The BAFF/APRIL system in SLE pathogenesis

Key Points

  • TNF ligand superfamily member 13B (also known as B cell-activating factor of the TNF family [BAFF]) and TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) are important modulators of autoimmunity

  • Data indicate that alteration of the BAFF/APRIL system affects the capacity of the innate immune system to regulate B-cell activation

  • BAFF and type I interferons function together in systemic lupus erythematosus (SLE) pathogenesis in both a Toll-like receptor-dependent and independent manner

  • Defining the clinical manifestations of disease related to alterations of the BAFF/APRIL system might help to stratify patients with SLE into subgroups that are more likely to benefit from anti-BAFF treatment

  • Differences in the molecular forms of BAFF might affect the efficacy of BAFF-specific therapies

Abstract

Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Soluble BAFF and APRIL signalling.
Figure 2: Structural variants of BAFF and APRIL.
Figure 3: Role of BAFF in the pathogenesis of SLE.

References

  1. 1

    Tsokos, G. C. Systemic lupus erythematosus. N. Eng. J. Med. 365, 2110–2121 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697–1710 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3

    Schneider, P. et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp. Med. 189, 1747–1756 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    CAS  Article  Google Scholar 

  6. 6

    Furie, R. et al. A phase 3, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits BLyS, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Vincent, F. B., Northcott, M., Hoi, A., Mackay, F. & Morand, E. F. 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 22, 873–884 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Figgett, W. A. et al. The TACI receptor regulates T-cell-independent marginal zone B cell responses through innate activation-induced cell death. Immunity 39, 573–583 (2013).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Zhang, L. et al. Identification of BLyS (B lymphocyte stimulator), a non-myelin-associated protein, as a functional ligand for Nogo-66 receptor. J. Neurosci. 29, 6348–6352 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Liu, Y. et al. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands. Cell 108, 383–394 (2002).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Cachero, T. G. et al. Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor). Biochemistry 45, 2006–2013 (2006).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Vincent, F. B., Morand, E. F. & Mackay, F. BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus. Immunol. Cell Biol. 90, 293–303 (2012).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Vincent, F. B., Saulep-Easton, D., Figgett, W. A., Fairfax, K. A. & Mackay, F. The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 24, 203–215 (2013).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Gorelik, L. et al. Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells. J. Exp. Med. 198, 937–945 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Moore, P. A. et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285, 260–263 (1999).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Hahne, M. et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J. Exp. Med. 188, 1185–1190 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    López-Fraga, M., Fernandez, R., Albar, J. P. & Hahne, M. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO Rep. 2, 945–951 (2001).

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Maia, S. et al. Aberrant expression of functional BAFF-system receptors by malignant B-cell precursors impacts leukemia cell survival. PLoS ONE 6, e20787 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Pradet-Balade, B. et al. An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. EMBO J. 21, 5711–5720 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Bossen, C. et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood 111, 1004–1012 (2008).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Dillon, S. R. et al. B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin. Arthritis Res. Ther. 12, R48 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22

    Roschke, V. et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J. Immunol. 169, 4314–4321 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Bossen, C. et al. Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses. E. J. Immunol. 41, 787–797 (2011).

    CAS  Article  Google Scholar 

  24. 24

    Le Pottier, L. et al. New ELISA for B cell-activating factor. Clin. Chem. 55, 1843–1851 (2009).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Gavin, A. L. et al. ΔBAFF, a splice isoform of BAFF, opposes full-length BAFF activity in vivo in transgenic mouse models. J. Immunol. 175, 319–328 (2005).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Gavin, A. L., Aït-Azzouzene, D., Ware, C. F. & Nemazee, D. ΔBAFF, an alternate splice isoform that regulates receptor binding and biopresentation of the B cell survival cytokine, BAFF. J. Biol. Chem. 278, 38220–38228 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Krumbholz, M. et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 201, 195–200 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Lopez De Padilla, C. M. et al. BAFF expression correlates with idiopathic inflammatory myopathy disease activity measures and autoantibodies. J. Rheumatol. 40, 294–302 (2013).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Gross, J. A. et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity 15, 289–302 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Huard, B., Tran, N. L., Benkhoucha, M., Manzin-Lorenzi, C. & Santiago-Raber, M. L. Selective APRIL blockade delays systemic lupus erythematosus in mouse. PLoS ONE 7, e31837 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Jacob, C. O. et al. Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum. 64, 1610–1619 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Baker, K. P. et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, 3253–3265 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Bombardier, C., Gladman, D. D., Urowitz, M. B., Caron, D. & Chang, C. H. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 35, 630–640 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Hay, E. M. et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q. J. Med. 86, 447–458 (1993).

    CAS  PubMed  Google Scholar 

  38. 38

    Furie, R. A. et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 61, 1143–1151 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Strand, V. et al. Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials. Ann. Rheum. Dis. 10.1136/annrheumdis-2012-202865 (2013).

  40. 40

    Wallace, D. J. et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus 22, 144–154 (2013).

    CAS  Article  Google Scholar 

  41. 41

    Stohl, W. et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 64, 2328–2337 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    van Vollenhoven, R. F. et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann. Rheum. Dis. 71, 1343–1349 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Chatham, W. W. et al. Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. J. Rheumatol. 39, 1632–1640 (2012).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Petri, M. et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 58, 2453–2459 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Hegazy, M., Darwish, H., Darweesh, H., El-Shehaby, A. & Emad, Y. Raised serum level of APRIL in patients with systemic lupus erythematosus: correlations with disease activity indices. Clin. Immunol. 135, 118–124 (2010).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Stohl, W. et al. Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 63, 1096–1103 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Morel, J. 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. 68, 997–1002 (2009).

    CAS  PubMed  Article  Google Scholar 

  48. 48

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

    PubMed  Article  Google Scholar 

  49. 49

    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 

  50. 50

    Collins, C. E. et al. B lymphocyte stimulator (BLyS) isoforms in systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mRNA levels than with plasma BLyS protein levels. Arthritis Res. Ther. 8, R6 (2006).

    PubMed  Article  Google Scholar 

  51. 51

    Petri, M. A. et al. Baseline predictors of systemic lupus erythematosus flares: Data from the combined placebo groups in the Phase 3 belimumab trials. Arthritis Rheum. 65, 2143–2153 (2013).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Carter, L. M., Isenberg, D. A. & Ehrenstein, M. R. Elevated serum B-cell activating factor (BAFF/BLyS) is associated with rising anti-dsDNA antibody levels and flare following B-cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 65, 2672–2679 (2013).

    CAS  PubMed  Google Scholar 

  53. 53

    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 

  54. 54

    Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA 100, 2610–2615 (2003).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Vincent, F. B., Northcott, M., Hoi, A., Mackay, F. & Morand, E. F. Clinical associations of serum interleukin-17 in systemic lupus erythematosus. Arthritis Res. Ther. 15, R97 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Kirou, K. A. et al. Activation of the interferon-α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 52, 1491–1503 (2005).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Feng, X. et al. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2951–2962 (2006).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Landolt-Marticorena, C. et al. Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann. Rheum. Dis. 68, 1440–1446 (2009).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Bertsias, G. K., Salmon, J. E. & Boumpas, D. T. Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade. Ann. Rheum. Dis. 69, 1603–1611 (2010).

    PubMed  Article  Google Scholar 

  60. 60

    Rana, A. et al. Gene expression of cytokines (TNF-α, IFN-γ), serum profiles of IL-17 and IL-23 in paediatric systemic lupus erythematosus. Lupus 21, 1105–1112 (2012).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Vuyyuru, R., Mohan, C., Manser, T. & Rahman, Z. S. The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints. J. Immunol. 183, 5716–5727 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Liu, K. et al. Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis. Genes Immun. 8, 634–645 (2007).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Dooley, M. et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 22, 63–72 (2013).

    CAS  Article  Google Scholar 

  64. 64

    Manzi, S. et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann. Rheum. Dis. 71, 1833–1838 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Vincent, F. B., Bourke, P., Morand, E. F., Mackay, F. & Bossingham, D. Focus on systemic lupus erythematosus in Indigenous Australians: towards a better understanding of autoimmune diseases. Intern. Med. J. 43, 227–234 (2013).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Borchers, A. T., Naguwa, S. M., Shoenfeld, Y. & Gershwin, M. E. The geoepidemiology of systemic lupus erythematosus. Autoimmun. Rev. 9, A277–A287 (2010).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Thumboo, J. et al. A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Chinese in Singapore, from 1980 to 1992. Arthritis Rheum. 45, 494–500 (2001).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Golder, V., Connelly, K., Staples, M., Morand, E. & Hoi, A. Association of Asian ethnicity with disease activity in SLE: an observational study from the Monash Lupus Clinic. Lupus 22, 1425–1430 (2013).

    CAS  Article  Google Scholar 

  69. 69

    Ritterhouse, L. L. et al. B lymphocyte stimulator levels in systemic lupus erythematosus: higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 63, 3931–3941 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Kawasaki, A., Tsuchiya, N., Fukazawa, T., Hashimoto, H. & Tokunaga, K. Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis. Genes Immun. 3, 424–429 (2002).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Eilertsen, G. O., Van Ghelue, M., Strand, H. & Nossent, J. C. 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 50, 2197–2205 (2011).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Zayed, R. A. et al. B-cell activating factor promoter polymorphisms in Egyptian patients with systemic lupus erythematosus. Ann. Clin. Lab. Sci. 43, 289–294 (2013).

    CAS  PubMed  Google Scholar 

  73. 73

    Koyama, T. et al. A novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus. Rheumatology (Oxford) 42, 980–985 (2003).

    CAS  Article  Google Scholar 

  74. 74

    Lee, Y. H., Ota, F., Kim-Howard, X., Kaufman, K. M. & Nath, S. K. APRIL polymorphism and systemic lupus erythematosus (SLE) susceptibility. Rheumatology (Oxford) 46, 1274–1276 (2007).

    CAS  Article  Google Scholar 

  75. 75

    Kawasaki, A. et al. Role of APRIL (TNFSF13) polymorphisms in the susceptibility to systemic lupus erythematosus in Japanese. Rheumatology (Oxford) 46, 776–782 (2007).

    CAS  Article  Google Scholar 

  76. 76

    Furuya, T., Koga, M., Hikami, K., Kawasaki, A. & Tsuchiya, N. Effects of APRIL (TNFSF13) polymorphisms and splicing isoforms on the secretion of soluble APRIL. Mod. Rheumatol. 22, 541–549 (2012).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Jiang, C., Loo, W. M., Greenley, E. J., Tung, K. S. & Erickson, L. D. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. J. Immunol. 186, 6136–6147 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

    Jacob, C. O. et al. Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor. Arthritis Rheum. 65, 1043–1054 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Groom, J. R. et al. BAFF and MyD88 signals promote a lupus-like disease independent of T cells. J. Exp. Med. 204, 1959–1971 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Thangarajh, M., Masterman, T., Hillert, J., Moerk, S. & Jonsson, R. A proliferation-inducing ligand (APRIL) is expressed by astrocytes and is increased in multiple sclerosis. Scand. J. Immunol. 65, 92–98 (2007).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    George-Chandy, A., Trysberg, E. & Eriksson, K. Raised intrathecal levels of APRIL and BAFF in patients with systemic lupus erythematosus: relationship to neuropsychiatric symptoms. Arthritis Res. Ther. 10, R97 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82

    Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Peterson, K. S. et al. Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J. Clin. Invest. 113, 1722–1733 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Ytterberg, S. R. & Schnitzer, T. J. Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 25, 401–406 (1982).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Kim, T. et al. Serum levels of interferons in patients with systemic lupus erythematosus. Clin. Exp. Immunol. 70, 562–569 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Rönnblom, L. Potential role of IFNalpha in adult lupus. Arthritis research & therapy 12 (Suppl. 1), S3 (2010).

    Article  CAS  Google Scholar 

  87. 87

    Lovgren, T., Eloranta, M. L., Bave, U., Alm, G. V. & Ronnblom, L. Induction of interferon-α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 50, 1861–1872 (2004).

    PubMed  Article  CAS  Google Scholar 

  88. 88

    Vallin, H., Blomberg, S., Alm, G. V., Cederblad, B. & Rönnblom, L. Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-α (IFN-α) production acting on leucocytes resembling immature dendritic cells. Clin. Exp. Immunol. 115, 196–202 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Panchanathan, R. & Choubey, D. Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity. Mol. Immunol. 53, 15–23 (2013).

    CAS  PubMed  Article  Google Scholar 

  90. 90

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Harigai, M. et al. Excessive production of IFN-gamma in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B. J. Immunol. 181, 2211–2219 (2008).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Yao, Y. et al. Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus. Arthritis Rheum. 60, 1785–1796 (2009).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Jacob, N. et al. B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice. J. Immunol. 186, 4984–4993 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Blanco, P., Palucka, A. K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294, 1540–1543 (2001).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Joo, H. et al. Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J. Exp. Med. 209, 1335–1348 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Kikly, K., Manetta, J., Smith, H. & Wierda, D. Characterization of LY2127399, A neutralizing antibody for BAFF [abstract]. Arthritis Rheum. 60 (Suppl. 10), 693 (2009).

    Google Scholar 

  97. 97

    Hsu, H. et al. A novel modality of BAFF-specific inhibitor AMG623 peptibody reduces B-cell number and improves outcomes in murine models of autoimmune disease. Clin. Exp. Rheumatol. 30, 197–201 (2012).

    PubMed  Google Scholar 

  98. 98

    Wallweber, H. J., Compaan, D. M., Starovasnik, M. A. & Hymowitz, S. G. The crystal structure of a proliferation-inducing ligand, APRIL. J. Mol. Biol. 343, 283–290 (2004).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13, 170–180 (2012).

    CAS  Article  Google Scholar 

  100. 100

    Holden, N. J. et al. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann. Rheum. Dis. 70, 2229–2233 (2011).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Assi, L. K. et al. Tumor necrosis factor-α activates release of B lymphocyte stimulator by neutrophils infiltrating the rheumatoid joint. Arthritis Rheum. 56, 1776–1786 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102

    Suzuki, K. et al. Effect of interleukin-2 on synthesis of B cell activating factor belonging to the tumor necrosis factor family (BAFF) in human peripheral blood mononuclear cells. Cytokine 44, 44–48 (2008).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Zhang, W. et al. hsBAFF enhances activity of NK cells by regulation of CD4(+) T lymphocyte function. Immunol. Lett. 120, 96–102 (2008).

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors researched the data for the article. F.B.V. wrote the manuscript and all authors reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Fabienne Mackay.

Ethics declarations

Competing interests

F.M. and E.F.M declare that they have acted as consultants for Eli Lilly and GSK. P.S. declares that he has a research agreement with Merck-Serono. F.B.V. declares no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vincent, F., Morand, E., Schneider, P. et al. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol 10, 365–373 (2014). https://doi.org/10.1038/nrrheum.2014.33

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing