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.
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References
Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9:491–502.
Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131:959–71.
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.
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.
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.
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.
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.
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.
La Cava A. Targeting the BLyS-APRIL signaling pathway in SLE. Clin Immunol. 2013;148:322–7.
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.
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.
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.
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.
Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol. 2005;17:282–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
La Cava A. Common variable immunodeficiency: two mutations are better than one. J Clin Invest. 2013;123:4142–3.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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The authors declare that they have no conflict of interest.
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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
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DOI: https://doi.org/10.1007/s10875-014-0047-y