Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: alloimmunization in renal diseases

Nature Clinical Practice Nephrology volume 2, pages 388–397 (2006)Cite this article

Abstract

Graft rejection has long been considered the paradigm of renal diseases induced by alloimmunization, particularly alloimmunization directed against HLA antigens. Accumulating evidence indicates that non-HLA immunity also has an important role in clinical transplantation. Targets of alloimmunization include antigens of tubular basement membrane, tubular epithelial cells and endothelial cells. They can be polymorphic allovariants (as shown in the rat) or 'hidden' antigens exposed when the graft is damaged. Alloimmunization can also occur when a person genetically deficient in a renal protein (e.g. the α5 (IV) collagen chain in X-linked Alport's syndrome or nephrin in Finnish-type nephrotic syndrome) is transplanted to treat end-stage renal failure. The non-mutated protein in the donor kidney is recognized as a foreign antigen, and the resulting alloimmune response can damage the graft. We have demonstrated that alloimmunity can also affect the native kidney. We have characterized a novel fetomaternal disease in which a genetic defect in the MME gene encoding neutral endopeptidase (NEP) in the mother leads to the development of membranous nephropathy in her fetus (maternal anti-NEP antibodies bind to NEP on fetal podocytes). Our findings raise the possibility that mutations or genetic polyporphisms in MME or other genes expressed by the podocyte are involved in alloimmune-mediated development of membranous nephropathy after kidney or bone marrow transplantation.

Key Points

  • Alloimmunization—an immune response to antigens from a genetically distinct organism of the same species—can occur in transplanted, as well as native, kidneys

  • In grafted kidneys, alloimmunization can occur in response to donor HLA and non-HLA antigens (e.g. of tubular and glomerular basement membranes)

  • Alloimmunization causing nephropathy of native kidneys can occur in response to transplantation of bone marrow or stem cells, and microchimerism (arising from cell exchange between mother and fetus)

  • The authors have described a new form of alloimmunity in native kidneys—transplacental transfer of antibodies against podocyte-localized neutral endopeptidase from a mother, in whom the gene encoding neutral endopeptidase is mutated, to her fetus, resulting in nephrotic syndrome

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of alloimmunization against the renal graft.
Figure 2: Schematic representation of membrane metallo-endopeptidase complementary DNA and neutral endopeptidase protein showing sites of mutation.
Figure 3: Proposed mechanisms of fetomaternal alloimmunization.

Similar content being viewed by others

References

  1. Dausset J (1971) The genetics of the HL-A system and its implications in transplantation. Vox Sang 20: 97–108

    Article  CAS  Google Scholar 

  2. Dausset J (1966) Leucocyte and tissue groups. Vox Sang 11: 263–75

    Article  CAS  Google Scholar 

  3. Aluvihare VR et al. (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 5: 266–271

    Article  CAS  Google Scholar 

  4. Mellor AL et al. (2001) Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol 2: 64–68

    Article  CAS  Google Scholar 

  5. Salmon JE (2004) A noninflammatory pathway for pregnancy loss: innate immune activation? J Clin Invest 114: 15–17

    Article  CAS  Google Scholar 

  6. Xu C et al. (2000) A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 287: 498–501

    Article  CAS  Google Scholar 

  7. Varla-Leftherioti M (2004) Role of a KIR/HLA-C allorecognition system in pregnancy. J Reprod Immunol 62: 19–27

  8. Bowman JM (1994) Hemolytic disease of the newborn. In Immunobiology of Transfusion Medicine, 553–584 (Ed. Garratty G) New York: Dekker

    Google Scholar 

  9. Peters B et al. (2004) Effect of heterosexual intercourse on mucosal alloimmunisation and resistance to HIV-1 infection. Lancet 363: 518–524

    Article  Google Scholar 

  10. Jennes W and Kestens L (2004) Unprotected sex and alloimmune activation. Lancet 363: 1474

    Article  Google Scholar 

  11. Debiec H et al. (2002) Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med 346: 2053–2060

    Article  Google Scholar 

  12. Debiec H et al. (2004) Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies. Lancet 364: 1252–1259

    Article  CAS  Google Scholar 

  13. Bianchi DW et al. (1996) Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum Proc Natl Acad Sci USA 93: 705–708

    Article  CAS  Google Scholar 

  14. Nelson JL et al. (1998) Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351: 559–562

    Article  CAS  Google Scholar 

  15. Collins ZV et al. (1973) A naturally occurring monospecific anti-HL-A8 isoantibody. Tissue Antigens 3: 358–363

    Article  CAS  Google Scholar 

  16. Lepage V et al. (1976) A “natural” anti-HLA-A2 antibody reacting with homozygous cells. Tissue Antigens 8: 139–142

    Article  CAS  Google Scholar 

  17. Tongio MM et al. (1985) Natural HLA antibodies. Tissue Antigens 26: 271–285

    Article  CAS  Google Scholar 

  18. Suthanthiran M and Strom TB (2005) Transplant immunology. In Oxford Textbook of Clinical Nephrology, vol 3, 2049–2059 (Ed. Davison AM) Oxford: Oxford University Press

    Google Scholar 

  19. Halloran PF (2002) Call for revolution: a new approach to describing allograft deterioration. Am J Transplant 2: 195–200

    Article  Google Scholar 

  20. Poggio ED et al. (2004) Alloreactivity in renal transplant recipients with and without chronic allograft nephropathy. J Am Soc Nephrol 15: 1952–1960

    Article  Google Scholar 

  21. Dong VM et al. (1999) Transplantation tolerance: the concept and its applicability. Pediatr Transplant 3: 181–192

    Article  CAS  Google Scholar 

  22. Li XC et al. (2001) T cell death and transplantation tolerance. Immunity 14: 407–416

    Article  CAS  Google Scholar 

  23. Paul LC (1999) Chronic allograft nephropathy: an update. Kidney Int 56: 783–793

    Article  CAS  Google Scholar 

  24. Lehman DH et al. (1974) Induction of antitubular basement membrane antibodies in rats by renal transplantation. Transplantation 17: 429–431

    Article  CAS  Google Scholar 

  25. Mancilla-Jimenez R et al. (1977) Antitubular basement membrane antibodies in renal allograft rejection. Transplantation 24: 39–44

    Article  CAS  Google Scholar 

  26. Clayman MD et al. (1985) Isolation and characterization of the nephritogenic antigen producing anti-tubular basement membrane disease. J Exp Med 161: 290–305

    Article  CAS  Google Scholar 

  27. Clayman MD et al. (1986) Isolation of the target antigen of human anti-tubular basement membrane antibody-associated interstitial nephritis. J Clin Invest 77: 1143–1147

    Article  CAS  Google Scholar 

  28. Butkowski RJ et al. (1990) Characterization of a tubular basement membrane component reactive with autoantibodies associated with tubulointerstitial nephritis. J Biol Chem 265: 21091–21098

    CAS  PubMed  Google Scholar 

  29. Butkowski RJ et al. (1991) Distribution of tubulointerstitial nephritis antigen and evidence for multiple forms. Kidney Int 40: 838–846

    Article  CAS  Google Scholar 

  30. Ivanyi B et al. (1998) Childhood membranous nephropathy, circulating antibodies to the 58-kD TIN antigen, and anti-tubular basement membrane nephritis: an 11-year follow-up. Am J Kidney Dis 32: 1068–1074

    Article  CAS  Google Scholar 

  31. Thoenes GH et al. (1979) Transplantation-induced immune complex kidney disease in rats with unilateral manifestation in the allografted kidney. Lab Invest 41: 321–333

    CAS  PubMed  Google Scholar 

  32. Joosten SA et al. (2002) Antibody response against perlecan and collagen types IV and VI in chronic renal allograft rejection in the rat. Am J Pathol 160: 1301–1310

    Article  CAS  Google Scholar 

  33. Joosten SA et al. (2005) Antibodies against mesangial cells in a rat model of chronic renal allograft rejection. Nephrol Dial Transplant 20: 692–698

    Article  CAS  Google Scholar 

  34. Joosten SA et al. (2005) Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy. Am J Transplant 5: 383–393

    Article  CAS  Google Scholar 

  35. Racusen LC (2004) Antibody-mediated rejection in the kidney. Transplant Proc 36: 768–769

    Article  CAS  Google Scholar 

  36. van der Woude FJ et al. (1995) Tissue antigens in tubulointerstitial and vascular rejection. Kidney Int 52 (Suppl): S11–S13

    CAS  Google Scholar 

  37. Le Bas-Bernardet S et al. (2003) Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis. Am J Transplant 3: 167–177

    Article  CAS  Google Scholar 

  38. Opelz G ; Collaborative Transplant Study (2005) Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 365: 1570–1576

    Article  CAS  Google Scholar 

  39. Dragun D et al. (2005) Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352: 558–569

  40. Barker DF et al. (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248: 1224–1227

    Article  CAS  Google Scholar 

  41. Lemmink HH et al. (1994) Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3: 1269–1273

    Article  CAS  Google Scholar 

  42. Mochizuki T et al. (1994) Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8: 77–81

    Article  CAS  Google Scholar 

  43. Longo I et al. (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61: 1947–1956

    Article  CAS  Google Scholar 

  44. Kalluri R et al. (1997) Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 99: 2470–2478

    Article  CAS  Google Scholar 

  45. Kashtan CE (2005) The nongenetic diagnosis of thin basement membrane nephropathy. Semin Nephrol 25: 159–162

    Article  Google Scholar 

  46. Hudson BG et al. (2003) Alport's syndrome, Goodpasture's syndrome, and type IV collagen. New Engl J Med 348: 2543–2556

    Article  CAS  Google Scholar 

  47. Byrne MC et al. (2002) Renal transplant in patients with Alport's syndrome. Am J Kidney Dis 39: 769–775

    Article  Google Scholar 

  48. Kalluri R et al. (2000) Identification of α3, α4, and α5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation 69: 679–683

    Article  CAS  Google Scholar 

  49. Kalluri R et al. (1996) The Goodpasture autoantigen: structural delineation of two immunologically privileged epitopes on α3(IV) chain of type IV collagen. J Biol Chem 271: 9062–9068

    Article  CAS  Google Scholar 

  50. Borza DB et al. (2000) The goodpasture autoantigen: identification of multiple cryptic epitopes on the NC1 domain of the α3(IV) collagen chain. J Biol Chem 275: 6030–6037

    Article  CAS  Google Scholar 

  51. Kestila M et al. (1998) Positionally cloned gene for a novel glomerular protein-nephrin is mutated in congenital nephrotic syndrome. Mol Cell 1: 575–582

    Article  CAS  Google Scholar 

  52. Patrakka J et al. (2002) Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 73: 394–403

    Article  Google Scholar 

  53. Orikasa M et al. (1988) Massive proteinuria induced in rats by a single intravenous injection of a monoclonal antibody. J Immunol 141: 807–814

    CAS  PubMed  Google Scholar 

  54. Topham PS et al. (1999) Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin. J Clin Invest 104: 1559–1566

    Article  CAS  Google Scholar 

  55. Billing H et al. (2004) NPHS2 mutation associated with recurrence of proteinuria after transplantation. Pediatr Nephrol 19: 561–564

    Article  Google Scholar 

  56. Turner AJ et al. (2001) The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. Bioessays 23: 261–269

    Article  CAS  Google Scholar 

  57. Lu B et al. (1997) The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat Med 3: 904–907

    Article  CAS  Google Scholar 

  58. Ikeda K et al. (1999) Molecular identification and characterization of novel membrane-bound metalloprotease, the soluble secreted form of which hydrolyzes a variety of vasoactive peptides. J Biol Chem 274: 32469–32477

    Article  CAS  Google Scholar 

  59. Bonvouloir N et al. (2001) Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-24.11 family. DNA Cell Biol 20: 493–498

    Article  CAS  Google Scholar 

  60. Ronco P and Debiec H (2005) Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization. J Am Soc Nephrol 16: 1205–1213.

    Article  CAS  Google Scholar 

  61. Riemersma S et al. (1996) Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest 98: 2358–2363

    Article  CAS  Google Scholar 

  62. Whitington PF and Hibbard JU (2004) High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 364: 1690–1698

    Article  CAS  Google Scholar 

  63. Whitington PF and Malladi P (2005) Neonatal hemochromatosis: is it an alloimmune disease? J Pediatr Gastroenterol Nutr 40: 544–549

    Article  Google Scholar 

  64. Lin J et al. (2001) Membranous glomerulopathy associated with graft-versus-host disease following allogeneic stem cell transplantation: report of 2 cases and review of the literature. Am J Nephrol 21: 351–356

    Article  CAS  Google Scholar 

  65. Rossi L et al. (2001) Membranous glomerulonephritis after haematopoietic cell transplantation for multiple myeloma. Nephron 88: 260–263

    Article  CAS  Google Scholar 

  66. Miyazaki Y et al. (2003) Membranous nephropathy associated with donor lymphocyte infusion following allogeneic bone marrow transplantation. Int J Hematol 78: 262–265

    Article  Google Scholar 

  67. Tsutsumi C et al. (2004) Membranous nephropathy after allogeneic stem cell transplantation: report of 2 cases. Int J Hematol 79: 193–197

    Article  Google Scholar 

  68. Stevenson WS et al. (2005) Nephrotic syndrome after stem cell transplantation. Clin Transplant 19: 141–144

    Article  Google Scholar 

  69. Ikee R et al. (2004) Recurrent nephrotic syndrome associated with graft-versus-host disease. Bone Marrow Transplant 34: 1005–1006

    Article  CAS  Google Scholar 

  70. Bruijn JA et al. (1988) Murine chronic graft-versus-host disease as a model for lupus nephritis. Am J Pathol 130: 639–641

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Maloney S et al. (1999) Microchimerism of maternal origin persists into adult life. J Clin Invest 104: 41–47

    Article  CAS  Google Scholar 

  72. Adams KM and Nelson JL (2004) Microchimerism: an investigative frontier in autoimmunity and transplantation. JAMA 291: 1127–1131

    Article  CAS  Google Scholar 

  73. Reed AM et al. (2000) Chimerism in children with juvenile dermatomyositis. Lancet 356: 2156–2157

    Article  CAS  Google Scholar 

  74. Stevens AM et al. (2003) Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 362: 1617–1623

    Article  Google Scholar 

  75. Khosrotehrani K and Bianchi DW (2003) Fetal cell microchimerism: helpful or harmful to the parous woman? Curr Opin Obstet Gynecol 15: 195–199

    Article  Google Scholar 

  76. Lambert NC et al. (2005) Male microchimerism in women with systemic sclerosis and healthy women who have never given birth to a son. Ann Rheum Dis 64: 845–848

    Article  CAS  Google Scholar 

  77. Lambert NC et al. (2002) Male microchimerism in healthy women and women with scleroderma: cells or circulating DNA? A quantitative answer. Blood 100: 2845–2851

    Article  CAS  Google Scholar 

  78. Artlett CM et al. (2002) Increased microchimeric CD4+ T lymphocytes in peripheral blood from women with systemic sclerosis. Clin Immunol 103: 303–308

    Article  CAS  Google Scholar 

  79. Srivatsa B et al. (2001) Microchimerism of presumed fetal origin in thyroid specimens from women: a case-control study. Lancet 358: 2034–2038

    Article  CAS  Google Scholar 

  80. Artlett CM et al. (2002) Influence of prior pregnancies on disease course and cause of death in systemic sclerosis. Ann Rheum Dis 61: 346–350

    Article  CAS  Google Scholar 

  81. Johnson KL et al. (2002) Significant fetal cell microchimerism in a nontransfused woman with hepatitis C: evidence of long-term survival and expansion. Hepatology 36: 1295–1297

    Article  Google Scholar 

  82. Nagahama K et al. (2005) Possible role of autoantibodies against nephrin in an experimental model of chronic graft-versus-host disease. Clin Exp Immunol 141: 215–222

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from INSERM, University Paris 6, GIS-Institute of Rare Diseases, Amgen France, and a gift from Mrs Halpin to the American branch of the Foundation of France. We are grateful to Christine Vial for assistance in preparing the manuscript.

Author information

Author notes

  1. P Ronco is the Head of, and H Debiec is a research director

Authors and Affiliations

  1. INSERM Unit 702, University Pierre and Marie Curie, Tenon Hospital, Paris, France

    Pierre Ronco & Hanna Debiec

  2. senior pediatrician in the Pediatrics Department, University Hospital, Limoges, France

    Vincent Guigonis

Authors
  1. Pierre Ronco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanna Debiec
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vincent Guigonis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Pierre Ronco or Hanna Debiec.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ronco, P., Debiec, H. & Guigonis, V. Mechanisms of Disease: alloimmunization in renal diseases. Nat Rev Nephrol 2, 388–397 (2006). https://doi.org/10.1038/ncpneph0198

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0198

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing