Clinical and Experimental Medicine

, Volume 19, Issue 2, pp 183–190 | Cite as

High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene

  • M. Marín-Rosales
  • A. Cruz
  • D. C. Salazar-Camarena
  • E. Santillán-López
  • N. Espinoza-García
  • J. F. Muñoz-Valle
  • M. G. Ramírez-Dueñas
  • E. Oregón-Romero
  • G. Orozco-Barocio
  • C. A. Palafox-SánchezEmail author
Original Article


B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR–RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742 ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403 ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.


Systemic lupus erythematosus TNFSF13B polymorphisms Disease activity BAFF 


Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2:465–75.CrossRefPubMedGoogle Scholar
  4. 4.
    Litinskiy MB, Nardelli B, Hilbert DM, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol. 2002;3:822–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    MacKay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9:491–502.CrossRefPubMedGoogle Scholar
  6. 6.
    Sjöstrand M, Johansson A, Aqrawi L, et al. The expression of BAFF is controlled by IRF transcription factors. J Immunol. 2016;196:91–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Nardelli B, Belvedere O, Roschke V, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood. 2001;97:198–204.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu Y, Xu L, Opalka N, et al. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands. Cell. 2002;108:383–94.CrossRefPubMedGoogle Scholar
  9. 9.
    Cachero TG, Schwartz IM, Qian F, et al. Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor). Biochemistry. 2006;45:2006–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Hahne M, Kataoka T, Schröter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med. 1998;188:1185–90.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Schuepbach-Mallepell S, Das D, Willen L, et al. Stoichiometry of heteromeric BAFF and April cytokines dictates their receptor binding and signaling properties. J Biol Chem. 2015;290:16330–42.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vincent FB, Saulep-Easton D, Figgett WA, et al. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013;24:203–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–710.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Vincent FB, Morand EF, Schneider P, MacKay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10:365–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Thompson N, Isenberg DA, Jury EC, Ciurtin C. Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome. Rheumatol Oxf. 2016;55:1548–55.CrossRefGoogle Scholar
  17. 17.
    Han Q, Yang C, Li N, et al. Association of genetic variation in B-cell activating factor with chronic hepatitis B virus infection. Immunol Lett. 2017;188:53–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Ayad MW, Elbanna AA, Elneily DA, Sakr AS. Association of BAFF −871C/T promoter polymorphism with hepatitis C-related mixed cryoglobulinemia in a cohort of Egyptian patients. Mol Diagnosis Ther. 2015;19:99–106.CrossRefGoogle Scholar
  19. 19.
    Theodorou E, Nezos A, Antypa E, et al. B-cell activating factor and related genetic variants in lupus related atherosclerosis. J Autoimmun. 2018;92:87.CrossRefPubMedGoogle Scholar
  20. 20.
    Abdel-Hamid SM, Al-Lithy HN. B cell activating factor gene polymorphisms in patients with risk of idiopathic thrombocytopenic purpura. Am J Med Sci. 2011;342:9–14.CrossRefPubMedGoogle Scholar
  21. 21.
    Zayed RA, Sheba HF, Abo Elazaem MAK, et al. B-cell activating factor promoter polymorphisms in Egyptian patients with systemic lupus erythematosus. Ann Clin Lab Sci. 2013;43:289–94.PubMedGoogle Scholar
  22. 22.
    Nezos A, Papageorgiou A, Fragoulis G, et al. B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren’s syndrome. J Autoimmun. 2014;51:89–98.CrossRefPubMedGoogle Scholar
  23. 23.
    Kawasaki A, Tsuchiya N, Fukazawa T, et al. Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis. Genes Immun. 2002;3:424–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Nossent HC, Lester S, Zahra D, et al. Polymorphism in the 5′ regulatory region of the B-lymphocyte activating factor gene is associated with the Ro/La autoantibody response and serum BAFF levels in primary Sjögren’s syndrome. Rheumatology. 2008;47:1311–6.CrossRefPubMedGoogle Scholar
  25. 25.
    World Medical Association. World Medical Association Declaration of Helsinki Ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.CrossRefGoogle Scholar
  26. 26.
    Tan E, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.CrossRefGoogle Scholar
  27. 27.
    Hochberg M. Updating the American College of Rheumatology. Arthritis Rheum. 1997;40:1997.CrossRefGoogle Scholar
  28. 28.
    Guzman J, Cardiel MH, Arce-Salinas A, Sánchez-Guerrero J, Alarcón-Segovia D. Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices. J Rheumatol. 1992;19:1551–8.PubMedGoogle Scholar
  29. 29.
    Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39:363–9.CrossRefGoogle Scholar
  30. 30.
    Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bustin SA, Vladimir B, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55:611–22.CrossRefGoogle Scholar
  32. 32.
    Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97–8.CrossRefGoogle Scholar
  33. 33.
    Li Z, Zhang Z, He Z, et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis ( Cell Res. 2009;19:519–23.CrossRefPubMedGoogle Scholar
  34. 34.
    Livak KJ, Schmittegen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.CrossRefGoogle Scholar
  35. 35.
    Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12:716–30.CrossRefGoogle Scholar
  36. 36.
    Schiemann B, Gommerman JL, Vora K, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 2001;293:2111–4.CrossRefPubMedGoogle Scholar
  37. 37.
    Stohl W, Jacob N, Guo S, Morel L. Constitutive overexpression of BAFF in autoimmune-resistant mice drives only some aspects of systemic lupus erythematosus-like autoimmunity. Arthritis Rheum. 2010;62:2432–42.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Eilertsen G, Van Ghelue M, Strand H, Nossent JC. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: a case-control study. Rheumatology. 2011;50:2197–205.CrossRefPubMedGoogle Scholar
  39. 39.
    Martínez-Cortés G, Salazar-Flores J, Fernández-Rodríguez LG, et al. Admixture and population structure in Mexican-Mestizos based on paternal lineages. J Hum Genet. 2012;57:568–74.CrossRefPubMedGoogle Scholar
  40. 40.
    Gottenberg J-E, Sellam J, Ittah M, et al. No evidence for an association between the −871 T/C promoter polymorphism in the B-cell-activating factor gene and primary Sjögren’s syndrome. Arthritis Res Ther. 2006;8:R30.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Novak AJ, Grote DM, Ziesmer SC, et al. Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders. J Clin Oncol. 2006;24:983–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Morris JF, Hromas R, Rauscher FJ. Characterization of the DNA-binding properties of the myeloid zinc finger protein MZF1: two independent DNA-binding domains recognize two DNA consensus sequences with a common G-rich core. Mol Cell Biol. 1994;14:1786–95.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zollars E, Bienkowska J, Czerkowicz J, et al. BAFF (B cell activating factor) transcript level in peripheral blood of patients with SLE is associated with same-day disease activity as well as global activity over the next year. Lupus Sci Med. 2015;2:1–8.CrossRefGoogle Scholar
  44. 44.
    Duan JH, Jiang Y, Mu H, Tang ZQ. Expression of BAFF and BR3 in patients with systemic lupus erythematosus. Braz J Med Biol Res. 2016;49:3–7.CrossRefGoogle Scholar
  45. 45.
    Treamtrakanpon W, Tantivitayakul P, Benjachat T, et al. APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis. Arthritis Res Ther. 2012;14:R252.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Morel J, Roubille C, Planelles L, et al. Serum levels of tumour necrosis factor family members a proliferation-inducing ligand (APRIL) and B lymphocyte stimulator (BLyS) are inversely correlated in systemic lupus erythematosus. Ann Rheum Dis. 2009;68:997–1002.CrossRefPubMedGoogle Scholar
  47. 47.
    Elbirt D, Asher I, Mahlab-Guri K, et al. BlyS levels in sera of patients with systemic lupus erythematosus: clinical and serological correlation. Isr Med Assoc J. 2014;16:491–6.PubMedGoogle Scholar
  48. 48.
    Petri M, Stohl W, Chatham W, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58:2453–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Petri MA, Van Vollenhoven RF, Buyon J, et al. Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials. Arthritis Rheum. 2013;65:2143–53.CrossRefPubMedGoogle Scholar
  50. 50.
    Stohl W, Metyas S, Tan SM, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 2003;48:3475–86.CrossRefPubMedGoogle Scholar
  51. 51.
    Salazar-Camarena DC, Ortiz-Lazareno PC, Cruz A, et al. Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus. 2016;25:582–92.CrossRefPubMedGoogle Scholar
  52. 52.
    Vincent FB, Northcott M, Hoi A, et al. Association of serum B cell activating factor from the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) with central nervous system and renal disease in systemic lupus erythematosus. Lupus. 2013;22:873–84.CrossRefPubMedGoogle Scholar
  53. 53.
    Phatak S, Chaurasia S, Mishra SK, et al. Urinary B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL): potential biomarkers of active lupus nephritis. Clin Exp Immunol. 2017;187:376–82.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • M. Marín-Rosales
    • 1
    • 2
    • 3
  • A. Cruz
    • 1
  • D. C. Salazar-Camarena
    • 1
  • E. Santillán-López
    • 1
    • 2
  • N. Espinoza-García
    • 1
  • J. F. Muñoz-Valle
    • 1
  • M. G. Ramírez-Dueñas
    • 4
  • E. Oregón-Romero
    • 1
  • G. Orozco-Barocio
    • 3
  • C. A. Palafox-Sánchez
    • 1
    Email author
  1. 1.Research Institute of Biomedical Sciences (IICB), University Center for Health SciencesUniversity of GuadalajaraGuadalajaraMexico
  2. 2.Biomedical Sciences, University Center for Health SciencesUniversity of GuadalajaraGuadalajaraMexico
  3. 3.Department of Rheumatology, West General HospitalMinistry of HealthGuadalajaraMexico
  4. 4.Department of Physiology, Immunology Laboratory, University Center for Health SciencesUniversity of GuadalajaraGuadalajaraMexico

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