Skip to main content

Advertisement

SpringerLink
Log in

Reduced BAFF-R and Increased TACI Expression in Common Variable Immunodeficiency

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

Abstract

Purpose

B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood.

Methods and Results

We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID.

Conclusions

Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets.

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
Fig. 6

Similar content being viewed by others

References

  1. Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9:491–502.

    Article  CAS  PubMed  Google Scholar 

  2. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131:959–71.

    Article  CAS  PubMed  Google Scholar 

  3. Mantchev GT, Cortesao CS, Rebrovich M, Cascalho M, Bram RJ. TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. J Immunol. 2007;179:2282–8.

    Article  CAS  PubMed  Google Scholar 

  4. Tsuji S, Cortesao C, Bram RJ, Platt JL, Cascalho M. TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood. 2011;118:5832–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Jin R, Kaneko H, Suzuki H, Arai T, Teramoto T, Fukao T, et al. Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency. Int J Mol Med. 2008;21:233–8.

    CAS  PubMed  Google Scholar 

  6. Knight AK, Radigan L, Marron T, Langs A, Zhang L, Cunningham-Rundles C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol. 2007;124:182–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol. 2012;188:497–503.

    Article  CAS  PubMed  Google Scholar 

  8. Barbosa RR, Silva SP, Silva SL, Melo AC, Pedro E, Barbosa MP, et al. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation. PLoS One. 2011;6:e22848.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. La Cava A. Targeting the BLyS-APRIL signaling pathway in SLE. Clin Immunol. 2013;148:322–7.

    Article  PubMed  Google Scholar 

  10. Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–710.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Khare SD, Sarosi I, Xia XZ, McCabe S, Miner K, Solovyev I, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci U S A. 2000;97:3370–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Gorelik L, Gilbride K, Dobles M, Kalled SL, Zandman D, Scott ML. Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells. J Exp Med. 2003;198:937–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol. 2005;17:282–9.

    Article  CAS  PubMed  Google Scholar 

  15. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005;37:829–34.

    Article  CAS  PubMed  Google Scholar 

  16. Losi CG, Silini A, Fiorini C, Soresina A, Meini A, Ferrari S, et al. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J Clin Immunol. 2005;25:496–502.

    Article  CAS  PubMed  Google Scholar 

  17. Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J, et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci U S A. 2009;106:13945–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820–8.

    Article  CAS  PubMed  Google Scholar 

  19. Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372:489–502.

    Article  PubMed  Google Scholar 

  20. Barbosa RR, Silva SP, Silva SL, Tendeiro R, Melo AC, Pedro E, et al. Monocyte activation is a feature of common variable immunodeficiency irrespective of plasma lipopolysaccharide levels. Clin Exp Immunol. 2012;169:263–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Pieper K, Rizzi M, Speletas M, Smulski CR, Sic H, Kraus H et al. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133:1222–5.

  22. 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 

  23. Romberg N, Chamberlain N, Saadoun D, Gentile M, Kinnunen T, Ng YS, et al. CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest. 2013;123:4283–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Martinez-Gallo M, Radigan L, Almejun MB, Martinez-Pomar N, Matamoros N, Cunningham-Rundles C. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013;131:468–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Fabris M, Quartuccio L, Sacco S, De Marchi G, Pozzato G, Mazzaro C, et al. B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection. Rheumatology (Oxford). 2007;46:37–43.

    Article  CAS  Google Scholar 

  26. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.

    Article  CAS  PubMed  Google Scholar 

  27. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Hahne M, Kataoka T, Schroter M, Hofmann K, Irmler M, Bodmer JL, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med. 1998;188:1185–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science. 2001;293:2108–11.

    Article  CAS  PubMed  Google Scholar 

  30. Yan M, Brady JR, Chan B, Lee WP, Hsu B, Harless S, et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol. 2001;11:1547–52.

    Article  CAS  PubMed  Google Scholar 

  31. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–9.

    Article  CAS  PubMed  Google Scholar 

  32. Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M, et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med. 2000;192:137–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Albuquerque AS, Marques JG, Silva SL, Ligeiro D, Devlin BH, Dutrieux J, et al. Human FOXN1-deficiency is associated with alphabeta double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantation. PLoS One. 2012;7:e37042.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001;2:638–43.

    Article  CAS  PubMed  Google Scholar 

  35. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113:1967–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. La Cava A. Common variable immunodeficiency: two mutations are better than one. J Clin Invest. 2013;123:4142–3.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Sellam J, Miceli-Richard C, Gottenberg JE, Ittah M, Lavie F, Lacabaratz C, et al. Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjogren’s syndrome and systemic lupus erythematosus. Ann Rheum Dis. 2007;66:790–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Carter RH, Zhao H, Liu X, Pelletier M, Chatham W, Kimberly R, et al. Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus. Arthritis Rheum. 2005;52:3943–54.

    Article  CAS  PubMed  Google Scholar 

  39. Xanthoulea S, Pasparakis M, Kousteni S, Brakebusch C, Wallach D, Bauer J, et al. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J Exp Med. 2004;200:367–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis. 2003;62:168–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Becker-Merok A, Nikolaisen C, Nossent HC. B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus. 2006;15:570–6.

    Article  CAS  PubMed  Google Scholar 

  42. Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44:1313–9.

    Article  CAS  PubMed  Google Scholar 

  43. Kim J, Gross JA, Dillon SR, Min JK, Elkon KB. Increased BCMA expression in lupus marks activated B cells, and BCMA receptor engagement enhances the response to TLR9 stimulation. Autoimmunity. 2011;44:69–81.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10.

    Article  CAS  PubMed  Google Scholar 

  45. Zhao LD, Li Y, Smith Jr MF, Wang JS, Zhang W, Tang FL, et al. Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients. Lupus. 2010;19:1534–49.

    Article  CAS  PubMed  Google Scholar 

  46. Ju S, Zhang D, Wang Y, Ni H, Kong X, Zhong R. Correlation of the expression levels of BLyS and its receptors mRNA in patients with systemic lupus erythematosus. Clin Biochem. 2006;39:1131–7.

    Article  CAS  PubMed  Google Scholar 

  47. Koyama T, Tsukamoto H, Miyagi Y, Himeji D, Otsuka J, Miyagawa H, et al. Raised serum APRIL levels in patients with systemic lupus erythematosus. Ann Rheum Dis. 2005;64:1065–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Stewart DM, McAvoy MJ, Hilbert DM, Nelson DL. B lymphocytes from individuals with common variable immunodeficiency respond to B lymphocyte stimulator (BLyS protein) in vitro. Clin Immunol. 2003;109:137–43.

    Article  CAS  PubMed  Google Scholar 

  49. Resnick ES, Cunningham-Rundles C. The many faces of the clinical picture of common variable immune deficiency. Curr Opin Allergy Clin Immunol. 2012;12:595–601.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Elisa Pedro and Manuel Barbosa from the Department of Immunoallergology of the University Hospital de Santa Maria, Lisbon, Portugal, for the clinical collaboration; Rui M. M. Victorino, Íris Caramalho, Adriana S. Albuquerque and Russell B. Foxall for the helpful discussions and critical revision of the manuscript, as well as Ana Isabel Pinheiro, Ana Rita Pires and Paula Matoso, for the invaluable technical assistance, all from the Instituto de Medicina Molecular, Lisbon, Portugal. R.R.B. and S.L.S. received PhD scholarships from Fundação para a Ciência e Tecnologia (FCT) and Programa Operacional Ciência e Inovação 2010, Portugal.

Conflict of Interest Disclosures

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

    Rita R. Barbosa, Susana L. Silva, Sara P. Silva, Alcinda C. Melo, M. Conceição Pereira-Santos, João T. Barata & Ana E. Sousa

  2. Serviço de Imunoalergologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte - EPE, Lisboa, Portugal

    Susana L. Silva & Sara P. Silva

  3. Karolinska Institutet Huddinge, Stockholm, Sweden

    Lennart Hammarström

  4. Transplantation Biology, Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA

    Marília Cascalho

Authors
  1. Rita R. Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susana L. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara P. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alcinda C. Melo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Conceição Pereira-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. João T. Barata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lennart Hammarström
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marília Cascalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ana E. Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana E. Sousa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource (PDF 685 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barbosa, R.R., Silva, S.L., Silva, S.P. et al. Reduced BAFF-R and Increased TACI Expression in Common Variable Immunodeficiency. J Clin Immunol 34, 573–583 (2014). https://doi.org/10.1007/s10875-014-0047-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-014-0047-y

Keywords

Search

Navigation