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Immune Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria

  • Progress in Hematology
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Somatic mutation in the PIG-A gene is the initial event in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), but the pathophysiologic mechanisms leading to clonal expansion remain unclear. The intricate association of PNH with immune-mediated bone marrow failure syndromes, including aplastic anemia (AA), suggests an immunologic selection process for the glycosylphosphatidyl-inositol (GPI)-deficient hematopoietic clone. The mechanism for the growth advantage of PNH cells may be related to the nature of the antigens targeted by the immune response or to the function of immunomodulatory GPI-anchored proteins on the surface of the hematopoietic target cells. Alternative theories of PNH evolution may include intrinsic properties of the mutated cells, but the experimental evidence is largely lacking. Elucidation of the pathogenesis of PNH may provide key information about the causes of idiopathic AA and help understand the regulation of the hematopoietic stem cell compartment.

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References

  1. Araten DJ, Luzzatto L. The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2006 Mar 16 [Epub ahead of print].

  2. Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: variation in clinical severity and association with bone-marrow hypoplasia. Br J Haematol. 1961;7:442–457.

    Article  PubMed  CAS  Google Scholar 

  3. Dameshek W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and “hypoplastic” leukemia have in common? Blood. 1967;30(2):251–254.

    PubMed  CAS  Google Scholar 

  4. Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: clinical manifestations, haematology, and nature of the disease. Ser Haematol. 1972;5(3):3–23.

    PubMed  CAS  Google Scholar 

  5. Young NS. The problem of clonality in aplastic anemia: Dr Dameshek’s riddle, restated. Blood. 1992;79(6):1385–1392.

    PubMed  CAS  Google Scholar 

  6. Luzzatto L. Somatic mutation in paroxysmal nocturnal hemoglobinuria. Hosp Pract (Minneap). 1997;32(9):125–131, 135-136, 139-140.

    Article  CAS  Google Scholar 

  7. Schrezenmeier H, Hertenstein B, Wagner B, Raghavachar A, Heimpel H. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol. 1995;23(1):81–87. Erratum in: Exp Hematol. 1995;23(2):181.

    PubMed  CAS  Google Scholar 

  8. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med. 1999;131(6):401–408.

    Article  PubMed  CAS  Google Scholar 

  9. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol. 2001;115(4):1015–1022.

    Article  PubMed  CAS  Google Scholar 

  10. Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107(4):1308–1314.

    Article  CAS  PubMed  Google Scholar 

  11. Araten DJ, Nafa K, Pakdeesuwan K, Luzzatto L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc Natl Acad Sci U S A. 1999;96(9):5209–5214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Maciejewski JP, Follmann D, Nakamura R, et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome. Blood. 2001;98(13):3513–3519.

    Article  CAS  PubMed  Google Scholar 

  13. Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102(8):3025–3027.

    Article  CAS  PubMed  Google Scholar 

  14. Fermo E, Bianchi P, Barcellini W, et al. Immunoregulatory cytokine polymorphisms in Italian patients affected by paroxysmal nocturnal haemoglobinuria and aplastic anaemia. Eur J Immunogenet. 2004;31(6):267–269.

    Article  CAS  PubMed  Google Scholar 

  15. Howe EC, Wlodarski M, Ball EJ, Rybicki L, Maciejewski JP. Killer immunoglobulin-like receptor genotype in immune-mediated bone marrow failure syndromes. Exp Hematol. 2005;33(11):1357–1362.

    Article  CAS  PubMed  Google Scholar 

  16. Wlodarski MW, Gondek LP, Nearman ZP, Plasilova M, Kalaycio M, Maciejewski JP. Molecular strategies for detection and quantitation of clonal cytotoxic T cell responses in aplastic anemia and myelodysplastic syndrome. Blood. 2006 Apr 13 [Epub ahead of print].

  17. Hanaoka N, Kawaguchi T, Horikawa K, Nagakura S, Mitsuya H, Nakakuma H. Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Blood. 2006;107(3):1184–1191.

    Article  PubMed  CAS  Google Scholar 

  18. Tichelli A, Gratwohl A, Wursch A, Nissen C, Speck B. Late haematological complications in severe aplastic anaemia. Br J Haematol. 1988;69(3):413–418.

    Article  CAS  PubMed  Google Scholar 

  19. de Planque MM, Brand A, Kluin-Nelemans HC, et al. Haematopoietic and immunologic abnormalities in severe aplastic anaemia patients treated with anti-thymocyte globulin. Br J Haematol. 1989;71(3):421–430.

    Article  PubMed  Google Scholar 

  20. Chen G, Kirby M, Zeng W, Young NS, Maciejewski JP. Superior growth of glycophosphatidy linositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo. Exp Hematol. 2002;30(7):774–782.

    Article  PubMed  CAS  Google Scholar 

  21. Chen G, Zeng W, Maciejewski JP, Kcyvanfar K, Billings EM, Young NS. Differential gene expression in hematopoietic progenitors from paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis/immune response in ‘normal’ phenotype cells. Leukemia. 2005;19(5):862–868.

    Article  PubMed  CAS  Google Scholar 

  22. Nagakura S, Ishihara S, Dunn DE, et al. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Blood. 2002;100(3):1031–1037.

    Article  PubMed  CAS  Google Scholar 

  23. Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood. 2005;105(10):3848–3854.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Ware RE,Nishimura J, Moody MA, Smith C, Rosse WF,Howard TA. The PIG-A mutation and absence of glycosylphosphatidylinositollinked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria. Blood. 1998;92(7):2541–2550.

    PubMed  CAS  Google Scholar 

  25. Feng X, Chuhjo T, Sugimori C, et al. Diazepam-binding inhibitorrelated protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood. 2004;104(8):2425–2431.

    Article  PubMed  CAS  Google Scholar 

  26. Hirano N, Butler MO, Von Bergwelt-Baildon MS, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood. 2003;102(13):4567–4575.

    Article  PubMed  CAS  Google Scholar 

  27. Takami A, Nakao S,Tatsumi Y, et al. High inducibility of heat shock protein 72 (hsp72) in peripheral blood mononuclear cells of aplastic anaemia patients: a reliable marker of immune-mediated aplastic anaemia responsive to cyclosporine therapy. Br J Haematol. 1999;106(2):377–384.

    Article  PubMed  CAS  Google Scholar 

  28. Kook H, Risitano AM, Zeng W, et al. Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens. Blood. 2002;99(10):3668–3675.

    Article  PubMed  CAS  Google Scholar 

  29. Risitano AM, Maciejewski JP, Muranski P, et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia. 2005;19(2):217–222.

    Article  PubMed  CAS  Google Scholar 

  30. Plasilova M, Risitano AM, O’Keefe CL, et al. Shared and individual specificities of immunodominant cytotoxic T-cell clones in paroxysmal nocturnal hemoglobinuria as determined by molecular analysis. Exp Hematol. 2004;32(3):261–269.

    Article  CAS  PubMed  Google Scholar 

  31. Wlodarski MW, Gondek LP, Nearman ZP, Plasilova M, Kalaycio M, Maciejewski JP. Molecular strategies for detection and quantitation of clonal cytotoxic T cell responses in aplastic anemia and myelodysplastic syndrome. Blood. 2006 Apr 13 [Epub ahead of print].

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Authors and Affiliations

  1. Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Ramon Tiu & Jaroslaw Maciejewski

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  1. Ramon Tiu
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  2. Jaroslaw Maciejewski
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Correspondence to Jaroslaw Maciejewski.

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Tiu, R., Maciejewski, J. Immune Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria. Int J Hematol 84, 113–117 (2006). https://doi.org/10.1532/IJH97.06144

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  • DOI: https://doi.org/10.1532/IJH97.06144

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