Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus

A Retraction to this article was published on 19 August 2014

This article has been updated


Studies have suggested involvement of interleukin 17 (IL-17) in autoimmune diseases, although its effect on B cell biology has not been clearly established. Here we demonstrate that IL-17 alone or in combination with B cell–activating factor controlled the survival and proliferation of human B cells and their differentiation into immunoglobulin-secreting cells. This effect was mediated mainly through the nuclear factor-κB-regulated transcription factor Twist-1. In support of the relevance of our observations and the potential involvement of IL-17 in B cell biology, we found that the serum of patients with systemic lupus erythematosus had higher concentrations of IL-17 than did the serum of healthy people and that IL-17 abundance correlated with the disease severity of systemic lupus erythematosus.

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Figure 1: IL-17 and BAFF promote B cell survival in an NF-κB-dependent way.
Figure 2: Twist-1 mediates the antiapoptotic effects of IL-17 and BAFF through the induction of Twist-2 and Bfl-1.
Figure 3: IL-17 and BAFF promote the proliferation of B cells and their differentiation into immunoglobulin-secreting cells.
Figure 4: Effects of differentiation on the expression of TWIST1, TWIST2 and BCL2A1 in B cells.
Figure 5: Serum from patients with SLE induces the survival of peripheral B cells.
Figure 6: Serum from patients with SLE induces proliferation and differentiation into immunoglobulin-secreting cells.

Change history

  • 12 July 2013

    Despite many attempts to replicate these results, the authors have been unable to confirm the original data showing that IL-17 alone or in combination with B cell–activating factor controls the survival of human B cells (Fig. 1a,b). Because this weakens the conclusions of the paper, all the authors (except A.D. and P.T., who could not be contacted) now retract this paper.


  1. 1

    Yurasov, S., Hammersen, J., Tiller, T., Tsuiji, M. & Wardemann, H. B-cell tolerance checkpoints in healthy humans and patients with systemic lupus erythematosus. Ann. NY Acad. Sci. 1062, 165–174 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Meffre, E. & Wardemann, H. B-cell tolerance checkpoints in health and autoimmunity. Curr. Opin. Immunol. 20, 632–638 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Groom, J. & Mackay, F. B cells flying solo. Immunol. Cell Biol. 86, 40–46 (2008).

    CAS  Article  Google Scholar 

  4. 4

    Nagata, S. & Golstein, P. The Fas death factor. Science 267, 1449–1456 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Nagata, S. & Suda, T. Fas and Fas ligand: lpr and gld mutations. Immunol. Today 16, 39–43 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Hutcheson, J. et al. Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 28, 206–217 (2008).

    CAS  Article  Google Scholar 

  7. 7

    Rieux-Laucat, F., Le Deist, F. & Fischer, A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differ. 10, 124–133 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Andre, J. et al. Overexpression of the antiapoptotic gene Bfl-1 in B cells from patients with familial systemic lupus erythematosus. Lupus 16, 95–100 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Batten, M. et al. BAFF mediates survival of peripheral immature B lymphocytes. J. Exp. Med. 192, 1453–1466 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Hsu, B.L., Harless, S.M., Lindsley, R.C., Hilbert, D.M. & Cancro, M.P. Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. J. Immunol. 168, 5993–5996 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Cheema, G.S., Roschke, V., Hilbert, D.M. & Stohl, W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 44, 1313–1319 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Zhang, J. et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J. Immunol. 166, 6–10 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Stohl, W. et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 48, 3475–3486 (2003).

    Article  Google Scholar 

  14. 14

    Pene, J. et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J. Immunol. 180, 7423–7430 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Pan, H.F., Ye, D.Q. & Li, X.P. Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus. Nat. Clin. Pract. Rheumatol. 4, 352–353 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Wong, C.K. et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin. Immunol. 127, 385–393 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Garrett-Sinha, L.A., John, S. & Gaffen, S.L. IL-17 and the Th17 lineage in systemic lupus erythematosus. Curr. Opin. Rheumatol. 20, 519–525 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Wong, C.K., Ho, C.Y., Li, E.K. & Lam, C.W. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9, 589–593 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Crispin, J.C. et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 181, 8761–8766 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Kang, H.K., Liu, M. & Datta, S.K. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J. Immunol. 178, 7849–7858 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Hsu, H.C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Jacob, N. et al. Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. J. Immunol. 182, 2532–2541 (2009).

    CAS  Article  Google Scholar 

  23. 23

    Lai Kwan Lam, Q., King Hung Ko, O., Zheng, B.J. & Lu, L. Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc. Natl. Acad. Sci. USA 105, 14993–14998 (2008).

    Article  Google Scholar 

  24. 24

    Mackay, F. & Browning, J.L. BAFF: a fundamental survival factor for B cells. Nat. Rev. Immunol. 2, 465–475 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Li, X. Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 41, 105–113 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Stadanlick, J.E. et al. Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling. Nat. Immunol. 9, 1379–1387 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Chen, C., Edelstein, L.C. & Gelinas, C. The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-xL . Mol. Cell. Biol. 20, 2687–2695 (2000).

    Article  Google Scholar 

  28. 28

    Zong, W.X., Edelstein, L.C., Chen, C., Bash, J. & Gelinas, C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis. Genes Dev. 13, 382–387 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Pham, C.G. et al. Upregulation of Twist-1 by NF-κB blocks cytotoxicity induced by chemotherapeutic drugs. Mol. Cell. Biol. 27, 3920–3935 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Maestro, R. et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 13, 2207–2217 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Ishigami, T. et al. Anti-IgM antibody-induced cell death in a human B lymphoma cell line, B104, represents a novel programmed cell death. J. Immunol. 148, 360–368 (1992).

    CAS  PubMed  Google Scholar 

  32. 32

    Ruprecht, C.R. & Lanzavecchia, A. Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol. 36, 810–816 (2006).

    CAS  Article  Google Scholar 

  33. 33

    John, S.A., Clements, J.L., Russell, L.M. & Garrett-Sinha, L.A. Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J. Biol. Chem. 283, 951–962 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Ansieau, S. et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14, 79–89 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Grumont, R.J., Rourke, I.J. & Gerondakis, S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev. 13, 400–411 (1999).

    CAS  Article  Google Scholar 

  36. 36

    Lee, H.H., Dadgostar, H., Cheng, Q., Shu, J. & Cheng, G. NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc. Natl. Acad. Sci. USA 96, 9136–9141 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Sims, G.P. et al. Identification and characterization of circulating human transitional B cells. Blood 105, 4390–4398 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Ettinger, R., Kuchen, S. & Lipsky, P.E. Interleukin 21 as a target of intervention in autoimmune disease. Ann. Rheum. Dis. 67 Suppl 3, iii83–iii86 (2008).

    CAS  Article  Google Scholar 

  39. 39

    Litinskiy, M.B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3, 822–829 (2002).

    CAS  Article  Google Scholar 

  40. 40

    Vanden Bush, T.J. & Bishop, G.A. TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation. Eur. J. Immunol. 38, 400–409 (2008).

    CAS  Article  Google Scholar 

  41. 41

    Wilker, P.R. et al. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat. Immunol. 9, 603–612 (2008).

    CAS  Article  Google Scholar 

  42. 42

    Khiem, D., Cyster, J.G., Schwarz, J.J. & Black, B.L. A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proc. Natl. Acad. Sci. USA 105, 17067–17072 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Sosic, D., Richardson, J.A., Yu, K., Ornitz, D.M. & Olson, E.N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169–180 (2003).

    CAS  Article  Google Scholar 

  44. 44

    Niesner, U. et al. Autoregulation of Th1-mediated inflammation by twist1. J. Exp. Med. 205, 1889–1901 (2008).

    CAS  Article  Google Scholar 

  45. 45

    Bubier, J.A. et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl. Acad. Sci. USA 106, 1518–1523 (2009).

    CAS  Article  Google Scholar 

  46. 46

    Sasaki, Y. et al. Canonical NF-κB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24, 729–739 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Brien, G., Trescol-Biemont, M.C. & Bonnefoy-Berard, N. Downregulation of Bfl-1 protein expression sensitizes malignant B cells to apoptosis. Oncogene 26, 5828–5832 (2007).

    CAS  Article  Google Scholar 

  48. 48

    de Brouwer, A.P., van Bokhoven, H. & Kremer, H. Comparison of 12 reference genes for normalization of gene expression levels in Epstein-Barr virus-transformed lymphoblastoid cell lines and fibroblasts. Mol. Diagn. Ther. 10, 197–204 (2006).

    CAS  Article  Google Scholar 

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We thank H. Mitchison and G. Hinkal for critical reading of the manuscript; C. Delprat and G. Salles for scientific discussions; the laboratory of A. Puisieux (INSERM U590) for anti-Twist-1 as well as the Twist-1- and Twist-2-related vectors; and C. Bella for cell sorting. Supported by INSERM, UCB Lyon 1, the Arthritis Fondation Courtin (A.D.), the Association pour la Recherche sur le Cancer and the Ligue Contre le Cancer (07 and 26).

Author information




N.B.-B. designed and supervised the study and wrote the manuscript; A.D. did all experiments presented in Figures 1,2,3,4,5,6 and Supplementary Figures 1,2,3,4,5,6; A.B. did statistical analysis and collected clinical data in Supplementary Tables 1 and 2; J.B. helped design the Twist-related experiments and wrote the manuscript; M.-C.T.-B. analyzed BCL2A1 expression in B cells from patients with SLE and healthy volunteers; B. Riche did statistical analysis; B. Ranchin, N.F., P.C., C.P.-N., P.T., I.D, J.T. and B.K. recruited patients; and S.A., A.P. and J.-F.E. contributed to the design and interpretation of experiments and to the editing of the manuscript.

Corresponding author

Correspondence to Nathalie Bonnefoy-Bérard.

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Supplementary Figures 1–6, Tables 1–2 and Supplementary Methods (PDF 2734 kb)

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Doreau, A., Belot, A., Bastid, J. et al. Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 10, 778–785 (2009).

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