Skip to main content

Advertisement

SpringerLink
Log in

Downregulation of B regulatory cells and upregulation of T helper 1 cells in children with Gaucher disease undergoing enzyme replacement therapy

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Gaucher disease (GD) involves a broad spectrum of immunological cells, including T helper (Th) cells and regulatory B cells (Bregs), which function to resolve the immune response and inhibit excessive inflammation. This study aimed to explore T helper cells, B cells, and Bregs in GD children undergoing enzyme replacement therapy (ERT). Our study included 20 GD patients; six patients were categorized as type 1 and 14 as type 3 GD. All patients were on regular ERT. Twenty healthy children were enrolled as controls. All patients and controls were subjected to complete blood analysis, abdominal ultrasound, and flow cytometric detection of T helper cells, B cells, and Bregs. Despite undergoing ERT, CD4+ T helper lymphocytes and Bregs were still significantly lower in patients with GD compared with the controls. Th1 and B cells were more in the patients than in the healthy controls. Lower levels of Bregs were found in type 3, compared with type 1 patients. Increased platelet count was directly associated with increased levels of Bregs and lower levels of B cells. Elevated children’s height was also accompanied by decreasing levels of Th1. Our results propose that ERT in GD is associated with partial improvement in immune status, and long-term ERT might be needed for the restoration of the desired immune response levels. Levels of Bregs and Th1 can be employed for monitoring improvement of immune status in GD patients undergoing ERT.

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. Grabowsky G. Phenotype, diagnosis and treatment of Gaucher disease. Lancet. 2008;372:1263–71.

    Article  CAS  Google Scholar 

  2. Grabowski GA. Gaucher disease and other storage disorders. Am Soc Hematol Educ Program. 2012;2012(1):13–8.

    Article  Google Scholar 

  3. Pandey MK, Grabowski GA. Immunological cells and functions in Gaucher disease. Crit Rev Oncog. 2013;18(3):197–220. https://doi.org/10.1615/critrevoncog.2013004503.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–41.

    Article  CAS  PubMed  Google Scholar 

  5. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–40. https://doi.org/10.1016/j.immuni.2009.11.009.

    Article  CAS  PubMed  Google Scholar 

  6. Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–41. https://doi.org/10.1182/blood-2010-07-294249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bao W, Zhong H, Manwani D, Vasovic L, Uehlinger J, Lee MT, et al. Regulatory B-cell compartment in transfused alloimmunized and non-alloimmunized patients with sickle cell disease. Am J Hematol. 2013;88(9):736–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li X, Zhong H, Bao W, Boulad N, Evangelista J, Haider MA, et al. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood. 2012;120(16):3318–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bouaziz J, de Masson A, Bagot M, Bensussan A. IL-10 producing regulatory B cells: where are we? MOJ Immunol. 2014;1(1):00003.

    Google Scholar 

  10. Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Balreira A, Cavallari M, Miranda MCS, Arosa FA. Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness. Immunobiology. 2010;215(6):505–13.

    Article  CAS  PubMed  Google Scholar 

  12. Lacerda L, Arosa FA, Lacerda R, Cabeda J, Porto G, Amaral O, et al. T cell numbers relate to bone involvement in Gaucher disease. Blood Cell Mol Dis. 1999;25(2):130–8.

    Article  CAS  Google Scholar 

  13. Mistry PK, Liu J, Yang M, Nottoli T, McGrath J, Jain D, et al. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl Acad Sci. 2010;107(45):19473–8.

    Article  CAS  PubMed  Google Scholar 

  14. Stockinger B, Veldhoen M, Martin B, editors. Th17 T cells: linking innate and adaptive immunity. Seminars in immunology; 2007: Elsevier.

  15. Shoenfeld Y, Gallant L, Shaklai M, Livni E, Djaldetti M, Pinkhas J. Gaucher’s disease: a disease with chronic stimulation of the immune system. Arch Pathol Lab Med. 1982;106(8):388–91.

    CAS  PubMed  Google Scholar 

  16. Goker-Alpan O. Optimal therapy in Gaucher disease. Ther Clin Risk Manag. 2010;6:315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother. 2013;47(9):1182–93.

    Article  PubMed  Google Scholar 

  18. Zimran A, Elstein D. Management of Gaucher disease: enzyme replacement therapy. Pediatr Endocrinol Rev. 2014;12:82–7.

    PubMed  Google Scholar 

  19. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M et al., editors. Therapeutic goals in the treatment of Gaucher disease. Seminars in hematology; 2004: Elsevier.

  20. Charrow J, Scott CR. Long-term treatment outcomes in G aucher disease. Am J Hematol. 2015;90:S19–24.

    Article  PubMed  Google Scholar 

  21. Limgala RP, Ioanou C, Plassmeyer M, Ryherd M, Kozhaya L, Austin L, et al. Time of initiating enzyme replacement therapy affects immune abnormalities and disease severity in patients with gaucher disease. PLoS One. 2016;11(12):e0168135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Camou F, Viallard J-F. Extended remission of B-cell lymphoma with monoclonal gammopathy in a patient with type 1 Gaucher disease treated with enzyme replacement therapy. Blood Cells Mol Dis. 2012;48(1):51.

    Article  PubMed  Google Scholar 

  23. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.

    Article  CAS  PubMed  Google Scholar 

  24. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140(6):871–82.

    Article  CAS  PubMed  Google Scholar 

  25. Barak V, Acker M, Nisman B, Kalickman I, Abrahamov A, Zimran A, et al. Cytokines in Gaucher’s disease. Eur Cytokine Netw. 1999;10(2):205–10.

    CAS  PubMed  Google Scholar 

  26. Bosma A, Abdel-Gadir A, Isenberg DA, Jury EC, Mauri C. Lipid-antigen presentation by CD1d+ B cells is essential for the maintenance of invariant natural killer T cells. Immunity. 2012;36(3):477–90.

    Article  CAS  PubMed  Google Scholar 

  27. Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol. 2012;189(8):3925–35. https://doi.org/10.4049/jimmunol.1103139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra23. https://doi.org/10.1126/scitranslmed.3005407.

    Article  CAS  PubMed  Google Scholar 

  29. Rogowski O, Shapira I, Zimran A, Zeltser D, Elstein D, Attias D, et al. Automated system to detect low-grade underlying inflammatory profile: Gaucher disease as a model. Blood Cell Mol Dis. 2005;34(1):26–9.

    Article  CAS  Google Scholar 

  30. De Fost M, Out T, De Wilde F, Tjin E, Pals S, van Oers M, et al. Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature. Ann Hematol. 2008;87(6):439–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shemesh E, Deroma L, Bembi B, Deegan P, Hollak C, Weinreb NJ, et al. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database Syst Rev. 2015;3.

  32. Brooks DA, Kakavanos R, Hopwood JJ. Significance of immune response to enzyme-replacement therapy for patients with a lysosomal storage disorder. Trends Mol Med. 2003;9(10):450–3.

    Article  CAS  PubMed  Google Scholar 

  33. Marti G, Ryan E, Papadopoulos N, Filling-Katz M, Barton N, Fleischer T, et al. Polyclonal B-cell lymphocytosis and hypergammaglobulinemia in patients with Gaucher disease. Am J Hematol. 1988;29(4):189–94.

    Article  CAS  PubMed  Google Scholar 

  34. Dondurmacı M, Canda E, Köse M, Uçar SK, Çoker M, Sağın F, et al. Higher levels of CD19+ leukocytes in Gaucher disease patients as a potential marker for malignancy. J Clin Anal Med. 2018;9(1):56–60.

    Article  Google Scholar 

  35. Pandey MK, Jabre NA, Xu Y-H, Zhang W, Setchell KD, Grabowski GA. Gaucher disease: chemotactic factors and immunological cell invasion in a mouse model. Mol Genet Metab. 2014;111(2):163–71.

    Article  CAS  PubMed  Google Scholar 

  36. Hollak CE, Evers L, Aerts JM, van Oers MH. Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood Cell Mol Dis. 1997;23(2):201–12.

    Article  CAS  Google Scholar 

  37. Rodic P, Kurtovic NK, Vukovic NS, Djordjevic M, Mitrovic M, Sumarac Z, et al. Flow cytometric assessment of lymphocyte subsets in Gaucher type 1 patients. Blood Cell Mol Dis. 2014;4(53):169–70.

    Article  Google Scholar 

  38. Jelley-Gibbs DM, Brown DM, Dibble JP, Haynes L, Eaton SM, Swain SL. Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med. 2005;202(5):697–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matta MC, Soares DC, Kerstenetzky MS, Freitas ACP, Kim CA, Torres LC. CD4+ CD25highFoxp3+ Treg deficiency in a Brazilian patient with Gaucher disease and lupus nephritis. Hum Immunol. 2016;77(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  40. Sotiropoulos C, Theodorou G, Repa C, Marinakis T, Verigou E, Solomou E et al. Severe impairment of regulatory T-cells and Th1-lymphocyte polarization in patients with Gaucher disease. JIMD Reports, Volume 18. Springer; 2014. p. 107–15.

  41. Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21(10):1105–11.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pathology, South Egypt Cancer Institute, Assiut, Egypt

    Asmaa M. Zahran & Engy Adel Shafik

  2. Children’s Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt

    Mervat A. M. Youssef, Amir M. Abo Elgheet & Khalid I. Elsayh

  3. Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt

    Zeinab Albadry M. Zahran

  4. Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt

    Omnia El-Badawy

Authors
  1. Asmaa M. Zahran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mervat A. M. Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Engy Adel Shafik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeinab Albadry M. Zahran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omnia El-Badawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amir M. Abo Elgheet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Khalid I. Elsayh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Omnia El-Badawy.

Ethics declarations

Informed consent was obtained from the guardians of the controls and patients before enrollment in the study. All procedures complied with the Health and Human Ethical Clearance Committee guidelines for Clinical Research at Assiut University (IRB no. 17300210).

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zahran, A.M., Youssef, M.A.M., Shafik, E.A. et al. Downregulation of B regulatory cells and upregulation of T helper 1 cells in children with Gaucher disease undergoing enzyme replacement therapy. Immunol Res 68, 73–80 (2020). https://doi.org/10.1007/s12026-020-09129-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-020-09129-5

Keywords

Search

Navigation