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B-Cell and T-Cell Phenotypes in CVID Patients Correlate with the Clinical Phenotype of the Disease

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Abstract

Background

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent infections and defective immunoglobulin production.

Methods

The DEFI French national prospective study investigated peripheral T-cell and B-cell compartments in 313 CVID patients grouped according to their clinical phenotype, using flow cytometry.

Results

In patients developing infection only (IO), the main B-cell or T-cell abnormalities were a defect in switched memory B cells and a decrease in naive CD4+ T cells associated with an increase in CD4+CD95+ cells. These abnormalities were more pronounced in patients developing lymphoproliferation (LP), autoimmune cytopenia (AC), or chronic enteropathy (CE). Moreover, LP and AC patients presented an increase in CD21low B cells and CD4+HLA-DR+ T cells and a decrease in regulatory T cells.

Conclusion

In these large series of CVID patients, the major abnormalities of the B-cell and T-cell compartments, although a hallmark of CVID, were only observed in half of the IO patients and were more frequent and severe in patients with additional lymphoproliferative, autoimmune, and digestive complications.

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References

  1. 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;93:190–7.

    Article  CAS  PubMed  Google Scholar 

  2. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.

    Article  CAS  PubMed  Google Scholar 

  3. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27:308–16.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med. 1993;86:31–42.

    CAS  PubMed  Google Scholar 

  6. 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;23:385–400.

    Article  CAS  PubMed  Google Scholar 

  7. 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;99:1544–51.

    Article  CAS  PubMed  Google Scholar 

  8. 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;111:77–85.

    Article  CAS  PubMed  Google Scholar 

  9. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J Immunol. 2007;178:3932–43.

    CAS  PubMed  Google Scholar 

  10. Guazzi V, Aiuti F, Mezzaroma I, Mazzetta F, Andolfi G, Mortellaro A, et al. Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles. Clin Exp Immunol. 2002;129:346–53.

    Article  CAS  PubMed  Google Scholar 

  11. Di Renzo M, Serrano D, Zhou Z, George I, Becker K, Cunningham-Rundles C. Enhanced T cell apoptosis in common variable immunodeficiency: negative role of the fas/fas ligand system and of the Bcl-2 family proteins and possible role of TNF-RS. Clin Exp Immunol. 2001;125:117–22.

    Article  PubMed  Google Scholar 

  12. Aukrust P, Muller F, Froland SS. Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4+ lymphocytes. Clin Immunol Immunopathol. 1994;70:217–24.

    Article  CAS  PubMed  Google Scholar 

  13. Sneller MC, Strober W. Abnormalities of lymphokine gene expression in patients with common variable immunodeficiency. J Immunol. 1990;144:3762–9.

    CAS  PubMed  Google Scholar 

  14. Kondratenko I, Amlot PL, Webster AD, Farrant J. Lack of specific antibody response in common variable immunodeficiency (CVID) associated with failure in production of antigen-specific memory T cells. MRC Immunodeficiency Group. Clin Exp Immunol. 1997;108:9–13.

    Article  CAS  PubMed  Google Scholar 

  15. Stagg AJ, Funauchi M, Knight SC, Webster AD, Farrant J. Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID). Clin Exp Immunol. 1994;96:48–53.

    Article  CAS  PubMed  Google Scholar 

  16. Oliva A, Scala E, Quinti I, Paganelli R, Ansotegui IJ, Giovannetti A, et al. IL-10 production and CD40L expression in patients with common variable immunodeficiency. Scand J Immunol. 1997;46:86–90.

    Article  CAS  PubMed  Google Scholar 

  17. Farrington M, Grosmaire LS, Nonoyama S, Fischer SH, Hollenbaugh D, Ledbetter JA, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci USA. 1994;91:1099–103.

    Article  CAS  PubMed  Google Scholar 

  18. Paccani SR, Boncristiano M, Patrussi L, Ulivieri C, Wack A, Valensin S, et al. Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects. Blood. 2005;106:626–34.

    Article  CAS  PubMed  Google Scholar 

  19. Boncristiano M, Majolini MB, D'Elios MM, Pacini S, Valensin S, Ulivieri C, et al. Defective recruitment and activation of ZAP-70 in common variable immunodeficiency patients with T cell defects. Eur J Immunol. 2000;30:2632–8.

    Article  CAS  PubMed  Google Scholar 

  20. Oksenhendler E, Gerard L, Fieschi C, Malphettes M, Mouillot G, Jaussaud R, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46:1547–54.

    Article  PubMed  Google Scholar 

  21. Malphettes M, Gerard L, Carmagnat M, Mouillot G, Vince N, Boutboul D, et al. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis. 2009;49:1329–38.

    Article  CAS  PubMed  Google Scholar 

  22. Fournier S, Rabian C, Alberti C, Carmagnat MV, Garin JF, Charron D, et al. Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-gamma production in the presence of Toxoplasma gondii antigens. J Infect Dis. 2001;183:1586–91.

    Article  CAS  PubMed  Google Scholar 

  23. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–12.

    Article  CAS  PubMed  Google Scholar 

  24. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.

    Google Scholar 

  25. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol. 1997;159:6236–41.

    CAS  PubMed  Google Scholar 

  26. Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R, et al. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology. 2006;131:748–56.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. 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;147:521–5.

    Article  CAS  PubMed  Google Scholar 

  29. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Camara NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132:215–21.

    Article  CAS  PubMed  Google Scholar 

  30. 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;128:314–21.

    Article  CAS  PubMed  Google Scholar 

  31. Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol. 2006;120:310–8.

    Article  CAS  PubMed  Google Scholar 

  32. Ko J, Radigan L, Cunningham-Rundles C. Immune competence and switched memory B cells in common variable immunodeficiency. Clin Immunol. 2005;116:37–41.

    Article  CAS  PubMed  Google Scholar 

  33. Moratto D, Gulino AV, Fontana S, Mori L, Pirovano S, Soresina A, et al. Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients. Clin Immunol. 2006;121:203–14.

    Article  CAS  PubMed  Google Scholar 

  34. Livaditi O, Giamarellos-Bourboulis EJ, Kakkas I, Kapsimali V, Lymberi P, Papastariades C, et al. Grouping of patients with common variable immunodeficiency based on immunoglobulin biosynthesis: comparison with a classification system on CD4-naive cells. Immunol Lett. 2007;15:103–9.

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by a national program on rare diseases (GIS-Maladies Rares), by the National Program for Clinical Research (PHRC 2005), and by the National Center on Hereditary Immune Deficiencies (CEREDIH).

Author information

Authors and Affiliations

  1. Immunology Laboratory, INSERM UMR-S945, CIB Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France

    Gaël Mouillot, Jean-Luc Garnier & Patrice Debré

  2. Immunology and Histocompatibility Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

    Maryvonnick Carmagnat, Dominique Charron & Claire Rabian

  3. Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

    Laurence Gérard, Claire Fieschi, Lionel Karlin, Lionel Galicier & Eric Oksenhendler

  4. Centre Hayem EA 3963, Hôpital Saint-Louis, Paris, France

    Nicolas Vince

  5. Department of Internal Medicine, Hôpital Haut-Lévèque, Pessac, France

    Jean-François Viallard

  6. Department of Internal Medicine, Hôpital Robert Debré, Reims, France

    Roland Jaussaud

  7. Department of Clinical Immunology and Internal Medicine, CNRS UPR9021, Strasbourg, France

    Julien Boileau

  8. Department of Pediatric Hematology, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France

    Jean Donadieu

  9. Department of Hematology, CHU d’Angers, Angers, France

    Martine Gardembas

  10. Department of Internal Medicine, Hôpital de la Conception, Marseille, France

    Nicolas Schleinitz

  11. Department of Hematology, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France

    Felipe Suarez

  12. Department of Internal Medicine, Hôpital Claude Hurriez, Lille, France

    Eric Hachulla

  13. Department of Internal Medicine, Pr Adoue, CHU Toulouse, Toulouse, France

    Karen Delavigne

  14. Department of Internal Medicine and Immunology, CHU de Nancy, Nancy, France

    Martine Morisset

  15. Immunology Laboratory, Rouen University Hospital and INSERM U905, Rouen University, Rouen, France

    Serge Jacquot

  16. Department of Pneumo-Allergology, CHR Roubaix, Roubaix, France

    Nicolas Just

  17. Laboratoire d’Immunologie Cellulaire et Tissulaire, Bat CERVI, GH Pitié-Salpêtrière, 83 bd de l’Hôpital, 75651, Paris Cedex 13, France

    Gaël Mouillot

Authors
  1. Gaël Mouillot
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  8. Jean-François Viallard
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  11. Jean Donadieu
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  12. Martine Gardembas
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  13. Nicolas Schleinitz
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  14. Felipe Suarez
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  15. Eric Hachulla
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  16. Karen Delavigne
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  17. Martine Morisset
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  18. Serge Jacquot
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  19. Nicolas Just
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  20. Lionel Galicier
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  24. Claire Rabian
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Consortia

for the DEFI Study Group

Corresponding author

Correspondence to Gaël Mouillot.

Additional information

A complete list of the DEFI Study Group is presented in Appendix A.

Appendix A. DEFI Study Group

Appendix A. DEFI Study Group

  • Coordination: Hôpital Saint Louis, Paris: E. Oksenhendler

  • Clinical Centers: Hôpital Saint Louis, Paris: C. Fieschi, M. Malphettes, L. Galicier, S. Georgin, J.P. Fermand. Bordeaux: J.F. Viallard. Limoges: A. Jaccard. Tours: C. Hoarau, Y. Lebranchu. Hôpital Cochin, Paris: A. Bérezné, L. Mouthon. HEGP, Paris: M. Karmochkine. Marseille: N. Schleinitz. Lyon Sud: I. Durieu, R. Nove-Josserand. Clermont-Ferrand: V. Chanet. Montpellier: V. Le-Moing. Roubaix: N. Just. Hôtel-Dieu, Paris: C. Salanoubat. Reims: R. Jaussaud. Hôpital Necker, Paris: F. Suarez, O. Hermine. Le Mans: P. Solal-Celigny. Lille: E. Hachulla. Perpignan: L. Sanhes. Angers: M. Gardembas, I. Pellier. Troyes: P. Tisserant. Lyon Armée: M. Pavic. Dijon: B. Bonnotte. Pitié-Salpêtrière, Paris: J. Haroche, Z. Amoura. Toulouse: L. Alric, M.F. Thiercelin, L. Tetu, D. Adoue. Nancy Vandoeuvre: P. Bordigoni. Lyon Croix Rousse: T. Perpoint. Lyon Hotel-Dieu: P. Sève. Besançon: P. Rohrlich. Strasbourg: J.L. Pasquali, P. Soulas. Hôpital Foch, Suresnes: L.J. Couderc. Montauban: P. Giraud. Hôpital Saint-Louis, Pédiatrie, Paris: A. Baruchel. Clermont-Ferrand 2: I. Deleveau. Kremlin-Bicêtre: F. Chaix. Hôpital Trousseau, Paris: J. Donadieu. Rouen: F. Tron. Bobigny: C. Larroche. Aix: A.P. Blanc. Nantes: A. Masseau, M. Hamidou. Nancy: G. Kanny, M. Morisset. Poitiers: F. Millot. Bondy: O. Fain. Hôpital Bichat, Paris: R. Borie. Rennes: A. Perlat

  • Laboratories: Pitié-Salpêtrière, INSERM U543, Paris: P. Debré, G. Mouillot, I. Théodorou. Saint-Louis, Immunologie, Paris: C. Rabian, M. Carmagnat. Saint-Louis, EA 3963, Paris: C. Fieschi, M. Malphettes, N. Vince, D. Boutboul

  • Clinical research assistants: A. De Gouvello, A. Gardeur.

  • Data management and statistics: L. Gérard.

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Mouillot, G., Carmagnat, M., Gérard, L. et al. B-Cell and T-Cell Phenotypes in CVID Patients Correlate with the Clinical Phenotype of the Disease. J Clin Immunol 30, 746–755 (2010). https://doi.org/10.1007/s10875-010-9424-3

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  • DOI: https://doi.org/10.1007/s10875-010-9424-3

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