Advertisement

Seminars in Immunopathology

, Volume 40, Issue 6, pp 539–543 | Cite as

IgA nephropathy: clearance kinetics of IgA-containing immune complexes

  • Ann Chen
  • Sung-Sen Yang
  • Tsai-Jung Lin
  • Shuk-Man Ka
Review
  • 175 Downloads

Abstract

IgA nephropathy (IgAN) is associated predominantly IgA deposition in the affected glomeruli and has been shown to be the most common glomerular disorder among young people in the world. Although the exact pathogenic mechanism underlying IgAN remains largely unknown, circulating IgA-containing immune complexes (IgA ICs) is considered to play a major role in initiating the development and evolution of the renal disorder. In this review article, we discuss the fundamental mechanisms of clearance kinetics of IgA ICs and related issues, covering the following: (1) role of circulating IgA ICs in the pathogenesis of IgAN and (2) elimination of IgA ICs from the body, with emphasis of the role of the liver and Fc receptors in immune cells.

Keywords

IgA nephropathy IgA immune complex Clearance kinetics Mononuclear phagocyte Kupffer cell Fc receptor CD89 (Fc alpha/muR) 

Notes

Funding information

This work was supported by grants Ministry of National Defense—Medical Affairs Bureau—MAB-106-007 from the National Defense Medical Center and TSGH-C107-063 from the Tri-Service General Hospital, Taipei, Taiwan.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    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(10):1795–1803CrossRefGoogle Scholar
  2. 2.
    Kiryluk K, Novak J (2014) The genetics and immunobiology of IgA nephropathy. J Clin Invest 124(6):2325–2332CrossRefGoogle Scholar
  3. 3.
    Novak J, Rizk D, Takahashi K, Zhang X, Bian Q, Ueda H, Ueda Y, Reily C, Lai LY, Hao C, Novak L, Huang ZQ, Renfrow MB, Suzuki H, Julian BA (2015) New insights into the pathogenesis of IgA nephropathy. Kidney Dis (Basel) 1(1):8–18 Epub 2015 May 1CrossRefGoogle Scholar
  4. 4.
    Salvadori M, Rosso G (2015) Update on immunoglobulin a nephropathy. Part I: Pathophysiology World J Nephrol 4(4):455–467PubMedGoogle Scholar
  5. 5.
    Allen AC, Willis FR, Beattie TJ, Feehally J (1998) Abnormal IgA glycosylation in Henoch-Schönlein purpura restricted to patients with clinical nephritis. Nephrol Dial Transplant 13(4):930–934CrossRefGoogle Scholar
  6. 6.
    Launay P, Grossetête B, Arcos-Fajardo M, Gaudin E, Torres SP, Beaudoin L, Patey-Mariaud de Serre N, Lehuen A, Monteiro RC. Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger’s disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice. J Exp Med 2000;191(11):1999–2009Google Scholar
  7. 7.
    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):504–513CrossRefGoogle Scholar
  8. 8.
    Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, Raska M, Renfrow MB, Julian BA, Novak J (2016) The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol 7:117CrossRefGoogle Scholar
  9. 9.
    Rodrigues JC, Haas M, Reich HN (2017) IgA nephropathy. Clin J Am Soc Nephrol 12(4):677–686 ReviewCrossRefGoogle Scholar
  10. 10.
    Canetta PA, Kiryluk K, Appel GB (2014) Glomerular diseases: emerging tests and therapies for IgA nephropathy. Clin J Am Soc Nephrol 9(3):617–625 ReviewCrossRefGoogle Scholar
  11. 11.
    Moreno JA, Martín-Cleary C, Gutiérrez E, Toldos O, Blanco-Colio LM, Praga M, Ortiz A, Egido J (2012) AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences. Clin J Am Soc Nephrol 7(1):175–184 ReviewCrossRefGoogle Scholar
  12. 12.
    Floege J, Eitner F (2011) Current therapy for IgA nephropathy. J Am Soc Nephrol 22(10):1785–1794 ReviewCrossRefGoogle Scholar
  13. 13.
    Ballardie FW (2007) Quantitative appraisal of treatment options for IgA nephropathy. J Am Soc Nephrol 18(11):2806–2809 ReviewCrossRefGoogle Scholar
  14. 14.
    Tumlin JA, Madaio MP, Hennigar R (2007) Idiopathic IgA nephropathy: pathogenesis, histopathology, and therapeutic options. Clin J Am Soc Nephrol 2(5):1054–1061 ReviewCrossRefGoogle Scholar
  15. 15.
    Yamada K, Huang ZQ, Raska M, Reily C, Anderson JC, Suzuki H, Ueda H, Moldoveanu Z, Kiryluk K, Suzuki Y, Wyatt RJ, Tomino Y, Gharavi AG, Weinmann A, Julian BA, Willey CD, Novak J (2017) Inhibition of STAT3 signaling reduces IgA1 autoantigen production in IgA nephropathy. Kidney Int Rep 2(6):1194–1207CrossRefGoogle Scholar
  16. 16.
    Nagai K, Tominaga T, Ueda S, Shibata E, Tamaki M, Matsuura M, Kishi S, Murakami T, Moriya T, Abe H, Doi T (2017) Mesangial cell mammalian target of rapamycin complex 1 activation results in mesangial expansion. J Am Soc Nephrol 28(10):2879–2885CrossRefGoogle Scholar
  17. 17.
    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 13(2):e1006609CrossRefGoogle Scholar
  18. 18.
    Mirfazeli ES, Marashi SA, Kalantari S (2016) In silico prediction of specific pathways that regulate mesangial cell proliferation in IgA nephropathy. Med Hypotheses 97:38–45CrossRefGoogle Scholar
  19. 19.
    Shen P, Shen J, Sun C, Yang X, He L (2016) A system biology approach to understanding the molecular mechanisms of Gubentongluo decoction acting on IgA nephropathy. BMC Complement Altern Med 16(1):312CrossRefGoogle Scholar
  20. 20.
    Moore JS, Kulhavy R, Tomana M, Moldoveanu Z, Suzuki H, Brown R, Hall S, Kilian M, Poulsen K, Mestecky J, Julian BA, Novak J (2007) Reactivities of N-acetylgalactosamine-specific lectins with human IgA1 proteins. Mol Immunol 44(10):2598–2604CrossRefGoogle Scholar
  21. 21.
    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 (2011) Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43(4):321–327CrossRefGoogle Scholar
  22. 22.
    Xu L, Li B, Huang M, Xie K, Li D, Li Y, Gu H, Fang J (2016 Jul 20) Critical role of Kupffer cell CD89 expression in experimental IgA nephropathy. PLoS One 11(7):e0159426CrossRefGoogle Scholar
  23. 23.
    Rifai A, Mannik M (1983) Clearance kinetics and fate of mouse IgA immune complexes prepared with monomeric or dimeric IgA. J Immunol 130(4):1826–1832PubMedGoogle Scholar
  24. 24.
    Rifai A, Mannik M (1983) The clearance kinetics and hepatic localization of IgA-immune complexes in mice. Ann N Y Acad Sci 409(1):861–863CrossRefGoogle Scholar
  25. 25.
    Morton HC, van Egmond M, van de Winkel JG. Structure and function of human IgA Fc receptors (Fc alpha R). Crit Rev Immunol 1996;16(4):423–440Google Scholar
  26. 26.
    Grossetête 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):1321–1335CrossRefGoogle Scholar
  27. 27.
    Emancipator SN, Gallo GR, Razaboni R, Lamm ME (1983) Experimental cholestasis promotes the deposition of glomerular IgA immune complexes. Am J Pathol 113(1):19–26PubMedPubMedCentralGoogle Scholar
  28. 28.
    Gormly AA, Smith PS, Seymour AE, Clarkson AR, Woodroffe AJ (1981) IgA glomerular deposits in experimental cirrhosis. Am J Pathol 104(1):50–54PubMedPubMedCentralGoogle Scholar
  29. 29.
    Hogg R, Silva F (1987) IgA nephropathy in children. In: Clarkson A (ed) IgA nephropathy. Martinus Nijhoff, Boston, pp 16–38CrossRefGoogle Scholar
  30. 30.
    Haakenstad AO, Mannik M (1974) Saturation of the reticuloendothelial system with soluble immune complexes. J Immunol 112(5):193919–193948Google Scholar
  31. 31.
    Arend WP, Mannik M (1971) Studies on antigen-antibody complexes. II. Quantification of tissue uptake of soluble complexes in normal and complement-depleted rabbits. J Immunol 107(1):63–75PubMedGoogle Scholar
  32. 32.
    Rifai A, Small P Jr, Ayoub EM (1984) Experimental IgA nephropathy. Factors governing the persistence of IgA-antigen complexes in the circulation of mice. Contrib Nephrol 40:37–44CrossRefGoogle Scholar
  33. 33.
    Melvin T, Burke B, Michael AF, Kim Y (1983) Experimental IgA nephropathy in bile duct ligated rats. Clin Immunol Immunopathol 27(3):369–377CrossRefGoogle Scholar
  34. 34.
    Egido J, Gonzalez E, Gonzalez Cabrero J, de Nicolas R, Herrero-Beaumont G, Sancho J. The role of circulating immune complexes and the liver in the development of IgA nephropathy in mice. Semin Nephrol 1987;7(4):289–293Google Scholar
  35. 35.
    Chen A, Ding SL, Sheu LF, Song YB, Shieh SD, Shaio MF, Chou WY, Ho YS (1994) Experimental IgA nephropathy. Enhanced deposition of glomerular IgA immune complex in proteinuric states. Lab Investig 70(5):639–647PubMedGoogle Scholar
  36. 36.
    Sato M, Ideura T, Koshikawa S (1986) Experimental IgA nephropathy in mice. Lab Investig 54(4):377–3784PubMedGoogle Scholar
  37. 37.
    Benacerraf B, Sebestyen M, Cooper NS (1959) The clearance of antigen antibody complexes from the blood by the reticuloendothelial system. J Immunol 82(2):131–137PubMedGoogle Scholar
  38. 38.
    Stewart WW, Kerr MA (1990) The specificity of the human neutrophil IgA receptor (Fc alpha R) determined by measurement of chemiluminescence induced by serum or secretory IgA1 or IgA2. Immunology 71(3):328–334PubMedPubMedCentralGoogle Scholar
  39. 39.
    Bakema JE, van Egmond M. The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity. Mucosal Immunol 2011;4(6):612–624. ReviewCrossRefGoogle Scholar
  40. 40.
    van Dijk TB, Bracke M, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP. Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils. Blood 1996;88(11):4229–4238Google Scholar
  41. 41.
    Yin N, Peng M, Xing Y, Zhang W (2007) Intracellular pools of FcalphaR (CD89) in human neutrophils are localized in tertiary granules and secretory vesicles, and two FcalphaR isoforms are found in tertiary granules. J Leukoc Biol 82(3):551–558CrossRefGoogle Scholar
  42. 42.
    Strober W, Hague NE, Lum LG, Henkart PA (1978) IgA-Fc receptors on mouse lymphoid cells. J Immunol 121(6):2440–2445PubMedGoogle Scholar
  43. 43.
    Rifai A, Mannik M (1984) Clearance of circulating IgA immune complexes is mediated by a specific receptor on Kupffer cells in mice. J Exp Med 160(1):125–137CrossRefGoogle Scholar
  44. 44.
    Monteiro RC, Van De Winkel JG. IgA Fc receptors. Annu Rev Immunol 2003;21:177–204Google Scholar
  45. 45.
    Patry C, Sibille Y, Lehuen A, Monteiro RC (1996) Identification of Fc alpha receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages. J Immunol 156(11):4442–4448PubMedGoogle Scholar
  46. 46.
    van Zandbergen G, van Kooten C, Mohamad NK, Reterink TJ, de Fijter JW, van de Winkel JG, Daha MR. Reduced binding of immunoglobulin A (IgA) from patients with primary IgA nephropathy to the myeloid IgA Fc-receptor, CD89. Nephrol Dial Transplant 1998;13(12):3058–3064Google Scholar
  47. 47.
    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. FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 2000;6(6):68068–68065Google Scholar
  48. 48.
    Bogers WM, Stad RK, Janssen DJ, Prins FA, van Rooijen N, van Es LA, Daha MR. Kupffer cell depletion in vivo results in clearance of large-sized IgA aggregates in rats by liver endothelial cells. Clin Exp Immunol 1991;85(1):128–136CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ann Chen
    • 1
  • Sung-Sen Yang
    • 2
    • 3
  • Tsai-Jung Lin
    • 1
  • Shuk-Man Ka
    • 4
  1. 1.Department of PathologyTri-Service General Hospital, National Defense Medical CenterTaipeiTaiwan
  2. 2.Graduate Institute of Medical SciencesNational Defense Medical CenterTaipeiTaiwan
  3. 3.Division of Nephrology, Department of Internal MedicineTri-Service General Hospital, National Defense Medical CenterTaipeiTaiwan
  4. 4.Graduate Institute of Aerospace and Undersea MedicineNational Defense Medical CenterTaipeiTaiwan

Personalised recommendations