Annals of Hematology

, Volume 93, Issue 5, pp 761–767 | Cite as

Immune status of Fanconi anemia patients: decrease in T CD8 and CD56dim CD16+ NK lymphocytes

  • Graça A. JustoEmail author
  • Marco A. Bitencourt
  • Ricardo Pasquini
  • Morgana T. L. Castelo-Branco
  • Aline Almeida-Oliveira
  • Hilda Rachel Diamond
  • Vivian M. Rumjanek
Original Article


Fanconi anemia (FA), a rare genetic disease in which patients' life is compromised mainly by hematological abnormalities and cancer prone, seems to be affected by subtle immune cell irregularities. Knowing that FA presents developmental abnormalities and, based on recent reports, suggesting that natural killer (NK) CD56dim and NK CD56bright correspond to sequential differentiation pathways, we investigated if there were changes on the total number of NK cells and subsets as well as on T CD4 and T CD8 lymphocytes and their ratio. A large sample of FA patients (n = 42) was used in this work, and the results were correlated to clinical hematological status of these patients. Among FA patients, a decreased proportion of T CD8+ and NK CD56dimCD16+ cells were observed when compared to healthy controls as well as an imbalance of the subsets NK lymphocytes. Data suggest that FA patients might have a defective cytotoxic response due to the lower number of cytotoxic cells as well as impairment in the differentiation process of the NK cells subsets which may be directly related to impairment of the immune surveillance observed in these patients.


Fanconi anemia Lymphocytes Immune system NK cells CD8 T cells Flow cytometry 



This work was supported by the National Counsel of Technological and Scientific Development (CNPq) and the Rio de Janeiro State Foundation for the Support of Research (FAPERJ).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Joenje H, Patel KJ (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2:446–457PubMedCrossRefGoogle Scholar
  2. 2.
    Bagby JRGC (2003) Genetic basis of Fanconi anemia. Curr Opin Hematol 10:68–76PubMedCrossRefGoogle Scholar
  3. 3.
    D'Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3:23–34PubMedCrossRefGoogle Scholar
  4. 4.
    Kennedy RD, D'Andrea AD (2005) The Fanconi anemia/BRCA pathway: new faces in the crowd. Genes Dev 19:2925–2940PubMedCrossRefGoogle Scholar
  5. 5.
    Li X, Yang Y, Yuan J, Hong P, Freie B, Orazi A, Haneline LS, Clapp DW (2004) Continuous in vivo infusion of interferon-gamma (IFN-γ) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc−/− mice. Blood 104(4):1204–1209PubMedCrossRefGoogle Scholar
  6. 6.
    Freie B, Li X, Ciccone SLM, Nawa K, Cooper S, Vogelweid C, Schantz L, Haneline LS, Orazi A, Broxmeyer HE, Lee S, Clapp DW (2003) Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood 102(12):4146–4152PubMedCrossRefGoogle Scholar
  7. 7.
    Hucl T, Gallmeier E (2011) DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res 60:453–465PubMedGoogle Scholar
  8. 8.
    Sejas DP, Rani R, Qiu Y, Zhang X, Fagerlie SR, Nakano H, Williams DA, Pang Q (2007) Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice. J Immunol 178:5277–5287PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Ibáñez A, Río P, Casado JA, Bueren JA, Fernández-Luna JL, Pipaón C (2009) Elevated levels of IL-1β in Fanconi anaemia group A patients due to a constitutively active phosphoinositide 3-kinase-Akt pathway are capable of promoting tumour cell proliferation. Biochem J 422:161–170PubMedCrossRefGoogle Scholar
  10. 10.
    Hersey P, Edwards A, Lewis R, Kemp A, Mcinnes J (1982) Deficient natural killer cell activity in a patient with Fanconi's anaemia and squamous cell carcinoma. Association with defect in interferon release. Clin Exp Immunol 48(1):205–212PubMedCentralPubMedGoogle Scholar
  11. 11.
    Fagerlie SR, Bagby GC (2006) Immune defects in Fanconi anemia. Crit Rev Immunol 26(1):81–96PubMedCrossRefGoogle Scholar
  12. 12.
    Zaizov R, Matoth Y, Mamon Z (1978) Long term observations in children with Fanconi's anemia. In: Hibino S et al (eds) Aplastic anemia. University Park Press, Baltimore, p 243Google Scholar
  13. 13.
    Pederson FK, Hertz H, Lundsteen C, Platz P, Thomsen M (1977) Indications of primary immune deficiency in Fanconi's anaemia. Acta Paediatr Scand 66:745CrossRefGoogle Scholar
  14. 14.
    Myers KC, Bleesing JJ, Davies SM, Zhang X, Martin LJ, Mueller R, Harris RE, Filipovich AH, Kovacic MB, Wells SI, Parinda A, Mehta PA (2011) Impaired immune function in children with Fanconi anaemia. Br J Haematol 154:234–240PubMedCrossRefGoogle Scholar
  15. 15.
    Korthof ET, Svahn J, Peffault de Latour R et al (2013) Immunological profile of Fanconi anemia: a multicentric retrospective analysis of 61 patients. Am J Hematol 88(6):472–476PubMedCrossRefGoogle Scholar
  16. 16.
    Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, Chávez R, Lascurain R (2009) Cell death mechanisms induced by cytotoxic lymphocytes. Cel Mol Immunol 6(1):15–25CrossRefGoogle Scholar
  17. 17.
    Cooley S, Weisdorf DS (2010) Natural killer cells and tumor control. Cur Opin Hematol 17:514–521CrossRefGoogle Scholar
  18. 18.
    Penack O, Gentilini C, Fischer L, Asemissen AM, Scheibenbogen C, Thiel E, Uharek L (2005) CD56dimCD16neg cells are responsible for natural cytotoxicity against tumor targets. Leukemia 19:835–840PubMedCrossRefGoogle Scholar
  19. 19.
    Moretta A, Marcenaro E, Parolini S, Ferlazzo G, Moretta L (2008) NK cells at the interface between innate and adaptive immunity. Cell Death Diff 15:226–233 (review)CrossRefGoogle Scholar
  20. 20.
    Orr MT, Lanier LL (2010) Natural killer cell education and tolerance. Cell 142:847–856PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Tarazona R, Casado JG, Delarosa O et al (2002) Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 22(3):176–183PubMedCrossRefGoogle Scholar
  22. 22.
    Hong HS, Eberhard JM, Keudel P et al (2010) Phenotypically and functionally distinct subsets contribute to the expansion of CD56−/CD16+ natural killer cells in HIV infection. AIDS 24(12):1823–1834PubMedCrossRefGoogle Scholar
  23. 23.
    Schepis D, Gunnarsson I, Eloranta ML et al (2009) Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus. Immunology 126(1):140–146PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Saraste M, Irjala H, Airas L (2007) Expansion of CD56Bright natural killer cells in the peripheral blood of multiple sclerosis patients treated with interferon-beta. Neurol Sci 28(3):121–126PubMedCrossRefGoogle Scholar
  25. 25.
    Lee S, Watson MW, Flexman JP, Cheng W, Hammond T, Price P (2010) Increased proportion of the CD56(bright) NK cell subset in patients chronically infected with hepatitis C virus (HCV) receiving interferon-alpha and ribavirin therapy. J Med Virol 82(4):568–574PubMedCrossRefGoogle Scholar
  26. 26.
    Auerbach AD, Rogatko A, Schroeder-Kurth TM (1989) International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood 73:391–396PubMedGoogle Scholar
  27. 27.
    Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640PubMedCrossRefGoogle Scholar
  28. 28.
    Baruque GA, Bitencourt MA, Pasquini R, Castelo-Branco MTL, Llerena JRJC, Rumjanek VM (2005) Apoptosis and expression of anti- and pro-apoptotic proteins in peripheral blood mononuclear cells of Fanconi anaemia patients: a study of 73 cases. Eur J Haematol 75:384–390PubMedCrossRefGoogle Scholar
  29. 29.
    Castello G, Gallo C, Napolitano M, Ascierto PA (1998) Immunological phenotype analysis of patients with Fanconi's anaemia and their family members. Acta Haematol 100(1):39–43PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang N, Bevan MJ (2011) CD8+ T cells: foot soldiers of the immune system. Immunity 35:161–168PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease. Immunology 134:17–32PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro AS, Falcão RR, Abdelhay E, Bouzas LF, Thuler LCS, Ornellas MH, Diamond HR (2011) Age-related changes in natural killer cell receptors from childhood through old age. H Immunol 72:319–329CrossRefGoogle Scholar
  33. 33.
    Froom P, Aghai E, Dobinsky JB, Quitt M, Lahat N (1987) Reduced natural killer activity in patients with Fanconi's anemia and in family members. Leuk Res 11(2):197–199PubMedCrossRefGoogle Scholar
  34. 34.
    Lebbé C, Pinquier L, Rybojad M, Chomienne C, Ochonisky S, Miclea JM, Gluckman E, Morel P (1993) Fanconi's anaemia associated with multicentric Bowen's disease and decreased NK cytotoxicity. Br J Dermatol 129(5):615–618PubMedCrossRefGoogle Scholar
  35. 35.
    Moretta L (2010) Dissecting CD56dim human NK cells. Blood 116(19):3689–3691PubMedCrossRefGoogle Scholar
  36. 36.
    Chan A, Hong DL, Atzberger A, Kollnberger S, Filer AD, Buckley CD, McMichael A, Enver T, Bowness P (2007) CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts. J Immunol 179:89–94PubMedCrossRefGoogle Scholar
  37. 37.
    Loza MJ, Perussia B (2004) The IL-12 signature: NK cell terminal CD56+high stage and effector functions. J Immunol 172:88–96PubMedCrossRefGoogle Scholar
  38. 38.
    de Matos CT, Berg L, Michaëlsson J, Fellander-Tsai L, Kärre K, Söderström K (2007) Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology 122:291–301PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Belisle JA, Gubbels JA, Raphael CA et al (2007) Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 122:418–429PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Katchar K, Söderström K, Wahlstrom J, Eklund A, Grunewald J (2005) Characterisation of natural killer cells and CD56+ T-cells in sarcoidosis patients. Eur Respir J 26:77–85PubMedCrossRefGoogle Scholar
  41. 41.
    Inngjerdingen M, Kveberg L, Naper C, Vaage JT (2011) Natural killer cell subsets in man and rodents. Tissue Antigens 78:81–88PubMedCrossRefGoogle Scholar
  42. 42.
    Takahashi E, Kuranaga N, Satoh K, Habu Y, Shinomiya N, Asano T, Seki S, Hayakawa M (2007) Induction of CD16+CD56bright NK cells with antitumour cytotoxicity not only from CD16CD56bright NK cells but also from CD16CD56dim NK cells. Scand J Immunol 65:126–138PubMedCrossRefGoogle Scholar
  43. 43.
    Rosselli F, Sanceau J, Gluckman E, Wietzerbin J, Moustacchi E (1994) Abnormal lymphokine production: a novel feature of the genetic disease Fanconi anemia: II. In vitro and in vivo spontaneous overproduction of tumor necrosis factor α. Blood 83:1216–1225PubMedGoogle Scholar
  44. 44.
    Rathbun RK, Faulkner GR, Ostroski MH, Christianson TA, Hughes G, Jones G, Cahn R, Maziarz R, Royle G, Keeble W, Heinrich MC, Grompe M, Tower PA, Bagby GC (1997) Inactivation of the Fanconi anemia group C gene augments interferon-γ-induced apoptotic response in hematopoietic cells. Blood 90:974–985PubMedGoogle Scholar
  45. 45.
    Pilonetto DV, Pereira NF, Bitencourt MA, Magdalena NIR, Vieira ER, Veiga LBA, Cavalli IJ, Ribeiro RC, Pasquini R (2009) FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia. Br J Med Biol Res 42:237–243CrossRefGoogle Scholar
  46. 46.
    Levitus M, Rooimans MA, Steltenpool J, Cool NF, Oostra AB, Mathew CG et al (2004) Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes. Blood 103:2498–2503PubMedCrossRefGoogle Scholar
  47. 47.
    Shimamura A (2006) Inherited bone marrow failure syndromes: molecular features. Hematology Am Soc Hematol Educ Program 63–71Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Graça A. Justo
    • 1
    • 2
    • 7
    Email author
  • Marco A. Bitencourt
    • 3
  • Ricardo Pasquini
    • 3
  • Morgana T. L. Castelo-Branco
    • 4
  • Aline Almeida-Oliveira
    • 5
    • 6
  • Hilda Rachel Diamond
    • 5
  • Vivian M. Rumjanek
    • 2
  1. 1.Departamento de Bioquímica, IBRAGUERJRio de JaneiroBrazil
  2. 2.Instituto de Bioquímica Médica, CCSUFRJRio de JaneiroBrazil
  3. 3.Ambulatório de Anemia de Fanconi, Hospital de ClínicasUniversidade Federal do ParanáCuritibaBrazil
  4. 4.Departamento de Histologia e Embriologia, ICB-CCSUFRJRio de JaneiroBrazil
  5. 5.Centro de Transplante de Medula Óssea (CEMO)Instituto Nacional do Câncer (INCA)Rio de JaneiroBrazil
  6. 6.Fundação Oswaldo Cruz (Fiocruz)Instituto de Tecnologia Imunobiológica (Bio-Manguinhos)Rio de JaneiroBrazil
  7. 7.Laboratório de Imunologia Aplicada, Bioquímica de Proteínas e Produtos Naturais, Departamento de Bioquímica, Instituto de Biologia Alcântara GomesUniversidade Estadual do Rio de JaneiroRio de JaneiroBrazil

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