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  • Review Article
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Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?

Nature Reviews Rheumatology volume 12, pages 593–604 (2016)Cite this article

Subjects

Key Points

  • Inhibitory immune checkpoint receptors are essential for immunological homeostasis, and their function and/or expression is often disturbed in autoimmune rheumatic diseases

  • The immune-related adverse effects observed in patients receiving checkpoint blockade therapy for cancer might model the early stages of autoimmune rheumatic diseases

  • Hundreds of inhibitory immune receptors are encoded in the human genome

  • All immune cells express multiple inhibitory immune receptors

  • Inhibitory immune receptors can be targeted to inhibit inflammation in a disease-specific and tissue-specific manner

  • Rheumatologists and oncologists will benefit from joint efforts to investigate and therapeutically exploit inhibitory immune receptors

Abstract

The recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the inhibitory receptors cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in the regulation of antitumour immune responses. However, blocking signalling by these inhibitory immune checkpoint receptors is also associated with substantial inflammatory effects that can resemble autoimmune responses, which is consistent with the role of these receptors in protecting the host from excessive inflammation. The human genome encodes over 300 inhibitory receptors, which represent as many opportunities to modulate inflammation in a disease-specific and tissue-specific manner. We argue that rheumatologists and oncologists should join forces to study these inhibitory immune molecules. An improved understanding of these immune checkpoints will enable both fields to make progress in exploiting inhibitory immune receptors therapeutically. In this Review, we discuss data from studies reporting the adverse inflammatory effects of cancer therapies that target immune checkpoints. We discuss the potential implications of these findings on the biological understanding of autoimmune rheumatic diseases and highlight therapeutic strategies that could be used to target inhibitory receptors for the treatment of these conditions.

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Figure 1: Immune balance: autoimmunity versus cancer, and the role of immune checkpoints.
Figure 2: Expression of inhibitory immune receptors on different immune cells.
Figure 3: Multi-hit model for autoimmune diseases.
Figure 4: Approaches to targeting inhibitory immune receptors.

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References

  1. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ravetch, J. V. & Lanier, L. L. Immune inhibitory receptors. Science 290, 84–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Daeron, M., Jaeger, S., Du Pasquier, L. & Vivier, E. Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol. Rev. 224, 11–43 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Vivier, E. & Daeron, M. Immunoreceptor tyrosine-based inhibition motifs. Immunol. Today 18, 286–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H. & Riley, J. L. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Olde Nordkamp, M. J., Koeleman, B. P. & Meyaard, L. Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin. Immunol. 150, 31–42 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chambers, C. A. et al. The role of CTLA-4 in the regulation and initiation of T-cell responses. Immunol. Rev. 153, 27–46 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Michot, J. M. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. US National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v.4. NIH, http://evs.nci.nih.gov/ftp1/CTCAE/About.html (2010).

  20. Lacouture, M. E. et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J. Am. Acad. Dermatol. 71, 161–169 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Friedman, C. F., Proverbs-Singh, T. A. & Postow, M. A. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. http://dx.doi.org/10.1001/jamaoncol.2016.1051 (2016).

  22. Blank, C. U., Haanen, J. B., Ribas, A. & Schumacher, T. N. The “cancer immunogram”. Science 352, 658–660 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Barjaktarevic, I. Z., Qadir, N., Suri, A., Santamauro, J. T. & Stover, D. Organizing pneumonia as a side effect of ipilimumab treatment of melanoma. Chest 143, 858–861 (2013).

    Article  PubMed  Google Scholar 

  24. Antonia, S. et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 17, 299–308 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. de Velasco, G., Bermas, B. & Choueiri, T. K. Autoimmune arthropathy and uveitis as complications of programmed death 1 inhibitor treatment. Arthritis Rheumatol. 68, 556–557 (2016).

    Article  PubMed  Google Scholar 

  26. Cappelli, L. C. et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2016-209595 (2016).

  27. Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Markle, J. G. & Fish, E. N. SeXX matters in immunity. Trends Immunol. 35, 97–104 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Karnam, G. et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS. Pathog. 8, e1002710 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02671955 (2016).

  33. Kyi, C., Carvajal, R. D., Wolchok, J. D. & Postow, M. A. Ipilimumab in patients with melanoma and autoimmune disease. J. Immunother. Cancer 2, 35 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2015).

    Article  Google Scholar 

  35. Pedersen, M. et al. Successful treatment with ipilimumab and interleukin-2 in two patients with metastatic melanoma and systemic autoimmune disease. Cancer Immunol. Immunother. 63, 1341–1346 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Bostwick, A. D., Salama, A. K. & Hanks, B. A. Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis. J. Immunother. Cancer 3, 19 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu, C. et al. Soluble PD-1 aggravates progression of collagen-induced arthritis through TH1 and TH17 pathways. Arthritis Res. Ther. 17, 340 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lebbink, R. J. et al. The soluble leukocyte-associated Ig-like receptor (LAIR)-2 antagonizes the collagen/LAIR-1 inhibitory immune interaction. J. Immunol. 180, 1662–1669 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Ilan, N. & Madri, J. A. PECAM-1: old friend, new partners. Curr. Opin. Cell Biol. 15, 515–524 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Prokunina, L. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat. Genet. 32, 666–669 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39, 721–723 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cooper, J. D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399–1401 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Plagnol, V. et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS. Genet. 7, e1002216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ceeraz, S., Nowak, E. C., Burns, C. M. & Noelle, R. J. Immune checkpoint receptors in regulating immune reactivity in rheumatic disease. Arthritis Res. Ther. 16, 469 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Gaalen, F., Ioan-Facsinay, A., Huizinga, T. W. & Toes, R. E. The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J. Immunol. 175, 5575–5580 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheumatol. 50, 380–386 (2004).

    Article  Google Scholar 

  50. Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989–2003 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Koenig, M. et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheumatol. 58, 3902–3912 (2008).

    Article  Google Scholar 

  52. van Bon, L., Cossu, M. & Radstake, T. R. An update on an immune system that goes awry in systemic sclerosis. Curr. Opin. Rheumatol 23, 505–510 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Tarhini, A. A. et al. Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J. Immunother. Cancer 3, 39 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lubberts, E. The IL-23–IL-17 axis in inflammatory arthritis. Nat. Rev. Rheumatol 11, 415–429 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. van der Merwe, P. A., Bodian, D. L., Daenke, S., Linsley, P. & Davis, S. J. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J. Exp. Med. 185, 393–403 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00442611 (2015).

  57. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02161406 (2015).

  58. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00119678 (2014).

  59. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00430677 (2016).

  60. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00774852 (2016).

  61. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02270957 (2015).

  62. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00705367 (2013).

  63. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02067910 (2015).

  64. Mease, P. et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheumatol. 63, 939–948 (2011).

    Article  CAS  Google Scholar 

  65. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01860976 (2016).

  66. Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10, 48–57 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Joller, N. et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J. Immunol. 186, 1338–1342 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Zhao, W. et al. TIGIT overexpression diminishes the function of CD4 T cells and ameliorates the severity of rheumatoid arthritis in mouse models. Exp. Cell Res. 340, 132–138 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Levin, S. D. et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur. J. Immunol. 41, 902–915 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang, L. et al. Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity. Proc. Natl Acad. Sci. USA 111, 14846–14851 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ceeraz, S., Sergent, P., Schned, A., Burns, C. & Noelle, R. J. Therapeutic role of the novel checkpoint regulator VISTA in murine autoimmune disease models. (P5174). J. Immunol. 190 (Suppl. 1), 194.4 (2013).

    Google Scholar 

  73. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 62, 3077–3087 (2010).

    Article  CAS  Google Scholar 

  74. Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 66, 379–389 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Bolland, S. & Ravetch, J. V. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277–285 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Yuasa, T. et al. Deletion of Fcγ receptor IIB renders H-2b mice susceptible to collagen-induced arthritis. J. Exp. Med. 189, 187–194 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Veri, M. C. et al. Therapeutic control of B cell activation via recruitment of Fcγ receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold. Arthritis Rheumatol. 62, 1933–1943 (2010).

    CAS  Google Scholar 

  78. Horton, H. M. et al. Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J. Immunol. 186, 4223–4233 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Tada, Y. et al. Acceleration of the onset of collagen-induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1. Arthritis Rheumatol. 48, 3280–3290 (2003).

    Article  CAS  Google Scholar 

  80. Wong, M. X., Hayball, J. D., Hogarth, P. M. & Jackson, D. E. The inhibitory co-receptor, PECAM-1 provides a protective effect in suppression of collagen-induced arthritis. J. Clin. Immunol. 25, 19–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Fornasa, G. et al. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. J. Immunol. 184, 5485–5492 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Clement, M. et al. Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo. J. Autoimmun. 56, 23–33 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Muller, J. & Nitschke, L. The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat. Rev. Rheumatol. 10, 422–428 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Fleischer, V. et al. Epratuzumab inhibits the production of the proinflammatory cytokines IL-6 and TNFα, but not the regulatory cytokine IL-10, by B cells from healthy donors and SLE patients. Arthritis Res. Ther. 17, 185 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sieger, N. et al. CD22 ligation inhibits downstream B cell receptor signaling and Ca2+ flux upon activation. Arthritis Rheumatol. 65, 770–779 (2013).

    Article  CAS  Google Scholar 

  86. Wallace, D. J. et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology (Oxford) 52, 1313–1322 (2013).

    Article  CAS  Google Scholar 

  87. Wallace, D. J. et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann. Rheum. Dis. 73, 183–190 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Strand, V. et al. Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006. Rheumatology (Oxford) 53, 502–511 (2014).

    Article  CAS  Google Scholar 

  89. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01262365 (2016).

  90. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01261793 (2016).

  91. Rossi, E. A. et al. Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab. Blood 122, 3020–3029 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tan, F. K. et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford) 45, 694–702 (2006).

    Article  CAS  Google Scholar 

  94. Wildenberg, M. E., van Helden-Meeuwsen, C. G., van de Merwe, J. P., Drexhage, H. A. & Versnel, M. A. Systemic increase in type I interferon activity in Sjogren's syndrome: a putative role for plasmacytoid dendritic cells. Eur. J. Immunol. 38, 2024–2033 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Kalunian, K. C. et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196–202 (2016).

    Article  PubMed  Google Scholar 

  96. Pellerin, A. et al. Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms. EMBO Mol. Med. 7, 464–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Corsiero, E. et al. Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2015-208356 (2015).

  100. Knight, J. S. et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann. Rheum. Dis. 74, 2199–2206 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Mousseau, D. D., Banville, D., L'Abbe, D., Bouchard, P. & Shen, S. H. PILRα, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRβ. J. Biol. Chem. 275, 4467–4474 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Steevels, T. A. M., Lebbink, R. J., Westerlaken, G. H. A., Coffer, P. J. & Meyaard, L. Signal inhibitory receptor on leukocytes-1 (SIRL-1) is a novel functional inhibitory immune receptor expressed on human phagocytes. J. Immunol. 184, 4741–4748 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Van Avondt, K., Fritsch-Stork, R., Derksen, R. H. & Meyaard, L. Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus. PLoS ONE 8, e78459 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, J., Shiratori, I., Uehori, J., Ikawa, M. & Arase, H. Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation. Nat. Immunol. 14, 34–40 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Sun, Y. et al. PILRα negatively regulates mouse inflammatory arthritis. J. Immunol. 193, 860–870 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Wright, G. J. et al. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 13, 233–242 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Wright, G. J. et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J. Immunol. 171, 3034–3046 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Rijkers, E. S. K. et al. The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Mol. Immunol. 45, 1126–1135 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Rygiel, T. P. & Meyaard, L. CD200R signaling in tumor tolerance and inflammation: a tricky balance. Curr. Opin. Immunol. 24, 233–238 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Mukhopadhyay, S. et al. Immune inhibitory ligand CD200 induction by TLRs and NLRs limits macrophage activation to protect the host from meningococcal septicemia. Cell Host. Microbe 8, 236–247 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Simelyte, E., Alzabin, S., Boudakov, I. & Williams, R. CD200R1 regulates the severity of arthritis but has minimal impact on the adaptive immune response. Clin. Exp. Immunol. 162, 163–168 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Copland, D. A. et al. Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am. J. Pathol. 171, 580–588 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu, Y. et al. CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis. J. Neurosci. 30, 2025–2038 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Simelyte, E. et al. CD200-Fc, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis. Arthritis Rheumatol. 58, 1038–1043 (2008).

    Article  CAS  Google Scholar 

  115. Varin, A., Pontikoglou, C., Labat, E., Deschaseaux, F. & Sensebe, L. CD200R/CD200 inhibits osteoclastogenesis: new mechanism of osteoclast control by mesenchymal stem cells in human. PLoS ONE 8, e72831 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lee, L., Liu, J., Manuel, J. & Gorczynski, R. M. A role for the immunomodulatory molecules CD200 and CD200R in regulating bone formation. Immunol. Lett. 105, 150–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Ren, Y. et al. Aberrant CD200/CD200R1 expression and its potential role in TH17 cell differentiation, chemotaxis and osteoclastogenesis in rheumatoid arthritis. Rheumatology (Oxford) 54, 712–721 (2015).

    Article  CAS  Google Scholar 

  118. Kurlander, R. J. Blockade of Fc receptor-mediated binding to U-937 cells by murine monoclonal antibodies directed against a variety of surface antigens. J. Immunol. 131, 140–147 (1983).

    CAS  PubMed  Google Scholar 

  119. Shibayama, S., Imai, M., Shimbo, T., Tezuka, T. & Nakano, Y. A novel therapeutic approach for autoimmunity: PD-1 agonist. ECI Vienna http://www.eci-vienna2015.org/images/docs/ECI2015_Poster-Sessions.pdf (2015).

  120. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Vafa, O. et al. An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods 65, 114–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Brezski, R. J. & Georgiou, G. Immunoglobulin isotype knowledge and application to Fc engineering. Curr. Opin. Immunol. 40, 62–69 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Finck, B. K., Linsley, P. S. & Wofsy, D. Treatment of murine lupus with CTLA4Ig. Science 265, 1225–1227 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Newman, P. J. Switched at birth: a new family for PECAM-1. J. Clin. Invest. 103, 5–9 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Dunussi-Joannopoulos, K. et al. B-Cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model. Blood 106, 2235–2243 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Fournier, N. et al. FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells. J. Immunol. 165, 1197–1209 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Boruchov, A. M. et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 115, 2914–2923 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02376036 (2016).

  129. Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to K.P.M. Suijkerbuijk for critically reading the manuscript. M.v.d.V. and L.M. are supported by the Netherlands Organization for Scientific Research (NWO) through NWO Veni grant 863.14.016 (M.v.d.V.), NWO Vici grant 91815608 (L.M.), and NWO Open Programme 821.02.025 (L.M.), and by the Dutch Arthritis Foundation (grants 12-2-406 and 2014-2-023). J.K. is supported by The Netherlands Organisation for Health Research and Development (ZonMW; grant 43400003) and NWO Vidi grant 917.11.337, the Dutch Cancer Society KWF (grants UU 2010–4669, UU 2013–6426, UU 2014–6790 and UU 2015–7601), Vrienden van het University Medical Centre Utrecht, and the Association for International Cancer Research (AICR; grants 10–0736 and 15–0049). T.R.D.R. is supported by an European Research Council starting grant (CIRCUMVENT 281322).

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Authors and Affiliations

  1. Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Michiel van der Vlist, Jurgen Kuball, Timothy R. D. Radstake & Linde Meyaard

  2. Department of Immunology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Michiel van der Vlist & Linde Meyaard

  3. Department of Hematology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Jurgen Kuball

  4. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands

    Timothy R. D. Radstake

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  1. Michiel van der Vlist
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  4. Linde Meyaard
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Contributions

L.M. and M.v.d.V. researched data for the article. All authors contributed to discussions of the content, writing the article, and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Linde Meyaard.

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Competing interests

J.K. declares that he is the co-founder and Chief Scientific Officer of Gadeta. M.v.d.V, T.R. and L.M. declare that they have no competing interests.

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Glossary

Trogocytosis

Plasma membrane transfer from one cell to another, which results in decreased expression of a molecule on the donor cell and increased expression on the acceptor cell.

Neutrophil extracellular traps

(NETs). NETs are composed of chromatin from neutrophils. They are formed by decondensation of genomic DNA upon stimulation of neutrophils with inflammatory signals such as immune complexes and opsonized bacteria. NETs are coated with antimicrobial peptides and proteins like histones and neutrophil elastase, and they are involved in bacterial killing.

NETosis

The process of decondensation of nuclear DNA, followed by the release of this DNA into the extracellular milieu.

Licensing

Before an immune-inhibitory checkpoint receptor can start signalling and dampen inflammatory signals, it requires initial phosphorylation events that are provided by kinases recruited to stimulatory receptors, a process called 'licensing'. In absence of this 'go' signal, inhibitory signalling is presumed to be less potent.

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van der Vlist, M., Kuball, J., Radstake, T. et al. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?. Nat Rev Rheumatol 12, 593–604 (2016). https://doi.org/10.1038/nrrheum.2016.131

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