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  • Review Article
  • Published:

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

Key Points

  • TNF inhibitors are among the most effective protein-based drugs for reducing inflammation associated with several rheumatic diseases

  • In addition to TNF, the TNF superfamily (TNFSF) comprises other ligand–receptor combinations that might participate in the pathogenesis of rheumatic disease

  • TNFSF members initiate several processes, including immune activation, tissue inflammatory responses and cell death or suppression

  • Many TNFSF proteins other than TNF are being evaluated in preclinical mouse or human studies as possible therapeutic targets in rheumatic diseases

  • TNFSF members can be targeted to either restore tolerance in rheumatic diseases or to regulate tissue cell responses

Abstract

TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.

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Figure 1: Select members of the TNF and TNFR superfamily implicated in rheumatic diseases.
Figure 2: General TNFSF receptor signalling.
Figure 3: TNFSF activities enhancing immune cell activation.
Figure 4: TNFSF inflammatory activities in tissue cells.

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References

  1. Beutler, B. et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316, 552–554 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. Feldman, M., Taylor, P., Paleolog, E., Brennan, F. M. & Maini, R. N. Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn's disease: analysis of the mechanism of action predicts utility in other diseases. Transplant. Proc. 30, 4126–4127 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Croft, M. The role of TNF superfamily members in T-cell function and diseases. Nat. Rev. Immunol. 9, 271–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Croft, M. et al. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 33, 144–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Kalliolias, G. D. & Ivashkiv, L. B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49–62 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Cessak, G. et al. TNF inhibitors — mechanisms of action, approved and off-label indications. Pharmacol. Rep. 66, 836–844 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Walsh, M. C. & Choi, Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front. Immunol. 5, 511 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Stohl, W. Therapeutic targeting of the BAFF/APRIL axis in systemic lupus erythematosus. Expert Opin. Ther. Targets 18, 473–489 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Croft, M., Benedict, C. A. & Ware, C. F. Clinical targeting of the TNF and TNFR superfamilies. Nat. Rev. Drug Discov. 12, 147–168 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Caso, F., Costa, L., Del Puente, A. & Scarpa, R. Psoriatic arthritis and TNF inhibitors: advances on effectiveness and toxicity. Expert Opin. Biol. Ther. 15, 1–2 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, X. & Oppenheim, J. J. Therapy: paradoxical effects of targeting TNF signalling in the treatment of autoimmunity. Nat. Rev. Rheumatol. 12, 625–626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zaheer, S., LeBoff, M. & Lewiecki, E. M. Denosumab for the treatment of osteoporosis. Expert Opin. Drug Metab. Toxicol. 11, 461–470 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nagy, V. & Penninger, J. M. The RANKL-RANK story. Gerontology 61, 534–542 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Wei, F., Chang, Y. & Wei, W. The role of BAFF in the progression of rheumatoid arthritis. Cytokine 76, 537–544 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Vincent, F. B., Morand, E. F., Schneider, P. & Mackay, F. The BAFF/APRIL system in SLE pathogenesis. Nat. Rev. Rheumatol. 10, 365–373 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Schnitzer, T. J. & Marks, J. A. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 23 (Suppl. 1), S8–S17 (2015).

    Article  PubMed  Google Scholar 

  19. Sanga, P. et al. Long-term safety and efficacy of fulranumab in patients with moderate-to-severe osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39943 (2016).

  20. Kan, S. L. et al. Tanezumab for patients with osteoarthritis of the knee: a meta-analysis. PLoS ONE 11, e0157105 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Rosenthal, A. & Lin, J. C. Modulation of neurotrophin signaling by monoclonal antibodies. Handb. Exp. Pharmacol. 220, 497–512 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Richard, A. C. et al. Targeted genomic analysis reveals widespread autoimmune disease association with variants that regulate gene expression in the TNF superfamily cytokine signalling network. Genome Med. 8, 76 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Silke, J. & Brink, R. Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs. Cell Death Differ. 17, 35–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Karin, M. & Gallagher, E. TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol. Rev. 228, 225–240 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Eissner, G. Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev. 15, 353–366 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Peters, A. L., Stunz, L. L. & Bishop, G. A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Law, C. L. & Grewal, I. S. Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Adv. Exp. Med. Biol. 647, 8–36 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Allen, R. C. et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259, 990–993 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Splawski, J. B. & Lipsky, P. E. CD40-mediated regulation of human B-cell responses. Res. Immunol. 145, 226–234 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Grewal, I. S. & Flavell, R. A. The role of CD40 ligand in costimulation and T-cell activation. Immunol. Rev. 153, 85–106 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Blotta, M. H., Marshall, J. D., DeKruyff, R. H. & Umetsu, D. T. Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis. J. Immunol. 156, 3133–3140 (1996).

    CAS  PubMed  Google Scholar 

  34. Durie, F. H. et al. Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 261, 1328–1330 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Mohan, C., Shi, Y., Laman, J. D. & Datta, S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J. Immunol. 154, 1470–1480 (1995).

    CAS  PubMed  Google Scholar 

  36. Early, G. S., Zhao, W. & Burns, C. M. Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. J. Immunol. 157, 3159–3164 (1996).

    CAS  PubMed  Google Scholar 

  37. Citores, M. J. et al. The dinucleotide repeat polymorphism in the 3′UTR of the CD154 gene has a functional role on protein expression and is associated with systemic lupus erythematosus. Ann. Rheum. Dis. 63, 310–317 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. van der Linden, M. P. et al. Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis. Arthritis Rheum. 60, 2242–2247 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Orozco, G. et al. Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study. Ann. Rheum. Dis. 69, 813–816 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, F. et al. CD40 gene polymorphisms confer risk of Behcet's disease but not of Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Rheumatology (Oxford) 51, 47–51 (2012).

    Article  CAS  Google Scholar 

  42. Joo, Y. B. et al. Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population. Rheumatology 52, 623–630 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, J. M. et al. The association of CD40 polymorphisms with CD40 serum levels and risk of systemic lupus erythematosus. BMC Genet. 16, 121 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Lee, Y. H., Bae, S. C., Choi, S. J., Ji, J. D. & Song, G. G. Associations between the functional CD40 rs4810485 G/T polymorphism and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Lupus 24, 1177–1183 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Davis, J. C. et al. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J. Rheumatol. 28, 95–101 (2001).

    CAS  PubMed  Google Scholar 

  47. Kalunian, K. C. et al. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 3251–3258 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Ferrant, J. L. et al. The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge. Int. Immunol. 16, 1583–1594 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Xie, J. H. et al. Engineering of a novel anti-CD40L domain antibody for treatment of autoimmune diseases. J. Immunol. 192, 4083–4092 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Shock, A. et al. CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study. Arthritis Res. Ther. 17, 234 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Cordoba, F. et al. A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion. Am. J. Transplant. 15, 2825–2836 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02291029 (2016).

  53. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02089087 (2017).

  54. Croft, M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57–78 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoshioka, T. et al. Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis. Eur. J. Immunol. 30, 2815–2823 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Gwyer Findlay, E. et al. OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis. Proc. Natl Acad. Sci. USA 111, 2289–2294 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Horai, R. et al. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J. Clin. Invest. 114, 1603–1611 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Giacomelli, R. et al. T lymphocytes in the synovial fluid of patients with active rheumatoid arthritis display CD134-OX40 surface antigen. Clin. Exp. Rheumatol. 19, 317–320 (2001).

    CAS  PubMed  Google Scholar 

  59. Boot, E. P. et al. CD134 as target for specific drug delivery to auto-aggressive CD4+ T cells in adjuvant arthritis. Arthritis Res. Ther. 7, R604–R615 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Aten, J. et al. Strong and selective glomerular localization of CD134 ligand and TNF receptor-1 in proliferative lupus nephritis. J. Am. Soc. Nephrol. 11, 1426–1438 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Jacquemin, C. et al. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity 42, 1159–1170 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Patschan, S. et al. CD134 expression on CD4+ T cells is associated with nephritis and disease activity in patients with systemic lupus erythematosus. Clin. Exp. Immunol. 145, 235–242 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Abo-Elenein, A., Shaaban, D. & Gheith, O. Flowcytometric study of expression of perforin and CD134 in patients with systemic lupus erythematosus. Egypt. J. Immunol. 15, 135–143 (2008).

    PubMed  Google Scholar 

  64. Dolff, S. et al. Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus. Arthritis Res. Ther. 12, R150 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Farres, M. N., Al-Zifzaf, D. S., Aly, A. A. & Abd Raboh, N. M. OX40/OX40L in systemic lupus erythematosus: association with disease activity and lupus nephritis. Ann. Saudi Med. 31, 29–34 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cunninghame Graham, D. S. et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat. Genet. 40, 83–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Qin, W. et al. Increased OX40 and soluble OX40 ligands in children with Henoch-Schonlein purpura: association with renal involvement. Pediatr. Allergy Immunol. 22, 54–59 (2011).

    Article  PubMed  Google Scholar 

  68. Murata, K. et al. Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J. Immunol. 169, 4628–4636 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Laustsen, J. K. et al. Soluble OX40L is associated with presence of autoantibodies in early rheumatoid arthritis. Arthritis Res. Ther. 16, 474 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Nordmark, G. et al. Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjogren's syndrome. Genes Immun. 12, 100–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Gourh, P. et al. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann. Rheum. Dis. 69, 550–555 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Komura, K. et al. Increased serum soluble OX40 in patients with systemic sclerosis. J. Rheumatol. 35, 2359–2362 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Wilde, B. et al. CD4+CD25+ T-cell populations expressing CD134 and GITR are associated with disease activity in patients with Wegener's granulomatosis. Nephrol. Dial. Transplant. 24, 161–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Meylan, F. et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29, 79–89 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pappu, B. P. et al. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J. Exp. Med. 205, 1049–1062 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fang, L., Adkins, B., Deyev, V. & Podack, E. R. Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J. Exp. Med. 205, 1037–1048 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Meylan, F., Richard, A. C. & Siegel, R. M. TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunol. Rev. 244, 188–196 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Richard, A. C. et al. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. J. Leukoc. Biol. 98, 333–345 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shih, D. Q. et al. Insights into TL1A and IBD pathogenesis. Adv. Exp. Med. Biol. 691, 279–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Cassatella, M. A. et al. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J. Immunol. 178, 7325–7333 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Bamias, G. et al. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clin. Immunol. 129, 249–255 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Zhang, J. et al. Role of TL1A in the pathogenesis of rheumatoid arthritis. J. Immunol. 183, 5350–5357 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Bamias, G. et al. Circulating levels of TNF-like cytokine 1A correlate with the progression of atheromatous lesions in patients with rheumatoid arthritis. Clin. Immunol. 147, 144–150 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Sun, X. et al. Elevated serum and synovial fluid TNF-like ligand 1A (TL1A) is associated with autoantibody production in patients with rheumatoid arthritis. Scand. J. Rheumatol. 42, 97–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Cao, L., Xu, T., Huang, C. & Li, J. Elevated serum and synovial fluid TNF-like ligand 1A (TL1A) is associated with autoantibody production in patients with rheumatoid arthritis: comments on the article by Sun et al. Scand. J. Rheumatol. 43, 175 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Xiu, Z., Shen, H., Tian, Y., Xia, L. & Lu, J. Serum and synovial fluid levels of tumor necrosis factor-like ligand 1A and decoy receptor 3 in rheumatoid arthritis. Cytokine 72, 185–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Bull, M. J. et al. The death receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J. Exp. Med. 205, 2457–2464 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang, X. et al. TNF-like ligand 1A (TL1A) gene knockout leads to ameliorated collagen-induced arthritis in mice: implication of TL1A in humoral immune responses. J. Immunol. 191, 5420–5429 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Wang, E. C. et al. Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3. Arthritis Rheumatol. 66, 2762–2772 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Osawa, K., Takami, N., Shiozawa, K., Hashiramoto, A. & Shiozawa, S. Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis. Genes Immun. 5, 439–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Zinovieva, E. et al. Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis. PLoS Genet. 5, e1000528 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Bamias, G. et al. Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. Exp. Dermatol. 20, 725–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Li, L. et al. TNF-like ligand 1A is associated with the pathogenesis of psoriasis vulgaris and contributes to IL-17 production in PBMCs. Arch. Dermatol. Res. 306, 927–932 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Xu, W. D., Chen, D. J., Li, R., Ren, C. X. & Ye, D. Q. Elevated plasma levels of TL1A in newly diagnosed systemic lupus erythematosus patients. Rheumatol. Int. 35, 1435–1437 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Al-Lamki, R. S. et al. Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants. Am. J. Pathol. 163, 401–411 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Al-Lamki, R. S. et al. TL1A both promotes and protects from renal inflammation and injury. J. Am. Soc. Nephrol. 19, 953–960 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Al-Lamki, R. S. et al. DR3 signaling protects against cisplatin nephrotoxicity mediated by tumor necrosis factor. Am. J. Pathol. 180, 1454–1464 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Placke, T., Kopp, H. G. & Salih, H. R. Glucocorticoid-induced TNFR-related (GITR) protein and its ligand in antitumor immunity: functional role and therapeutic modulation. Clin. Dev. Immunol. 2010, 239083 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Nocentini, G., Ronchetti, S., Petrillo, M. G. & Riccardi, C. Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. Br. J. Pharmacol. 165, 2089–2099 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cuzzocrea, S. et al. Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis. FASEB J. 19, 1253–1265 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, S. et al. Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells. Am. J. Pathol. 180, 1059–1067 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Bae, E. et al. Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis. Clin. Exp. Immunol. 148, 410–418 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bae, E. M. et al. Reverse signaling initiated from GITRL induces NF-kappaB activation through ERK in the inflammatory activation of macrophages. Mol. Immunol. 45, 523–533 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Patel, M. et al. Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis. Eur. J. Immunol. 35, 3581–3590 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Gu, L. et al. Correlation of circulating glucocorticoid-induced TNFR-related protein ligand levels with disease activity in patients with systemic lupus erythematosus. Clin. Dev. Immunol. 2012, 265868 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Gan, X. et al. Correlation of increased blood levels of GITR and GITRL with disease severity in patients with primary Sjogren's syndrome. Clin. Dev. Immunol. 2013, 340751 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Nolte, M. A., van Olffen, R. W., van Gisbergen, K. P. & van Lier, R. A. Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol. Rev. 229, 216–231 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Oflazoglu, E. et al. Blocking of CD27-CD70 pathway by anti-CD70 antibody ameliorates joint disease in murine collagen-induced arthritis. J. Immunol. 183, 3770–3777 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Tak, P. P. et al. Expression of the activation antigen CD27 in rheumatoid arthritis. Clin. Immunol. Immunopathol. 80, 129–138 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Lee, W. W., Yang, Z. Z., Li, G., Weyand, C. M. & Goronzy, J. J. Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. J. Immunol. 179, 2609–2615 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Park, J. K. et al. CD70-expressing CD4 T cells produce IFN-gamma and IL-17 in rheumatoid arthritis. Rheumatology 53, 1896–1900 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Gattorno, M. et al. Levels of soluble CD27 in sera and synovial fluid and its expression on memory T cells in patients with juvenile idiopathic arthritides. Clin. Exp. Rheumatol. 20, 863–866 (2002).

    CAS  PubMed  Google Scholar 

  113. Swaak, A. J., Hintzen, R. Q., Huysen, V., van den Brink, H. G. & Smeenk, J. T. Serum levels of soluble forms of T cell activation antigens CD27 and CD25 in systemic lupus erythematosus in relation with lymphocytes count and disease course. Clin. Rheumatol. 14, 293–300 (1995).

    Article  CAS  PubMed  Google Scholar 

  114. Font, J. et al. Elevated soluble CD27 levels in serum of patients with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 81, 239–243 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Jacobi, A. M. et al. HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 69, 305–308 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Oelke, K. et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum. 50, 1850–1860 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Sawalha, A. H. & Jeffries, M. Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone mice. Eur. J. Immunol. 37, 1407–1413 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Shaw, J., Wang, Y. H., Ito, T., Arima, K. & Liu, Y. J. Plasmacytoid dendritic cells regulate B-cell growth and differentiation via CD70. Blood 115, 3051–3057 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jiang, H. et al. Demethylation of TNFSF7 contributes to CD70 overexpression in CD4+ T cells from patients with systemic sclerosis. Clin. Immunol. 143, 39–44 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Yin, H. et al. Hypomethylation and overexpression of CD70 (TNFSF7) in CD4+ T cells of patients with primary Sjogren's syndrome. J. Dermatol. Sci. 59, 198–203 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Snell, L. M., Lin, G. H., McPherson, A. J., Moraes, T. J. & Watts, T. H. T-Cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunol. Rev. 244, 197–217 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Sanchez-Paulete, A. R. et al. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur. J. Immunol. 46, 513–522 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Michel, J., Langstein, J., Hofstadter, F. & Schwarz, H. A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur. J. Immunol. 28, 290–295 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Jung, H. W., Choi, S. W., Choi, J. I. & Kwon, B. S. Serum concentrations of soluble 4-1BB and 4-1BB ligand correlated with the disease severity in rheumatoid arthritis. Exp. Mol. Med. 36, 13–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Seo, S. K. et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med. 10, 1088–1094 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Foell, J. L. et al. Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance. Immunology 113, 89–98 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Vinay, D. S., Choi, J. H., Kim, J. D., Choi, B. K. & Kwon, B. S. Role of endogenous 4-1BB in the development of systemic lupus erythematosus. Immunology 122, 394–400 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sun, Y. et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat. Med. 8, 1405–1413 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Foell, J. et al. CD137-mediated T cell co-stimulation terminates existing autoimmune disease in SLE-prone NZB/NZW F1 mice. Ann. NY Acad. Sci. 987, 230–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Foell, J. et al. CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J. Clin. Invest. 111, 1505–1518 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Browning, J. L. Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease. Immunol. Rev. 223, 202–220 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Ware, C. F. Targeting the LIGHT-HVEM pathway. Adv. Exp. Med. Biol. 647, 146–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Shui, J. W., Steinberg, M. W. & Kronenberg, M. Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J. Leukoc. Biol. 89, 517–523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Herro, R. & Croft, M. The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF Superfamily member 14). Pharmacol. Res. 104, 151–155 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Greenberg, J. D. et al. A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry. Ann. Rheum. Dis. 71, 1134–1142 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Kennedy, W. P. et al. Efficacy and safety of pateclizumab (anti-lymphotoxin-alpha) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study). Arthritis Res. Ther. 16, 467 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Gommerman, J. L. & Browning, J. L. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Shui, J. W. et al. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488, 222–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Petreaca, M. L. et al. Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans. Wound Repair Regen. 20, 353–366 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Anders, R. A., Subudhi, S. K., Wang, J., Pfeffer, K. & Fu, Y. X. Contribution of the lymphotoxin beta receptor to liver regeneration. J. Immunol. 175, 1295–1300 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. da Silva Antunes, R., Madge, L., Soroosh, P., Tocker, J. & Croft, M. The TNF family molecules LIGHT and lymphotoxin alphabeta induce a distinct steroid-resistant inflammatory phenotype in human lung epithelial cells. J. Immunol. 195, 2429–2441 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Edwards, J. R. et al. LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. Arthritis Rheum. 54, 1451–1462 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Pierer, M. et al. The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford) 46, 1063–1070 (2007).

    Article  CAS  Google Scholar 

  144. Herro, R., Antunes Rda, S., Aguilera, A. R., Tamada, K. & Croft, M. The tumor necrosis factor superfamily molecule LIGHT promotes keratinocyte activity and skin fibrosis. J. Invest. Dermatol. 135, 2109–2118 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Fava, R. A. et al. A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J. Immunol. 171, 115–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Gatumu, M. K. et al. Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren's syndrome in salivary glands of non-obese diabetic mice. Arthritis Res. Ther. 11, R24 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Fava, R. A., Browning, J. L., Gatumu, M., Skarstein, K. & Bolstad, A. I. LTBR-pathway in Sjogren's syndrome: CXCL13 levels and B-cell-enriched ectopic lymphoid aggregates in NOD mouse lacrimal glands are dependent on LTBR. Adv. Exp. Med. Biol. 691, 383–390 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Seleznik, G. et al. The lymphotoxin beta receptor is a potential therapeutic target in renal inflammation. Kidney Int. 89, 113–126 (2016).

    Article  CAS  PubMed  Google Scholar 

  149. Herro, R., Da Silva Antunes, R., Aguilera, A. R., Tamada, K. & Croft, M. Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis. J. Allergy Clin. Immunol. 136, 757–768 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bienkowska, J. et al. Lymphotoxin-LIGHT pathway regulates the interferon signature in rheumatoid arthritis. PLoS ONE 9, e112545 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Burkly, L. C. TWEAK/Fn14 axis: the current paradigm of tissue injury-inducible function in the midst of complexities. Semin. Immunol. 26, 229–236 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Burkly, L. C., Michaelson, J. S. & Zheng, T. S. TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol. Rev. 244, 99–114 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Wiley, S. R. et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15, 837–846 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Meighan-Mantha, R. L. et al. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J. Biol. Chem. 274, 33166–33176 (1999).

    Article  CAS  PubMed  Google Scholar 

  155. Park, M. C., Chung, S. J., Park, Y. B. & Lee, S. K. Relationship of serum TWEAK level to cytokine level, disease activity, and response to anti-TNF treatment in patients with rheumatoid arthritis. Scand. J. Rheumatol. 37, 173–178 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. van Kuijk, A. W. et al. TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade. Ann. Rheum. Dis. 69, 301–304 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Dharmapatni, A. A. et al. TWEAK and Fn14 expression in the pathogenesis of joint inflammation and bone erosion in rheumatoid arthritis. Arthritis Res. Ther. 13, R51 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Xia, L., Shen, H., Xiao, W. & Lu, J. Increased serum TWEAK levels in psoriatic arthritis: relationship with disease activity and matrix metalloproteinase-3 serum levels. Cytokine 53, 289–291 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Chicheportiche, Y. et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J. Biol. Chem. 272, 32401–32410 (1997).

    Article  CAS  PubMed  Google Scholar 

  160. Kamijo, S. et al. Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA. Rheumatology (Oxford) 47, 442–450 (2008).

    Article  CAS  Google Scholar 

  161. Novoyatleva, T., Sajjad, A. & Engel, F. B. TWEAK-Fn14 cytokine-receptor axis: a new player of myocardial remodeling and cardiac failure. Front. Immunol. 5, 50 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Ucero, A. C. et al. TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast. Biochim. Biophys. Acta 1832, 1744–1755 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Perper, S. J. et al. TWEAK is a novel arthritogenic mediator. J. Immunol. 177, 2610–2620 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Kamata, K. et al. Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J. Immunol. 177, 6433–6439 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. Park, J. S. et al. TWEAK promotes osteoclastogenesis in rheumatoid arthritis. Am. J. Pathol. 183, 857–867 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Wisniacki, N. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis. Clin. Ther. 35, 1137–1149 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. Sanz, A. B. et al. The cytokine TWEAK modulates renal tubulointerstitial inflammation. J. Am. Soc. Nephrol. 19, 695–703 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Xia, Y. et al. Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis. Clin. Immunol. 145, 108–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhao, Z. et al. TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. J. Immunol. 179, 7949–7958 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Wen, J. et al. Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway. J. Autoimmun. 43, 44–54 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Doerner, J. L. et al. TWEAK/Fn14 signaling involvement in the pathogenesis of cutaneous disease in the MRL/lpr model of spontaneous lupus. J. Invest. Dermatol. 135, 1986–1995 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Xia, Y. et al. Deficiency of fibroblast growth factor-inducible 14 (fn14) preserves the filtration barrier and ameliorates lupus nephritis. J. Am. Soc. Nephrol. 26, 1053–1070 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Campbell, S. et al. Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. J. Immunol. 176, 1889–1898 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Gao, H. X. et al. TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. Cytokine 46, 24–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Schwartz, N. et al. Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res. Ther. 11, R143 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01930890 (2016).

  177. Peter, M. E. & Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35 (2003).

    Article  CAS  PubMed  Google Scholar 

  178. Ramaswamy, M. et al. Specific elimination of effector memory CD4+ T cells due to enhanced Fas signaling complex formation and association with lipid raft microdomains. Cell Death Differ. 18, 712–720 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Janssen, E. M. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Ramaswamy, M. & Siegel, R. M. A. FAScinating receptor in self-tolerance. Immunity 26, 545–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).

    Article  CAS  PubMed  Google Scholar 

  182. Rieux-Laucat, F. et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268, 1347–1349 (1995).

    Article  CAS  PubMed  Google Scholar 

  183. Fisher, G. H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995).

    Article  CAS  PubMed  Google Scholar 

  184. Drappa, J., Vaishnaw, A. K., Sullivan, K. E., Chu, J. L. & Elkon, K. B. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N. Engl. J. Med. 335, 1643–1649 (1996).

    Article  CAS  PubMed  Google Scholar 

  185. Lamhamedi-Cherradi, S. E., Zheng, S. J., Maguschak, K. A., Peschon, J. & Chen, Y. H. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL−/− mice. Nat. Immunol. 4, 255–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  186. LeBlanc, H. N. & Ashkenazi, A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10, 66–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  187. Wang, J. et al. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98, 47–58 (1999).

    Article  CAS  PubMed  Google Scholar 

  188. Ichikawa, K. et al. TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. J. Immunol. 171, 1061–1069 (2003).

    Article  CAS  PubMed  Google Scholar 

  189. Pundt, N. et al. Susceptibility of rheumatoid arthritis synovial fibroblasts to FasL- and TRAIL-induced apoptosis is cell cycle-dependent. Arthritis Res. Ther. 11, R16 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Garcia, S., Liz, M., Gomez-Reino, J. J. & Conde, C. Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage. Arthritis Res. Ther. 12, R33 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Neve, A., Corrado, A. & Cantatore, F. P. TNF-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis: what's new? Clin. Exp. Med. 14, 115–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  192. Liu, Z. et al. CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. J. Clin. Invest. 112, 1332–1341 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yao, Q., Seol, D. W., Mi, Z. & Robbins, P. D. Intra-articular injection of recombinant TRAIL induces synovial apoptosis and reduces inflammation in a rabbit knee model of arthritis. Arthritis Res. Ther. 8, R16 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. Jin, C. H. et al. Effect of tumor necrosis factor-related apoptosis-inducing ligand on the reduction of joint inflammation in experimental rheumatoid arthritis. J. Pharmacol. Exp. Ther. 332, 858–865 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. Shi, Q. et al. Anti-arthritic effects of FasL gene transferred intra-articularly by an inducible lentiviral vector containing improved tet-on system. Rheumatol. Int. 34, 51–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  196. Zhang, W., Wang, B., Wang, F., Zhang, J. & Yu, J. CTLA4-FasL fusion product suppresses proliferation of fibroblast-like synoviocytes and progression of adjuvant-induced arthritis in rats. Mol. Immunol. 50, 150–159 (2012).

    Article  CAS  PubMed  Google Scholar 

  197. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  198. Schmitz, I. et al. An IL-2-dependent switch between CD95 signaling pathways sensitizes primary human T cells toward CD95-mediated activation-induced cell death. J. Immunol. 171, 2930–2936 (2003).

    Article  CAS  PubMed  Google Scholar 

  199. Maksimow, M., Soderstrom, T. S., Jalkanen, S., Eriksson, J. E. & Hanninen, A. Fas costimulation of naive CD4 T cells is controlled by NF-kappaB signaling and caspase activity. J. Leukoc. Biol. 79, 369–377 (2006).

    Article  CAS  PubMed  Google Scholar 

  200. Puliaeva, I., Puliaev, R., Shustov, A., Haas, M. & Via, C. S. Fas expression on antigen-specific T cells has costimulatory, helper, and down-regulatory functions in vivo for cytotoxic T cell responses but not for T cell-dependent B cell responses. J. Immunol. 181, 5912–5929 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Klebanoff, C. A. et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318–334 (2016).

    Article  PubMed  Google Scholar 

  202. Audo, R. et al. Distinct effects of soluble and membrane-bound fas ligand on fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheumatol. 66, 3289–3299 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. Li, X. et al. Effect of CD95 on inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Cell. Immunol. 290, 209–216 (2014).

    Article  CAS  PubMed  Google Scholar 

  204. Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Sanz, I., Yasothan, U. & Kirkpatrick, P. Belimumab. Nat. Rev. Drug Discov. 10, 335–336 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Mariette, X. et al. Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study. Ann. Rheum. Dis. 74, 526–531 (2015).

    Article  CAS  PubMed  Google Scholar 

  208. Stohl, W. et al. Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study. J. Rheumatol. 40, 579–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  209. Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  210. Croft, M. The TNF family in T cell differentiation and function — unanswered questions and future directions. Semin. Immunol. 26, 183–190 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Fukasawa, C. et al. Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur. J. Immunol. 33, 2792–2800 (2003).

    Article  CAS  PubMed  Google Scholar 

  212. Liu, M. F., Chao, S. C., Wang, C. R. & Lei, H. Y. Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity 34, 107–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  213. Shih, D. Q. et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 7, 1492–1503 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Anders, H. J., Jayne, D. R. & Rovin, B. H. Hurdles to the introduction of new therapies for immune-mediated kidney diseases. Nat. Rev. Nephrol. 12, 205–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  215. Genovese, M. C. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

    Article  CAS  PubMed  Google Scholar 

  216. Weinblatt, M. et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann. Rheum. Dis. 66, 228–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  217. Aringer, M. & Smolen, J. S. Therapeutic blockade of TNF in patients with SLE-promising or crazy? Autoimmun. Rev. 11, 321–325 (2012).

    Article  CAS  PubMed  Google Scholar 

  218. Stohl, W. Future prospects in biologic therapy for systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 705–720 (2013).

    Article  CAS  PubMed  Google Scholar 

  219. Soforo, E. et al. Induction of systemic lupus erythematosus with tumor necrosis factor blockers. J. Rheumatol. 37, 204–205 (2010).

    Article  CAS  PubMed  Google Scholar 

  220. Chen, X. et al. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J. Immunol. 190, 1076–1084 (2013).

    Article  CAS  PubMed  Google Scholar 

  221. McCann, F. E. et al. Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis. Arthritis Rheumatol. 66, 2728–2738 (2014).

    Article  CAS  PubMed  Google Scholar 

  222. Tsakiri, N., Papadopoulos, D., Denis, M. C., Mitsikostas, D. D. & Kollias, G. TNFR2 on non-haematopoietic cells is required for Foxp3+ Treg-cell function and disease suppression in EAE. Eur. J. Immunol. 42, 403–412 (2012).

    Article  CAS  PubMed  Google Scholar 

  223. Vinay, D. S., Kim, C. H., Choi, B. K. & Kwon, B. S. Origins and functional basis of regulatory CD11c+CD8+ T cells. Eur. J. Immunol. 39, 1552–1563 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Schreiber, T. H. et al. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J. Clin. Invest. 120, 3629–3640 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Wolf, D. et al. Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. Transplantation 94, 569–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  226. Ruby, C. E. et al. Cutting Edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J. Immunol. 183, 4853–4857 (2009).

    Article  CAS  PubMed  Google Scholar 

  227. Bresson, D., Fousteri, G., Manenkova, Y., Croft, M. & von Herrath, M. Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment. J. Autoimmun. 37, 342–351 (2011).

    Article  CAS  PubMed  Google Scholar 

  228. Ray, A., Basu, S., Williams, C. B., Salzman, N. H. & Dittel, B. N. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol. 188, 3188–3198 (2012).

    Article  CAS  PubMed  Google Scholar 

  229. Nowakowska, D. J. & Kissler, S. Ptpn22 modifies regulatory T cell homeostasis via GITR upregulation. J. Immunol. 196, 2145–2152 (2016).

    Article  CAS  PubMed  Google Scholar 

  230. Carrier, Y. et al. Enhanced GITR/GITRL interactions augment IL-27 expression and induce IL-10-producing Tr-1 like cells. Eur. J. Immunol. 42, 1393–1404 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.C. is supported by NIH grants AI070535, AI103021, AI110929 and AI123134. R.S. is supported by the NIAMS intramural research program.

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Both authors researched data for the article and made a substantial contribution to discussion of content, writing, reviewing and editing of the manuscript before submission.

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Correspondence to Michael Croft or Richard M. Siegel.

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Competing interests

M.C. has licensed patents on several TNF superfamily molecules. R.S. has issued patents on antibodies against the TNF superfamily molecule TL1A.

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Croft, M., Siegel, R. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13, 217–233 (2017). https://doi.org/10.1038/nrrheum.2017.22

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