks of gut-trophism. J Immunol 151(2):717–729PubMed

129.

Smith AC, de Wolff JF, Molyneux K, Feehally J, Barratt J (2006) O-glycosylation of serum IgD in IgA nephropathy. J Am Soc Nephrol 17(4):1192–1199PubMed

130.

Smith AC, Molyneux K, Feehally J, Barratt J (2006) O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J Am Soc Nephrol 17(12):3520–3528PubMed

131.

Stad RK, Bruijn JA, van Gijlswijk-Janssen DJ, van Es LA, Daha MR (1993) An acute model for IgA-mediated glomerular inflammation in rats induced by monoclonal polymeric rat IgA antibodies. Clin Exp Immunol 92(3):514–521PubMedCrossRef

132.

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(6):2286–2294PubMed

133.

Takatani T, Iwase H, Itoh A, Nakamura I, Hayashi M, Sakamoto H, Kamata K, Kobayashi Y, Hiki Y, Okamoto M, Higashihara M (2004) Compositional similarity between immunoglobulins binding to asialo-, agalacto-IgA1-Sepharose and those deposited in glomeruli in IgA nephropathy. J Nephrol 17(5):679–686PubMed

134.

Tarelli E, Smith AC, Hendry BM, Challacombe SJ, Pouria S (2004) 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 339(13):2329–2335PubMed

135.

Tarkowski M, Pacheco KA, Rosenwasser LJ (2000) The effect of antigen stimulation on alpha(4), beta(1) and beta(7) chain integrin expression and function in CD4+cells. Int Arch Allergy Immunol 121(1):25–33PubMed

136.

Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J (1997) Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int 52(2):509–516PubMed

137.

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(1):73–81PubMed

138.

Tomino Y (2007) Pathogenesis of IgA nephropathy. Contrib Nephrol 157:1–7PubMed

139.

Tomino Y, Endoh M, Nomoto Y, Sakai H (1982) Specificity of eluted antibody from renal tissues of patients with IgA nephropathy. Am J Kidney Dis 1(5):276–280PubMed

140.

van den Wall Bake AW, Beyer WE, Evers-Schouten JH, Hermans J, Daha MR, Masurel N, van Es LA (1989) Humoral immune response to influenza vaccination in patients with primary immunoglobulin A nephropathy. An analysis of isotype distribution and size of the influenza-specific antibodies. J Clin Invest 84(4):1070–1075PubMedCrossRef

141.

van den Wall Bake AW, Daha MR, Evers-Schouten J, van Es LA (1988) Serum IgA and the production of IgA by peripheral blood and bone marrow lymphocytes in patients with primary IgA nephropathy: evidence for the bone marrow as the source of mesangial IgA. Am J Kidney Dis 12(5):410–414PubMed

142.

van der Boog PJ, van Kooten C, de Fijter JW, Daha MR (2005) Role of macromolecular IgA in IgA nephropathy. Kidney Int 67(3):813–821PubMed

143.

Van Dixhoorn MG, Sato T, Muizert Y, Van Gijlswijk-Janssen DJ, De Heer E, Daha MR (2000) Combined glomerular deposition of polymeric rat IgA and IgG aggravates renal inflammation. Kidney Int 58(1):90–99PubMed

144.

van Egmond M, van Garderen E, van Spriel AB, Damen CA, van Amersfoort ES, van Zandbergen G, van Hattum J, Kuiper J, van de Winkel JG (2000) FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 6(6):680–685PubMed

145.

van Zandbergen G, van Kooten C, Mohamad NK, Reterink TJ, de Fijter JW, van de Winkel JG, Daha MR (1998) Reduced binding of immunoglobulin A (IgA) from patients with primary IgA nephropathy to the myeloid IgA Fc-receptor, CD89. Nephrol Dial Transplant 13(12):3058–3064PubMed

146.

Wang Y, Zhao MH, Zhang YK, Li XM, Wang HY (2004) Binding capacity and pathophysiological effects of IgA1 from patients with IgA nephropathy on human glomerular mesangial cells. Clin Exp Immunol 136(1):168–175PubMed

147.

Westberg NG, Baklien K, Schmekel B, Gillberg R, Brandtzaeg P (1983) Quantitation of immunoglobulin-producing cells in small intestinal mucosa of patients with IgA nephropathy. Clin Immunol Immunopathol 26(3):442–445PubMed

148.

Westerhuis R, Van Zandbergen G, Verhagen NA, Klar-Mohamad N, Daha MR, van Kooten C (1999) Human mesangial cells in culture and in kidney sections fail to express Fc alpha receptor (CD89). J Am Soc Nephrol 10(4):770–778PubMed

149.

Wiedle G, Dunon D, Imhof BA (2001) Current concepts in lymphocyte homing and recirculation. Crit Rev Clin Lab Sci 38(1):1–31PubMed

150.

Wiercinski R, Zoch-Zwierz W, Stasiak-Barmuta A, Wasilewska A, Tomaszewska B, Winiecka W (2004) Assessment of selected adhesion molecules and lymphocyte subpopulations in children with IgA nephropathy. Rocz Akad Med Bialymst 49:106–110PubMed

151.

Wyatt RJ (1993) The complement system in IgA nephropathy and Henoch-Schonlein purpura: functional and genetic aspects. Contrib Nephrol 104:82–91PubMed

152.

Xu LX, Yan Y, Zhang JJ, Zhang Y, Zhao MH (2005) The glycans deficiencies of macromolecular IgA1 is a contributory factor of variable pathological phenotypes of IgA nephropathy. Clin Exp Immunol 142(3):569–575PubMed

153.

Xu LX, Zhao MH (2005) Aberrantly glycosylated serum IgA1 are closely associated with pathologic phenotypes of IgA nephropathy. Kidney Int 68(1):167–172PubMed

154.

Yan Y, Xu LX, Zhang JJ, Zhang Y, Zhao MH (2006) Self-aggregated deglycosylated IgA1 with or without IgG were associated with the development of IgA nephropathy. Clin Exp Immunol 144(1):17–24PubMed

155.

Yoshioka K, Takemura T, Aya N, Akano N, Miyamoto H, Maki S (1989) Monocyte infiltration and cross-linked fibrin deposition in IgA nephritis and Henoch–Schoenlein purpura nephritis. Clin Nephrol 32(3):107–112PubMed

156.

Zhang W, Lachmann PJ (1994) Glycosylation of IgA is required for optimal activation of the alternative complement pathway by immune complexes. Immunology 81(1):137–141PubMed

Title: Immunopathogenesis of IgAN
Authors: Jonathan Barratt
Alice C. Smith
Karen Molyneux
John Feehally
Publication date: 01-11-2007
Publisher: Springer-Verlag
Published in: Seminars in Immunopathology / Issue 4/2007
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-007-0089-9

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