Studies of the properties of immune complexes (IC) in the circulation, urine, and mesangium of IgA nephropathy (IgAN) patients have provided data relevant to the pathogenesis of this disease. IC contain predominantly polymeric IgA1 molecules which are deficient in galactose (Gal) residues on O-linked glycan chains in the hinge region (HR) of their heavy (H) chains. As a result of this aberrancy, a novel antigenic determinant(s) involving N-acetylgalactosamine (GalNAc) and perhaps sialic acid (SA) of O-linked glycans is generated and recognized by naturally occurring GalNAc-specific antibodies. Thus, IC in IgAN consist of Gal-deficient IgA1 molecules as an antigen, and GalNAc-specific IgG and/or IgA1 as an antibody. IgG antibodies to Gal-deficient IgA1 are probably induced by cross-reactive microbial antigens; they are present at variable levels not only in humans with or without IgAN but also in many phylogenetically diverse vertebrate species. Incubation of human mesangial cells with IC from sera of IgAN patients indicated that stimulation of cellular proliferative activity was restricted to the large (>800 kDa) complexes. These findings suggest that experimental approaches that prevent the formation of large Gal-deficient IgA1-IgG IC may be applied ultimately in an immunologically mediated therapy.
© 2008 S. Karger AG, Basel
- IgA nephropathy
- Immune complexes
- Berger J, Hinglais N: Les dépôts intercapillaires d’IgA-IgG (intercapillary deposits of IgA-IgG). J Urol Nephrol 1968;74:694–695.
- Barratt J, Feehally J: IgA Nephropathy. J Am Soc Nephrol 2005;16:2088–2097.
- Coppo R, Amore A: Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int 2004;65:1544–1547.
- Smith AC, Feehally J: New insights into the pathogenesis of IgA nephropathy: pathogenesis of IgA nephropathy. Springer Semin Immunopathol 2003;24:477–493.
- Mestecky J, Russell MW: IgA subclasses. Monogr Allergy 1986;19:277–301.
- Mestecky J, Lue C, Tarkowski A, Ladjeva I, Peterman J, Moldoveanu Z, Russell MW, Brown TA, Radl J, Haaijman JJ, Kiyono H, McGhee JR: Comparative studies of the biological properties of human IgA subclasses. Protides Biol Fluids 1989;36:173–182.
- Mestecky J, Moro I, Kerr MA, Woof JM: Mucosal immunoglobulins; in Mestecky J, Bienenstock J, Lamm ME, Mayer L, McGhee JR, Strober W (eds): Mucosal Immunology, ed 3. Amsterdam, Elsevier/Academic Press, 2005, pp 153–181.
- Conley ME, Cooper MD, Michael AF: Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest 1980;66:1432–1436.
- Russell MW, Mestecky J, Julian BA, Galla JH: IgA-associated renal diseases: antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin Immunol 1986;6:74–86.
- Lai KN, Chan KW, Mac-Moune F, Ho CP, Yan KW, Lam CW, Vallance-Owen J: The immunochemical characterization of the light chains in the mesangial IgA deposits in IgA nephropathy. Am J Clin Pathol 1986;85:548–551.
- Czerkinsky C, Koopman WJ, Jackson S, Collins JE, Crago SS, Schrohenloher RE, Julian BA, Galla JH, Mestecky J: Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies. J Clin Invest 1986;77:1931–1938.
- Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J: Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int 1997;52:509–516.
- Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J: Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest 1999;104:73–81.
- Emancipator SN, Gallo GR, Lamm ME: Experimental IgA nephropathy induced by oral immunization. J Exp Med 1983;157:572–582.
- Mestecky J, Waldo FB, Britt WJ, Julian BA, Tomana M, van den Wall Bake AWL, Russell MW, Galla JH, Moldoveanu Z, Jackson S: Exogenous antigens deposited in the glomeruli of patients with IgA nephropathy; in Sakai H, Sakai O, Nomoto Y (eds): Pathogenesis of IgA Nephropathy. Tokyo, Harcourt Brace Jovanovich, 1990, pp 247–257.
- Ballardie FW, Brenchley PE, Williams S, O’Donoghue DJ: Autoimmunity in IgA nephropathy. Lancet 1988;ii:588–592.
- van den Wall Bake AWL, Kirk KA, Gay RE, Switalski LM, Julian BA, Jackson S, Gay S, Mestecky J: Binding of serum immunoglobulins to collagens in IgA nephropathy and HIV infection. Kidney Int 1992;42:374–382.
- André PM, Le Pogamp P, Chevet D: Impairment of jacalin binding to serum IgA in IgA nephropathy. J Clin Lab Anal 1990;4:115–119.
- Mestecky J, Tomana M, Crowley-Nowick PA, Moldoveanu Z, Julian BA, Jackson S: Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib Nephrol. Basel, Karger, 1993, vol 104, pp 172–182.
- Allen AC, Bailey EM, Brenchley PEC, Buck KS, Barratt J, and Feehally J: Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney Int 2001;60:969–973.
- 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;59:1077–1085.
- Mestecky J, Hashim OH, Tomana M: Alterations in the IgA carbohydrate chains influence the cellular distribution of IgA1. Contrib Nephrol. Basel, Karger, 1995, vol 111, pp 66–72.
- Conley ME, Delacroix DL: Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med 1987;106:892–899.
- Mestecky J, Russell MW, Jackson S, Brown TA: The human IgA system: a reassessment. Clin Immunol Immunopathol 1986;40:105–114.
- Stockert RJ, Kressner MS, Collins JC, Sternlieb I, Morell AG: IgA interaction with the asialoglycoprotein receptor. Proc Natl Acad Sci USA 1982;79:6229–6231.
- Mestecky J, Moldoveanu Z, Tomana M, Epps JM, Thorpe SR, Phillips JO, Kulhavy R: The role of the liver in catabolism of mouse and human IgA. Immunol Invest 1989;18:313–324.
- Moldoveanu Z, Moro I, Radl J, Thorpe SR, Komiyama K, Mestecky J: Site of catabolism of autologous and heterologous IgA in non-human primates. Scand J Immunol 1990;32:577–583.
- Tomana M, Kulhavy R, Mestecky J: Receptor-mediated binding and uptake of immunoglobulin A by human liver. Gastroenterology 1988;94:762–770.
- 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;62:465–475.
- Sumiyama K, Saitou N, Ueda S: Adaptive evolution of the IgA hinge region in primates. Mol Biol Evol 2002;19:1093–1099.
- Kilian M, Russell MW: Microbial evasion of IgA functions; in Mestecky J, Bienenstock J, Lamm ME, Mayer L, McGhee JR, Strober W (eds): Mucosal Immunology, ed 3. Amsterdam, Elsevier/Academic Press, 2005, pp 291–303.
- Novak J, Tomana M, Kilian M, Coward L, Kulhavy R, Barnes S, Mestecky J: Heterogeneity of O-glycosylation in the hinge region of human IgA1. Mol Immunol 2000;37:1047–1056.
- Renfrow MB, Cooper HJ, Tomana M, Kulhavy R, Hiki Y, Toma K, Emmett MR, Mestecky J, Marshall AG, Novak J: Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation Fourier transform-ion cyclotron resonance mass spectrometry. J Biol Chem 2005;280:19136–19145.
- Renfrow MB, Mackay CL, Chalmers MJ, Julian BA, Mestecky J, Kilian M, Poulsen K, Emmett MR, Marxhall AG, Novak J: Analysis of O-glycan heterogeneity in IgA1 myeloma proteins by Fourier transform ion cyclotron resonance mass spectrometry: implications for IgA nephropathy. Anal Bioanal Chem 2007;389:1397–1407.
- 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. Basel, Karger, 2007, vol 157, pp 134–138.
- Mestecky J, Suzuki H, Yanagihara T, Moldoveanu Z, Tomana M, Matousovic K, Julian BA, Novak J: IgA nephropathy: current views of immune complex formation. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 56–63.
- Moore JS, Kulhavy R, Tomana M, Moldoveanu Z, Suzuki H, Brown R, Hall S, Kilian M, Poulsen K, Mestecky J, Julian BA, Novak J: Reactivities of N-acetylgalactosamine-specific lectins with human IgA1 proteins. Mol Immunol 2007;44:2598–2604.
- Suzuki H, Moldoveanu Z, Hall S, Brown R, Julian BA, Wyatt RJ, Tomana M, Tomino Y, Novak J, Mestecky J: IgA nephropathy: characterization of IgG antibodies specific for galactose-deficient IgA1. Contrib Nephrol. Karger, Basel, 2007, vol 157, pp 129–133.
- Barratt J, Feehally J, Smith AC: Pathogenesis of IgA nephropathy. Semin Nephrol 2004;24:197–217.
- Novak J, Julian BA, Tomana M, Mestecky J: Progress in molecular and genetic studies of IgA nephropathy. J Clin Immunol 2001;21:310–327.
- Jackson S: Immunoglobulin A-antiimmunoglobulin interactions and immune complexes in IgA nephropathy. Am J Kidney Dis 1988;12:425–429.
- Jackson S, Montgomery RI, Julian BA, Galla JH, Czerkinsky C: Aberrant synthesis of antibodies directed at the Fab fragment of IgA in patients with IgA nephropathies. Clin Immunol Immunopathol 1987;45:208–213.
- Jackson S, Montgomery RI, Mestecky J, Czerkinsky C: Normal human sera contain antibodies directed at Fab of IgA. J Immunol 1987;138:2244–2248.
- Jackson S, Montgomery RI, Mestecky J, Julian BA, Galla JH, Czerkinsky C: Antibodies directed at Fab of IgA in the sera of normal individuals and IgA nephropathy patients. Adv Exp Med Biol 1987;216B:1537–1544.
- Iwasaki H, Zhang Y, Tachibana K, Gotoh M, Kikuchi N, Kwon YD, 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-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 2. J Biol Chem 2003;278:5613–5621.
- Ju T, Brewer K, D’Souza A, Cummings RD, Canfield WM: Cloning and expression of human core 1 β1,3-galactosyltransferase. J Biol Chem 2002;277:178–186.
- Ju T, Cummings RD: A unique molecular chaperone Cosmc required for activity of the mammalian core 1 β 3-galactosyltransferase. Proc Natl Acad Sci USA 2002;99:16613–16618.
- Ju T, Cummings RD: Protein glycosylation: chaperone mutation in Tn syndrome. Nature 2005;437:1252.
- Kudo T, Iwai T, Kubota T, Iwasaki H, Takayma Y, Hiruma T, Inaba N, Zhang Y, Gotoh M, Togayachi A, Narimatsu H: Molecular cloning and characterization of a novel UDP-Gal:GalNAc(α) peptide β 1,3-galactosyltransferase (C1Gal-T2), an enzyme synthesizing a core 1 structure of O-glycan. J Biol Chem 2002;277:47724–47731.
- Raska M, Moldoveanu Z, Suzuki H, Brown R, Kulhavy R, Andrasi J, Hall S, Vu HL, Carlsson F, Lindahl G, Tomana M, Julian BA, Wyatt RJ, Mestecky J, Novak J: Identification and characterization of CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase in IgA1-producing cells. J Mol Biol 2007;369:69–78.
- Schachter H, McGuire EJ, Roseman S: Sialic acids. 13. A uridine diphosphate D-galactose: mucin galactosyltransferase from porcine submaxillary gland. J Biol Chem 1971;246:5321–5328.
- Julian BA, Wyatt RJ, Matousovic K, Moldoveanu Z, Mestecky J, Novak J: IgA nephropathy: a clinical overview. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 19–26.
- 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;67:504–513.
- Matousovic K, Novak J, Yanagihara T, Tomana M, Moldoveanu Z, Kulhavy R, Julian BA, Konecny K, Mestecky J: IgA-containing immune complexes in the urine of IgA nephropathy patients. Nephrol Dial Transplant 2006;21:2478–2484.
- Leung JC, Tsang AW, Chan LY, Tang SC, Lam MF, Lai KN: Size-dependent binding of IgA to HepG2, U937, and human mesangial cells. J Lab Clin Med 2002;140:398–406.
- 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;11:241–249.
- Chui D, Sellakumar G, Green R, Sutton-Smith M, McQuistan T, Marek K, Morris H, Dell A, Marth J: Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc Natl Acad Sci USA 2001;98:1142–1147.
- Dwek RA: Glycobiology: more functions for oligosaccharides. Science 1995;269:1234–1235.
- Varki A: Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 1993;3:97–130.
- Nose M, Wigzell H: Biological significance of carbohydrate chains on monoclonal antibodies. Proc Natl Acad Sci USA 1983;80:6632–6637.
- Mestecky J, Tomana M: Structural heterogeneity of glycans in immunoglobulin molecules: Implications in IgA nephropathy. Nephrology 1997;3:S653–S657.
- Moore JS, Wu X, Kulhavy R, Tomana M, Novak J, Moldoveanu Z, Brown R, Goepfert PA, Mestecky J: Increased levels of galactose-deficient IgG in sera of HIV-1-infected individuals. AIDS 2005;19:381–389.
- Novak J, Tomana M, Shah GR, Brown R, Mestecky J: Heterogeneity of IgG glycosylation in adult periodontal disease. J Dent Res 2005;84:897–901.
- Keusch J, Lydyard PM, Delves PJ: The effect on IgG glycosylation of altering β1, 4-galactosyltransferase-1 activity in B cells. Glycobiology 1998;8:1215–1220.
- Malhotra R, Wormald MR, Rudd PM, Fischer PB, Dwek RA, Sim RB: Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat Med 1995;1:237–243.
- Berger EG: Tn-syndrome. Biochim Biophys Acta 1999;1455:255–268.
- Dahr W, Uhlenbruck G, Gunson HH, Van Der Hart M: Molecular basis of Tn-polyagglutinability. Vox Sang 1975;29:36–50.
- Thurnher M, Rusconi S, Berger EG: Persistent repression of a functional allele can be responsible for galactosyltransferase deficiency in Tn syndrome. J Clin Invest 1993;91:2103–2110.
- Dausset J, Moullec J, Bernard J: Acquired hemolytic anemia with polyagglutinability of red blood cells due to a new factor present in normal human serum (Anti-Tn). Blood 1959;14:1079–1093.
- 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: Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int 2007;71:1148–1154.
- Mattu TS, Pleass RJ, Willis AC, Kilian M, Wormald MR, Lellouch AC, Rudd PM, Woof JM, Dwek RA: The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fc α receptor interactions. J Biol Chem 1998;273:2260–2272.
- Mestecky J, Novak J, Julian BA, Tomana M: Pathogenic potential of galactose-deficient IgA1 in IgA nephropathy. Nephrology 2002;7:S92–S99.
Jiri Mestecky, MD, PhD
Department of Microbiology, University of Alabama at Birmingham
Box 1 845, 19th Street South
Birmingham, AL 35294-2170 (USA)
Tel. +1 205 934 2225, Fax +1 205 934 3894, E-Mail email@example.com
Received: September 19, 2007
Accepted: November 2, 2007
Published online: January 8, 2008
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 1, Number of References : 72
Kidney and Blood Pressure Research
Vol. 31, No. 1, Year 2008 (Cover Date: February 2008)
Journal Editor: Wanner, C. (Würzburg)
ISSN: 1420–4096 (Print), eISSN: 1423–0143 (Online)
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