Skip to main content

Advertisement

SpringerLink
Log in

Frequency of Treg Cells Is Reduced in CVID Patients with Autoimmunity and Splenomegaly and Is Associated with Expanded CD21lo B Lymphocytes

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Common variable immunodeficiency is a heterogeneous antibody deficiency syndrome with autoimmune and inflammatory complications in a significant proportion of patients. The study was designed to evaluate the role of T regulatory (Treg) cells in common variable immunodeficiency (CVID) patients with autoimmunity.

Methods

The number and frequency of Treg cells (CD4+, CD25hi, Foxp3+) were evaluated in patients and controls, and Foxp3 expression in different subgroups of CVID patients with common clinical manifestations was compared.

Results

CVID patients had significantly fewer Treg cells than controls, and low frequency of Treg cells was associated with expansion of CD21lo B cells in patients. Patients with autoimmunity had significantly reduced frequency but normal numbers of regulatory T cells, whilst patients with splenomegaly had significant reduction in frequency and number of regulatory T cells.

Conclusion

Foxp3 is useful on its own or as an adjunct to classify CVID patients although the possibility of reduction in Treg cells as a secondary phenomenon cannot be excluded.

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
Fig. 5

Similar content being viewed by others

References

  1. Rosen F, Eibl M, Fischer A, Volanakis J, Aiuti F, Notarangelo L, et al. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999;118(Suppl 1):1–28.

    Google Scholar 

  2. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111(1):77–85.

    Article  CAS  PubMed  Google Scholar 

  3. Bacchelli C, Buckridge S, Thrasher AJ, Gaspar HB. Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency. Clin Exp Immunol. 2007;149(3):401–9.

    Article  CAS  PubMed  Google Scholar 

  4. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34–48.

    Article  CAS  PubMed  Google Scholar 

  5. Bryant A, Calver NC, Toubi E, Webster AD, Farrant J. Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2. Clin Immunol Immunopathol. 1990;56(2):239–48.

    Article  CAS  PubMed  Google Scholar 

  6. Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99(5):1544–51.

    Article  CAS  PubMed  Google Scholar 

  7. Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van-der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol. 2003;23(5):385–400.

    Article  CAS  PubMed  Google Scholar 

  8. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115(2):412–7.

    Article  CAS  PubMed  Google Scholar 

  9. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.

    Article  CAS  PubMed  Google Scholar 

  10. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000;106(12):R75–81.

    Article  CAS  PubMed  Google Scholar 

  11. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20.

    Article  CAS  PubMed  Google Scholar 

  12. Nik Tavakoli N, Hambly BD, Sullivan DR, Bao S. Forkhead box protein 3: essential immune regulatory role. Int J Biochem Cell Biol. 2008;40:2369–73.

    Article  PubMed  CAS  Google Scholar 

  13. Shevach EM. Regulatory T cells in autoimmmunity*. Annu Rev Immunol. 2000;18:423–49.

    Article  CAS  PubMed  Google Scholar 

  14. Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006;117(3):289–300.

    Article  CAS  PubMed  Google Scholar 

  15. Torgerson TR. Regulatory T cells in human autoimmune diseases. Springer Semin Immunopathol. 2006;28(1):63–76.

    Article  CAS  PubMed  Google Scholar 

  16. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.

    Article  CAS  PubMed  Google Scholar 

  17. Gorg C, Weide R, Schwerk WB. Malignant splenic lymphoma: sonographic patterns, diagnosis and follow-up. Clin Radiol. 1997;52(7):535–40.

    Article  CAS  PubMed  Google Scholar 

  18. Warnatz K, Wehr C, Drager R, Schmidt S, Eibel H, Schlesier M, et al. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206(5):502–13.

    Article  PubMed  Google Scholar 

  19. Kingsley CI, Karim M, Bushell AR, Wood KJ. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol. 2002;168(3):1080–6.

    CAS  PubMed  Google Scholar 

  20. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9(9):1144–50.

    Article  CAS  PubMed  Google Scholar 

  21. Fevang B, Yndestad A, Sandberg WJ, Holm AM, Muller F, Aukrust P, et al. Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. Clin Exp Immunol. 2007;147(3):521–5.

    Article  CAS  PubMed  Google Scholar 

  22. Yu GP, Chiang D, Song SJ, Hoyte EG, Huang J, Vanishsarn C, et al. Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease. Clin Immunol. 2009;131:240–53.

    Article  CAS  PubMed  Google Scholar 

  23. Horn J, Manguiat A, Berglund LJ, Knerr V, Tahami F, Grimbacher B, et al. Decrease in phenotypic regulatory T cells in subsets of patients with common variable immunodeficiency. Clin Exp Immunol. 2009;156(3):446–54.

    Article  CAS  PubMed  Google Scholar 

  24. de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, et al. CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol. 2004;172(10):6435–43.

    PubMed  Google Scholar 

  25. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 2004;6(4):R335–46.

    Article  CAS  PubMed  Google Scholar 

  26. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.

    Article  CAS  PubMed  Google Scholar 

  27. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.

    Article  CAS  PubMed  Google Scholar 

  28. Zheng Y, Manzotti CN, Burke F, Dussably L, Qureshi O, Walker LS, et al. Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3. J Immunol. 2008;181(3):1683–91.

    CAS  PubMed  Google Scholar 

  29. Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008;111(2):715–22.

    Article  CAS  PubMed  Google Scholar 

  30. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179(8):5571–5.

    CAS  PubMed  Google Scholar 

  31. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood. 2008;112(8):3303–11.

    Article  PubMed  CAS  Google Scholar 

  32. Fearon DT, Carroll MC. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol. 2000;18:393–422.

    Article  CAS  PubMed  Google Scholar 

  33. Griffioen AW, Franklin SW, Zegers BJ, Rijkers GT. Expression and functional characteristics of the complement receptor type 2 on adult and neonatal B lymphocytes. Clin Immunol Immunopathol. 1993;69(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  34. Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc Natl Acad Sci USA. 2009;106(32):13451–6.

    Article  CAS  PubMed  Google Scholar 

  35. Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004;113(2):161–71.

    Article  CAS  PubMed  Google Scholar 

  36. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261–71.

    PubMed  Google Scholar 

  37. Sanchez-Ramon S, Radigan L, Yu JE, Bard S, Cunningham-Rundles C. Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clin Immunol. 2008;128(3):314–21.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank John Toolan and Kate Ford for their help in sample collection, June Cole for technical assistance and patients and controls from St. James’s University hospital for agreeing to take part in the study.

Author information

Authors and Affiliations

  1. Department of Clinical Immunology, Beckett Wing, St.James’s University Hospital, Leeds, UK, LS9 7TF

    Gururaj Arumugakani & Philip M. D. Wood

  2. Cellular Immunology Laboratory, Department of Immunology & Transplant Immunology, St. James’s University Hospital, Leeds, UK

    Philip M. D. Wood & Clive R. D. Carter

Authors
  1. Gururaj Arumugakani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip M. D. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clive R. D. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gururaj Arumugakani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arumugakani, G., Wood, P.M.D. & Carter, C.R.D. Frequency of Treg Cells Is Reduced in CVID Patients with Autoimmunity and Splenomegaly and Is Associated with Expanded CD21lo B Lymphocytes. J Clin Immunol 30, 292–300 (2010). https://doi.org/10.1007/s10875-009-9351-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-009-9351-3

Keywords

Search

Navigation