Skip to main content

Advertisement

SpringerLink
Log in

Autoimmunity in Common Variable Immunodeficiency

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

Abstract

Background

Autoimmunity has been increasingly recognized as a major issue in patients with common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency in adulthood. Different authors report high prevalences of autoimmune diseases in CVID, and several mechanisms have been proposed to explain this apparent paradox. Genetic predisposition, under current surveillance, innate and adaptive immunity deficiencies leading to persistent/recurrent infections, variable degrees of immune dysregulation, and possible failure in central and peripheral mechanisms of tolerance induction or maintenance may all contribute to increased autoimmunity.

Conclusions

Data on the clinical/immunological profile of affected patients and treatment are available mostly concerning autoimmune cytopenias, the most common autoimmune diseases in CVID. Treatment is based on conventional alternatives, in association with short experience with new agents, including rituximab and infliximab. Benefits of early immunoglobulin substitutive treatment and hypothetical premature predictors of autoimmunity are discussed as potential improvements to CVID patients’ follow-up.

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. I

Similar content being viewed by others

References

  1. Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. Common variable immunodeficiency: the immune system in chaos. Trends Mol Med 2005;11:370–6.

    Article  PubMed  CAS  Google Scholar 

  2. Pavic M, Sève P, Malcus C, Sarrot-Reynault F, Peyramond D, Debourdeau P, Andriamanantena D, Bouhour D, Philippe N, Rousset H, Broussolle C. Common variable immunodeficiency with autoimmune manifestations: study of nine cases; interest of a peripheral B-cell compartment analysis in seven patients. Rev Med Interne 2005;26:95–102.

    PubMed  CAS  Google Scholar 

  3. Bloch-Michel C, Viallard JF, Blanco P, Bloch Liferman F, Neau D, Moreau JF, Baillet L, Etienne G, Longy-Boursier M, Pellegrin JL. Common variable immunodeficiency: 17 observations in the adult. Rev Med Interne 2003;24:640–50.

    Article  PubMed  CAS  Google Scholar 

  4. Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, Hammarström L, Nonoyama S, Ochs HD, Puck JM, Roifman C, Seger R, Wedgwood J. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776–94.

    Article  PubMed  Google Scholar 

  5. Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun 2005;25:57–62.

    Article  PubMed  CAS  Google Scholar 

  6. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114:415–21.

    Article  PubMed  Google Scholar 

  7. Kokron CM, Errante PR, Toledo-Barros M, Baracho GV, Camargo MM, Kalil J, Rizzo LV. Clinical and laboratory aspects of common variable immunodeficiency. An Acad Bras Ciênc 2004;76:1–20.

    Article  Google Scholar 

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

    Article  Google Scholar 

  9. Warnatz K, Wehr C, Dräger R, Schmidt S, Eibel H, Schlesier M, Peter HH. Expansion of CD19hiCD21lo/neg B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology 2002;206:502–13.

    Article  PubMed  Google Scholar 

  10. Sarmiento E, Mora R, Rodríguez-Mahou M, Rodríguez-Molina J, Fernández-Cruz E, Carbone J. Autoimmune disease in primary antibody deficiencies. Allergol Immunopathol 2005;33:69–73.

    Article  CAS  Google Scholar 

  11. Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH, Litzman J, Holm A, Franco JL, Plebani A, Hammarstrom L, Skrabl A, Schwinger W, Grimbacher B. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol 2004;113:234–40.

    Article  PubMed  CAS  Google Scholar 

  12. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, Claudio P, Franco D, Maria Pesce A, Borghese F, Guerra A, Rondelli R, Plebani A. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. Clin Immunol 2007;27:308–16.

    Article  Google Scholar 

  13. Detková D, de Gracia J, Lopes-da-Silva S, Vendrell M, Alvarez A, Guarner L, Vidaller A, Rodrigo MJ, Caragol I, Espanol T, Hernández M. Common variable immunodeficiency: association between memory B cells and lung diseases. Chest 2007;131:1883–9.

    Article  PubMed  Google Scholar 

  14. Diamond B. Autoimmunity. Immunol Rev. 2005;204:5–8.

    Article  PubMed  CAS  Google Scholar 

  15. Michel M, Chanet V, Galicier L, Ruivard M, Levy Y, Hermine O, Oksenhendler E, Schaeffer A, Bierling P, Godeau B. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine 2004;83:254–63.

    Article  PubMed  CAS  Google Scholar 

  16. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3–40.

    PubMed  CAS  Google Scholar 

  17. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002;69:258–71.

    Article  PubMed  Google Scholar 

  18. Giannouli S, Anagnostou D, Soliotis F, Voulgarelis M. Autoimmune manifestations in common variable immunodeficiency. Clin Rheumatol 2004;23:449–52.

    Article  PubMed  Google Scholar 

  19. Swierkot J, Lewandowicz-Uszynska A, Chlebicki A, Szmyrka-Kaczmarek M, Polańska B, Jankowski A, Szechinski J. Rheumatoid arthritis in a patient with common variable immunodeficiency: difficulty in diagnosis and therapy. Clin Rheumatol 2006;25:92–4.

    Article  PubMed  CAS  Google Scholar 

  20. Sordet C, Cantagrel A, Schaeverbeke T, Sibilia J. Bone and joint disease associated with primary immune deficiencies. Jt Bone Spine 2005;72:503–14.

    Article  Google Scholar 

  21. Heeney MM, Zimmerman SA, Ware RE. Childhood autoimmune cytopenia secondary to unsuspected common variable immunodeficiency. Pediatrics 2003;143:662–5.

    Article  Google Scholar 

  22. Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev 2006;5:156–9.

    Article  PubMed  CAS  Google Scholar 

  23. Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood 2002;99:2694–702.

    Article  PubMed  CAS  Google Scholar 

  24. Brandt D, Gershwin ME. Common variable immune deficiency and autoimmunity. Autoimmun Rev 2006;5:465–70.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  26. Schäffer AA, Salzer U, Hammarström L, Grimbacher B. Deconstructing common variable immunodeficiency by genetic analysis. Curr Opin Genet Dev 2007;17:201–12.

    Article  PubMed  CAS  Google Scholar 

  27. Mullighan CG, Marshall SE, Welsh KI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol 2000;51:111–122.

    Article  PubMed  Google Scholar 

  28. Goldacker S, Warnatz K. Tackling the heterogeneity of CVID. Curr Opin Allergy Clin Immunol 2005;5:504–9.

    Article  PubMed  Google Scholar 

  29. Zhang L, Radigan L, Salzer U, Behrens TW, Grimbacher B, Diaz G, Bussel J, Cunningham-Rundles C. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol 2007;120:178–85.

    Article  CAS  Google Scholar 

  30. Di Renzo M, Pasqui AL, Auteri A. Common variable immunodeficiency: a review. Clin Exp Med 2004;3:211–7.

    Article  PubMed  Google Scholar 

  31. Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, Peter HH, Eibel H. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J Immunol 2005;175:5498–503.

    PubMed  CAS  Google Scholar 

  32. Brouet JC, Chedeville A, Fermand JP, Royer B. Study of the B cell memory compartment in common variable immunodeficiency. Eur J Immunol 2000;30:2516–20.

    Article  PubMed  CAS  Google Scholar 

  33. Jacquot S, Maçon-Lemaître L, Paris E, Kobata T, Tanaka Y, Morimoto C, Schlossman SF, Tron F. B cell co-receptors regulating T cell dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immunocompromised patients. Int Immunol 2001;13:871–6.

    Article  PubMed  CAS  Google Scholar 

  34. Warnatz K, Denz A, Dräger R, Braun M, Groth C, Wolff-Vorbeck G, Eibel H, Schlesier M, Peter HH. 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  PubMed  CAS  Google Scholar 

  35. Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, Debré P, Schmitt C, Oksenhendler E. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003;23:385–400.

    Article  PubMed  CAS  Google Scholar 

  36. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, De Felice M, Mora B, Esposito A, Carello R, Pizzuti A, Paggi MG, Paganelli R, Malorni W, Aiuti F. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J Immunol 2007;178:3932–43.

    PubMed  CAS  Google Scholar 

  37. Vlková M, Thon V, Sárfyová M, Bláha L, Svobodník A, Lokaj J, Litzman J. Age dependency and mutual relations in T and B lymphocyte abnormalities in common variable immunodeficiency patients. Clin Exp Immunol 2006;143:373–9.

    Article  PubMed  CAS  Google Scholar 

  38. Eisenstein EM, Jaffe JS, Strober W. Reduced interleukin-2 (IL-2) production in common variable immunodeficiency is due to a primary abnormality of CD4+ T cell differentiation. J Clin Immunol 1993;13:247–58.

    Article  PubMed  CAS  Google Scholar 

  39. Holm AM, Aukrust P, Damas JK, Muller F, Halvorsen B, Froland S. Abnormal interleukin-7 function in common variable immunodeficiency. Blood. 2005;105:2887–2890.

    Article  PubMed  CAS  Google Scholar 

  40. De Vera MJ, Al-Harthi L, Gewurz AT. Assessing thymopoiesis in patients with common variable immunodeficiency as measured by T-cell receptor excision circles. Ann Allergy Asthma Immunol 2004;93:478–84.

    Article  PubMed  Google Scholar 

  41. Isgrò A, Marziali M, Mezzaroma I, Luzi G, Mazzone AM, Guazzi V, Andolfi G, Cassani B, Aiuti A, Aiuti F. Bone marrow clonogenic capability, cytokine production, and thymic output in patients with common variable immunodeficiency. J Immunol 2005;174:5074–81.

    PubMed  Google Scholar 

  42. Goldberg AC, Eliaschewitz FG, Montor WR, Baracho GV, Errante PR, Callero MA, Cardoso MRA, Braga PE, Kalil J, Sogayar MC, Rizzo LV. Exogenous leptin restores in vitro T cell proliferation and cytokine synthesis in patients with common variable immunodeficiency syndrome. Clin Immunol 2005;114:147–53.

    Article  PubMed  CAS  Google Scholar 

  43. Holm AM, Sivertsen EA, Tunheim SH, Haug T, Bjerkeli V, Yndestad A, Aukrust P, Frøland SS. Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7− effector-memory T cells. Clin Exp Immunol 2004;138:278–89.

    Article  PubMed  CAS  Google Scholar 

  44. Cunningham-Rundles C, Radigan L. Deficient IL-12 and dendritic cell function in common variable immune deficiency. Clin Immunol 2005;115:147–53.

    Article  PubMed  CAS  Google Scholar 

  45. Aspalter RM, Sewell WA, Dolman K, Farrant J, Webster AD. Deficiency in circulating natural killer (NK) cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia. Clin Exp Immunol 2000;121:506–14.

    Article  PubMed  CAS  Google Scholar 

  46. Amoras AL, Kanegane H, Miyawaki T, Vilela MM. Defective Fc−, CR1− and CR3− mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients. J Investig Allergol Clin Immunol 2003;13:181–8.

    PubMed  CAS  Google Scholar 

  47. Holm AM, Aukrust P, Aandahl EM, Muller F, Tasken K, Froland SS. Impaired secretion of IL-10 by T cells from patients with common variable immunodeficiency—involvement of protein kinase A type I. J Immunol 2003;170:5772–7.

    PubMed  CAS  Google Scholar 

  48. Petrovsky N. The paradoxical association between immunodeficiency and autoimmunity: comment on the article by Atkinson. Arthritis Rheum 1996;39:179–80.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  50. Rump JA, Jahreis A, Schlesier M, Drager R, Melchers I, Peter HH. Possible role of IL-2 deficiency for hypogammaglobulinaemia in patients with common variable immunodeficiency. Clin Exp Immunol 1992;89:204–10.

    PubMed  CAS  Google Scholar 

  51. North ME, Ivory K, Funauchi M, Webster AD, Lane AC, Farrant J. Intracellular cytokine production by human CD4+ and CD8+ T cells from normal and immunodeficient donors using directly conjugated anti-cytokine antibodies and three-colour flow cytometry. Clin Exp Immunol 1996;105:517–22.

    Article  PubMed  CAS  Google Scholar 

  52. 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  PubMed  CAS  Google Scholar 

  53. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science 2003;301:1374–7.

    Article  PubMed  CAS  Google Scholar 

  54. Levy Y, Gupta N, Le Deist F, Garcia C, Fischer A, Weill JC, Reynaud CA. Defect in IgV gene somatic hypermutation in common variable immunodeficiency syndrome. Proc Natl Acad Sci USA 1998;95:13135–40.

    Article  PubMed  CAS  Google Scholar 

  55. Meffre E, Schaefer A, Wardemann H, Wilson P, Davis E, Nussenzweig MC. Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies. J Exp Med 2004;199:145–50.

    Article  PubMed  CAS  Google Scholar 

  56. Jiang H, Chess L. An integrated view of suppressor T cell subsets in immunoregulation. J Clin Invest 2004;114:1198–208.

    PubMed  CAS  Google Scholar 

  57. Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol 2005;116:949–59.

    Article  PubMed  CAS  Google Scholar 

  58. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–62.

    Article  PubMed  CAS  Google Scholar 

  59. Baecher-Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev 2006;212:203–16.

    Article  PubMed  CAS  Google Scholar 

  60. Lopes-da-Silva S, Detková D, Urban S. CD4+CD25high T cells and autoimmunity in Common Variable Immunodeficiency. Presented at the XI Meeting of the European Society for Immunodeficiencies (ESID). Versailles 2004.

  61. Fevang B, Yndestad A, Sandberg WJ, Holm AM, Müller F, Aukrust P, Frøland SS. Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. Clin Exp Immunol 2007;147:521–5.

    PubMed  CAS  Google Scholar 

  62. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004;4:665–74.

    Article  PubMed  CAS  Google Scholar 

  63. Scheffold A, Huhn J, Hofer T. Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL-) two to tango. Eur J Immunol 2005;35:1336–41.

    Article  PubMed  CAS  Google Scholar 

  64. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, Long LM, Bernstein D, Hill BJ, Douek DC, Berzofsky JA, Carter CS, Read EJ, Helman LJ, Mackall CL. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 2005;11:1238–43.

    Article  PubMed  CAS  Google Scholar 

  65. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmunity. 2003;21:273–6.

    Article  Google Scholar 

  66. Goleva E, Cardona ID, Ou LS, Leung DY. Factors that regulate naturally occurring T regulatory cell-mediated suppression. J Allergy Clin Immunol 2005;116:1094–100.

    Article  PubMed  CAS  Google Scholar 

  67. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med. 1991;325:110–7.

    PubMed  CAS  Google Scholar 

  68. RJ Kilic SS. Anti-tumour necrosis factor-alpha treatment of juvenile idiopathic arthritis in a patient with common variable immunodeficiency. J Trop Pediatr 2005;51:194–5.

    Article  Google Scholar 

  69. Nos P, Bastida G, Beltran B, Aguas M, Ponce J. Crohn’s disease in common variable immunodeficiency: treatment with antitumor necrosis factor alpha. Am J Gastroenterol 2006;101:2165–6.

    Article  PubMed  Google Scholar 

  70. Kanai T, Watanabe M. Clinical application of human CD4+ CD25+ regulatory T cells for the treatment of inflammatory bowel diseases. Expert Opin Biol Ther 2005;5:451–62.

    Article  PubMed  CAS  Google Scholar 

  71. Cunningham-Rundles C, Kazbay K, Hassett J, Zhou Z, Mayer L. Brief report: enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2. N Engl J Med 1994;331:918–21.

    Article  PubMed  CAS  Google Scholar 

  72. Rump JA, Jahreis A, Schlesier M, Stecher S, Peter HH. A double-blind, placebo-controlled, crossover therapy study with natural human IL-2 (nhuIL-2) in combination with regular intravenous gammaglobulin (IVIG) infusions in 10 patients with common variable immunodeficiency (CVID). Clin Exp Immunol 1997;110:167–73.

    PubMed  CAS  Google Scholar 

  73. Spickett GP, Farrant J, North ME, Zhang J, Morgan L, Webster ADB. Common variable immunodeficiency: how many diseases? Immunol Today 1998;18:315–28.

    Google Scholar 

  74. 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;56:239–48.

    Article  PubMed  CAS  Google Scholar 

  75. 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  PubMed  CAS  Google Scholar 

  76. 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  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Lopes-da-Silva S thanks Drahomira Detkova, Javier de Gracia, Manolo Hernandez, and Teresa Español from Hospital Vall d’Hebron, Barcelona, for invaluable contribution to CD4+CD25high regulatory T cells frequency evaluation in a cohort of Spanish patients with CVID (to be submitted).

Author information

Authors and Affiliations

  1. Serviço de Imunoalergologia, Hospital de Santa Maria, Unidade de Imunologia Clínica, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisbon, Portugal

    Susana Lopes-da-Silva

  2. Department of Immunology, Immunodeficiency Unit, University of São Paulo Medical School Hospital, Laboratory of Medical Investigation (LIM), 60, Heart Institute, Fundação Zerbini, University of São Paulo, São Paulo, Brazil

    Luiz Vicente Rizzo

Authors
  1. Susana Lopes-da-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luiz Vicente Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susana Lopes-da-Silva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lopes-da-Silva, S., Rizzo, L.V. Autoimmunity in Common Variable Immunodeficiency. J Clin Immunol 28 (Suppl 1), 46–55 (2008). https://doi.org/10.1007/s10875-008-9172-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-008-9172-9

Keywords

Search

Navigation