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Table of Contents
Vol. 31, No. 1, 2008
Issue release date: February 2008
Section title: Review
Free Access
Kidney Blood Press Res 2008;31:29–37
(DOI:10.1159/000112922)

Role of Aberrant Glycosylation of IgA1 Molecules in the Pathogenesis of IgA Nephropathy

Mestecky J.a, b, g · Tomana M.b · Moldoveanu Z.a · Julian B.A.a, b · Suzuki H.a, f · Matousovic K.a, g · Renfrow M.B.c · Novak L.d · Wyatt R.J.e · Novak J.a
Departments of aMicrobiology, bMedicine, cBiochemistry/Molecular Genetics, and dPathology, University of Alabama at Birmingham, Birmingham, Ala., and eUniversity of Tennessee Health Science Center, Memphis, Tenn., USA; fJuntendo University School of Medicine, Tokyo, Japan; gCharles University, Schools of Medicine, Prague and Pilsen, Czech Republic
email Corresponding Author

Abstract

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


  

Key Words

  • IgA nephropathy
  • Glycosylation
  • Immune complexes
  • Glycosyltransferases

References

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  2. Barratt J, Feehally J: IgA Nephropathy. J Am Soc Nephrol 2005;16:2088–2097.
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  4. Smith AC, Feehally J: New insights into the pathogenesis of IgA nephropathy: pathogenesis of IgA nephropathy. Springer Semin Immunopathol 2003;24:477–493.
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  6. 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.
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  8. 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.
  9. 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.
  10. 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.
  11. 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.
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    External Resources

  17. 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.
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  25. 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.
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  27. 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.
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Author Contacts

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 mestecky@uab.edu

  

Article Information

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

  

Publication Details

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)

For additional information: http://www.karger.com/KBR


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References

  1. Berger J, Hinglais N: Les dépôts intercapillaires d’IgA-IgG (intercapillary deposits of IgA-IgG). J Urol Nephrol 1968;74:694–695.
  2. Barratt J, Feehally J: IgA Nephropathy. J Am Soc Nephrol 2005;16:2088–2097.
  3. Coppo R, Amore A: Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int 2004;65:1544–1547.
  4. Smith AC, Feehally J: New insights into the pathogenesis of IgA nephropathy: pathogenesis of IgA nephropathy. Springer Semin Immunopathol 2003;24:477–493.
  5. Mestecky J, Russell MW: IgA subclasses. Monogr Allergy 1986;19:277–301.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Emancipator SN, Gallo GR, Lamm ME: Experimental IgA nephropathy induced by oral immunization. J Exp Med 1983;157:572–582.
  15. 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.
  16. Ballardie FW, Brenchley PE, Williams S, O’Donoghue DJ: Autoimmunity in IgA nephropathy. Lancet 1988;ii:588–592.

    External Resources

  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. Conley ME, Delacroix DL: Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med 1987;106:892–899.
  24. Mestecky J, Russell MW, Jackson S, Brown TA: The human IgA system: a reassessment. Clin Immunol Immunopathol 1986;40:105–114.
  25. 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.
  26. 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.
  27. 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.
  28. Tomana M, Kulhavy R, Mestecky J: Receptor-mediated binding and uptake of immunoglobulin A by human liver. Gastroenterology 1988;94:762–770.
  29. 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.
  30. Sumiyama K, Saitou N, Ueda S: Adaptive evolution of the IgA hinge region in primates. Mol Biol Evol 2002;19:1093–1099.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
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