Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Joenje H, Patel KJ (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2:446–457

    Article  PubMed  CAS  Google Scholar 

  2. Bagby JRGC (2003) Genetic basis of Fanconi anemia. Curr Opin Hematol 10:68–76

    Article  PubMed  CAS  Google Scholar 

  3. D'Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3:23–34

    Article  PubMed  CAS  Google Scholar 

  4. Kennedy RD, D'Andrea AD (2005) The Fanconi anemia/BRCA pathway: new faces in the crowd. Genes Dev 19:2925–2940

    Article  PubMed  CAS  Google Scholar 

  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):1204–1209

    Article  PubMed  CAS  Google Scholar 

  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):4146–4152

    Article  PubMed  CAS  Google Scholar 

  7. Hucl T, Gallmeier E (2011) DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res 60:453–465

    PubMed  CAS  Google Scholar 

  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 178:5277–5287

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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 422:161–170

    Article  PubMed  CAS  Google Scholar 

  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):205–212

    PubMed Central  PubMed  CAS  Google Scholar 

  11. Fagerlie SR, Bagby GC (2006) Immune defects in Fanconi anemia. Crit Rev Immunol 26(1):81–96

    Article  PubMed  CAS  Google Scholar 

  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 243

    Google Scholar 

  13. Pederson FK, Hertz H, Lundsteen C, Platz P, Thomsen M (1977) Indications of primary immune deficiency in Fanconi's anaemia. Acta Paediatr Scand 66:745

    Article  Google Scholar 

  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 154:234–240

    Article  PubMed  CAS  Google Scholar 

  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):472–476

    Article  PubMed  CAS  Google Scholar 

  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):15–25

    Article  Google Scholar 

  17. Cooley S, Weisdorf DS (2010) Natural killer cells and tumor control. Cur Opin Hematol 17:514–521

    Article  CAS  Google Scholar 

  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 19:835–840

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  20. Orr MT, Lanier LL (2010) Natural killer cell education and tolerance. Cell 142:847–856

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):176–183

    Article  PubMed  CAS  Google Scholar 

  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):1823–1834

    Article  PubMed  CAS  Google Scholar 

  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):140–146

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):121–126

    Article  PubMed  CAS  Google Scholar 

  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):568–574

    Article  PubMed  CAS  Google Scholar 

  26. Auerbach AD, Rogatko A, Schroeder-Kurth TM (1989) International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood 73:391–396

    PubMed  CAS  Google Scholar 

  27. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640

    Article  PubMed  CAS  Google Scholar 

  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 75:384–390

    Article  PubMed  Google Scholar 

  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):39–43

    Article  PubMed  CAS  Google Scholar 

  30. Zhang N, Bevan MJ (2011) CD8+ T cells: foot soldiers of the immune system. Immunity 35:161–168

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease. Immunology 134:17–32

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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 72:319–329

    Article  CAS  Google Scholar 

  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):197–199

    Article  PubMed  CAS  Google Scholar 

  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):615–618

    Article  PubMed  Google Scholar 

  35. Moretta L (2010) Dissecting CD56dim human NK cells. Blood 116(19):3689–3691

    Article  PubMed  CAS  Google Scholar 

  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 179:89–94

    Article  PubMed  CAS  Google Scholar 

  37. Loza MJ, Perussia B (2004) The IL-12 signature: NK cell terminal CD56+high stage and effector functions. J Immunol 172:88–96

    Article  PubMed  CAS  Google Scholar 

  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 122:291–301

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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 122:418–429

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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 26:77–85

    Article  PubMed  CAS  Google Scholar 

  41. Inngjerdingen M, Kveberg L, Naper C, Vaage JT (2011) Natural killer cell subsets in man and rodents. Tissue Antigens 78:81–88

    Article  PubMed  CAS  Google Scholar 

  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 CD16−CD56bright NK cells but also from CD16−CD56dim NK cells. Scand J Immunol 65:126–138

    Article  PubMed  CAS  Google Scholar 

  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 83:1216–1225

    PubMed  CAS  Google Scholar 

  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 90:974–985

    PubMed  CAS  Google Scholar 

  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 42:237–243

    Article  CAS  Google Scholar 

  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 103:2498–2503

    Article  PubMed  CAS  Google Scholar 

  47. Shimamura A (2006) Inherited bone marrow failure syndromes: molecular features. Hematology Am Soc Hematol Educ Program 63–71

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, IBRAG, UERJ, Rio de Janeiro, Brazil

    Graça A. Justo

  2. Instituto de Bioquímica Médica, CCS, UFRJ, Rio de Janeiro, Brazil

    Graça A. Justo & Vivian M. Rumjanek

  3. Ambulatório de Anemia de Fanconi, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil

    Marco A. Bitencourt & Ricardo Pasquini

  4. Departamento de Histologia e Embriologia, ICB-CCS, UFRJ, Rio de Janeiro, Brazil

    Morgana T. L. Castelo-Branco

  5. Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional do Câncer (INCA), Rio de Janeiro, RJ, Brazil

    Aline Almeida-Oliveira & Hilda Rachel Diamond

  6. Fundação Oswaldo Cruz (Fiocruz), Instituto de Tecnologia Imunobiológica (Bio-Manguinhos), Rio de Janeiro, RJ, Brazil

    Aline Almeida-Oliveira

  7. Laboratório de Imunologia Aplicada, Bioquímica de Proteínas e Produtos Naturais, Departamento de Bioquímica, Instituto de Biologia Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Boulevard 28 de Setembro 87, Vila Isabel, Rio de Janeiro, Brazil, 20551030

    Graça A. Justo

Authors
  1. Graça A. Justo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco A. Bitencourt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ricardo Pasquini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morgana T. L. Castelo-Branco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aline Almeida-Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hilda Rachel Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vivian M. Rumjanek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Graça A. Justo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Justo, G.A., Bitencourt, M.A., Pasquini, R. et al. Immune status of Fanconi anemia patients: decrease in T CD8 and CD56dim CD16+ NK lymphocytes. Ann Hematol 93, 761–767 (2014). https://doi.org/10.1007/s00277-013-1953-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-013-1953-4

Keywords

Search

Navigation