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  • Review Article
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Innate lymphoid cells in autoimmunity: emerging regulators in rheumatic diseases

Nature Reviews Rheumatology volume 13, pages 164–173 (2017)Cite this article

Subjects

Key Points

  • Innate lymphoid cells (ILCs) are important for the orchestration of immune responses against pathogens and the maintenance of tissue homeostasis, processes mediated mainly by cytokine crosstalk between ILCs and various cell types

  • ILCs play a role in the initiation and exacerbation of autoimmune responses through the amplification of the IL-23–IL-17 cytokine axis

  • ILC3s are emerging as plausible therapeutic targets in rheumatic disease as they are present in autoimmune inflamed tissue and ILC3-derived cytokines enhance disease-inflammatory processes

  • Despite improved understanding of the role of ILCs in chronic inflammation, the mechanisms by which ILC might influence rheumatic disease processes remain poorly characterized

Abstract

Innate lymphoid cells (ILCs) are important in the regulation of barrier homeostasis. These cells do not express T cell receptors but share many functional similarities with T helper cells and cytotoxic CD8+ T lymphocytes. ILCs are divided into three groups, namely group 1 ILCs, group 2 ILCs and group 3 ILCs, based on the transcription factors they depend on for their development and function, and the cytokines they produce. Emerging data indicate that ILCs not only have protective functions but can also have detrimental effects when dysregulated, leading to chronic inflammation and autoimmune diseases, including asthma, inflammatory bowel disease, graft-versus-host disease, psoriasis, rheumatoid arthritis and atopic dermatitis. Elucidation of the cytokine pathways involved in various autoimmune diseases — and the identification of ILCs as potent producers of these cytokines — points towards a potential role for these cellular players in the pathophysiology of these diseases. In this Review we discuss the current knowledge of the role of ILCs in the pathogenesis of rheumatic and other autoimmune diseases.

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Figure 1: Role of innate lymphoid cells (ILCs) in steady state, non-autoimmune and autoimmune chronic inflammatory diseases.
Figure 2: Human innate lymphoid cell (ILC) subsets.

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References

  1. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Mjösberg, J. & Spits, H. J. Human innate lymphoid cells. J. Allergy Clin. Immunol. 138, 1265–1276 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Oliphant, C. J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Drake, L. Y., Lijima, K & Kita, H. Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69, 1300–1307 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Halim, T. Y. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Halim, T. Y. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory Th2 cell responses. Nat. Immunol. 17, 57–64 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Krishnamoorthy, N. et al. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J. Immunol. 194, 863–867 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Hepworth, M. R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ciccia, F. et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 64, 1869–1878 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Ciccia, F. et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann. Rheum. Dis. 74, 1739–1747 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Teunissen, M. B. et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients. J. Invest. Dermatol. 134, 2351–2360 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127 group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Popko, K. & Górska, E. The role of natural killer cells in pathogenesis of autoimmune diseases. Cent. Eur. J. Immunol. 40, 470–476 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Klose, C. S. & Diefenbach, A. Transcription factors controlling innate lymphoid cell fate decisions. Curr. Top. Microbiol. Immunol. 381, 215–255 (2014).

    PubMed  Google Scholar 

  15. Klose, C. S. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. McKenzie, A. N., Spits, H. & Eberl, G. Innate lymphoid cells in inflammation and immunity. Immunity 41, 366–374 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38, 769–781 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Songhet, P. et al. Stromal IFN-γR-signaling modulates goblet cell function during Salmonella typhimurium infection. PLoS ONE 6, e22459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Fallon, P. G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McSorley, H. J., Blair, N. F., Smith, K. A., McKenzie, A. N. & Maizels, R. M. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 7, 1068–1078 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chang, Y. J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bartemes, K. R., Kephart, G. M., Fox, S. J. & Kita, H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J. Allergy Clin. Immunol. 134, 671–678.e4 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Halim, T. Y., Krauss, R. H., Sun, A. C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, B. S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl Med. 5, 170ra16 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Huang, Y. & Paul, W. E. Inflammatory group 2 innate lymphoid cells. Int. Immunol. 28, 23–28 (2016).

    CAS  PubMed  Google Scholar 

  30. Constantinides, M. G., McDonald, B. D., Verhoef, P. A. & Bendelac. A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ishizuka, I. E. et al. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat. Immunol. 17, 269–276 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhong, C. et al. Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat. Immunol. 17, 169–178 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Serafini, N., Vosshenrich, C. A. & Di Santo, J. P. Transcriptional regulation of innate lymphoid cell fate. Nat. Rev. Immunol. 15, 415–428 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Chan, I. H. et al. Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells. Mucosal Immunol. 7, 842–856 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Crellin, N. K., Trifari, S., Kaplan, C. D., Cupedo, T. & Spits, H. Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 207, 281–290 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol. 10, 66–74 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Mebius, R. E. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3, 292–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Spits, H., Bernink, J. H. & Lanier, L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat. Immunol. 17, 758–764 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3- LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Eberl, G., Di Santo, J. P. & Vivier, E. The brave new world of innate lymphoid cells. Nat. Immunol. 16, 1–5 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roan, F. et al. CD4+ group 1 innate lymphoid cells (ILC) form a functionally distinct ILC subset that is increased in systemic sclerosis. J. Immunol. 196, 2051–2062 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Robinette, M. L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. DuPage, M. & Bluestone, J. A. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Klose, C. S. et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Bal, S. M. et al. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat. Immunol. 17, 636–645 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Silver, J. S. et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat. Immunol. 17, 626–35 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ohne, Y. et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat. Immunol. 17, 646–655 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Gasteiger, G. & Rudensky, A. Y. Interactions between innate and adaptive lymphocytes. Nat. Rev. Immunol. 14, 631–639 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim, H. S. et al. A novel IL-10-producing innate lymphoid cells (ILC10) in a contact hypersensitivity mouse model. BMB Rep. 49, 293–296 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Brennan, F. M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNF α antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).

    Article  CAS  PubMed  Google Scholar 

  58. Nishimoto, N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50, 1761–1769 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Edwards, C. J. Immunological therapies for rheumatoid arthritis. Br. Med. Bull. 73–74, 71–82 (2005).

  60. Kennedy, W. P. et al. Efficacy and safety of pateclizumab (anti-lymphotoxin-α) 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  CAS  PubMed  PubMed Central  Google Scholar 

  61. Moelants, E. A., Mortier, A., Van Damme, J. & Proost, P. Regulation of TNF-α with a focus on rheumatoid arthritis. Immunol. Cell Biol. 91, 393–401 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Ren, J., Feng, Z., Ly, Z., Chen, X. & Li, J. Natural killer-22 cells in the synovial fluid of patients with rheumatoid arthritis are an innate source of interleukin 22 and tumor necrosis factor-α. J. Rheumatol. 38, 2112–2118 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Koo, J. et al. Increased lymphocyte infiltration in rheumatoid arthritis is correlated with an increase in LTi-like cells in synovial fluid. Immune Netw. 13, 240–248 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Dalbeth, N. & Callan, M. F. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum. 46, 1763–1772 (2002).

    Article  PubMed  Google Scholar 

  65. Dalbeth, N. et al. CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a reciprocal program of activation. J. Immunol. 173, 6418–6426 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Walker, J. A., Barlow, J. L. & McKenzie, A. N. Innate lymphoid cells — how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Leijten, E. F. et al. Brief report: enrichment of activated group 3 innate lymphoid cells are selectively enriched in psoriatic arthritis synovial fluid. Arthritis Rheumatol. 67, 2673–2678 (2015).

    Article  PubMed  Google Scholar 

  68. Stolwijk, C., van Tubergen, A., Castillo-Ortiz, J. D. & Boonen, A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann. Rheum. Dis. 74, 65–73 (2015).

    Article  PubMed  Google Scholar 

  69. Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Mease, P. J. et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N. Engl. J. Med. 373, 1329–1339 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Kenna, T. J. & Brown, M. A. The role of IL-17-secreting mast cells in inflammatory joint disease. Nat. Rev. Rheumatol. 9, 375–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Noordenbos, T. et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 64, 99–109 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Appel, H. et al. Analysis of IL-17+ cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res. Ther. 13, R95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yeremenko, N. N. et al. Human type 1 innate lymphoid cells accumulate in the inflamed synovium in spondyloarthritis [abstract AB0049]. Ann. Rheum. Dis. 74, 906 (2015).

    Article  Google Scholar 

  77. Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Rankin, L. C. et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nat. Immunol. 14, 389–395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fullard, N. & O'Reilly, S. Role of innate immune system in systemic sclerosis. Semin. Immunopathol. 37, 511–517 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. York, M. R. Novel insights on the role of the innate immune system in systemic sclerosis. Expert Rev. Clin. Immunol. 7, 481–489 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Wohlfahrt, T. et al. Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis. Ann. Rheum. Dis. 75, 623–626 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Schepis, D. et al. Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus. Immunology 126, 140–146 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Braudeau, C. et al. Persistent deficiency of circulating mucosal-associated invariant T (MAIT) cells in ANCA-associated vasculitis. J. Autoimmun. 70, 73–79 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Manzo, A. & Pitzalis, C. Lymphoid tissue reactions in rheumatoid arthritis. Autoimmun. Rev. 7, 30–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Cantaert, T. et al. B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis. J. Immunol. 181, 785–794 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ruddle, N. H. Lymphatic vessels and tertiary lymphoid organs. J. Clin. Invest. 124, 953–959 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stranford, S. & Ruddle, N. H. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: parallels with lymph node stroma. Front. Immunol. 3, 350 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  93. De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).

    Article  CAS  PubMed  Google Scholar 

  94. Barone, F. et al. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc. Natl Acad. Sci. USA 112, 11024–11029 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ciccia, F. et al. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome. Ann. Rheum. Dis. 71, 295–301 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Peters, C. P., Mjosberg, J. M., Bernink, J. H. & Spits, H. Innate lymphoid cells in inflammatory bowel diseases. Immunol. Lett. 172, 124–131 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Hepworth, M. R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Camelo, A. et al. Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J. Gastroenterol. 47, 1198–1211 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bailey, J. R. et al. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS ONE 7, e52332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Crellin, N. K. et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Ward, N. L. & Umetsu, D. T. A new player on the psoriasis block: IL-17A- and IL-22-producing innate lymphoid cells. J. Invest. Dermatol. 134, 2305–2307 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Suzuki, A., Kochi, Y., Okada, Y. & Yamamoto, K. Insight from genome-wide association studies in rheumatoid arthritis and multiple sclerosis. FEBS Lett. 585, 3627–3632 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Safavi, F. et al. c-kit plays a critical role in induction of intravenous tolerance in experimental autoimmune encephalomyelitis. Immunol. Res. 61, 294–302 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hatfield, J. K. & Brown, M. A. Group 3 innate lymphoid cells accumulate and exhibit disease-induced activation in the meninges in EAE. Cell. Immunol. 297, 69–79 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Perry, J. S. et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci. Transl Med. 4, 145ra06 (2012).

    Article  CAS  Google Scholar 

  109. Russi, A. E., Walker-Caulfield, M. E., Ebel, M. E. & Brown, M. A. Cutting edge: c-kit signaling differentially regulates type 2 innate lymphoid cell accumulation and susceptibility to central nervous system demyelination in male and female SJL mice. J. Immunol. 194, 5609–5613 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Milovanovic, M. et al. Deletion of IL-33R (ST2) abrogates resistance to EAE in BALB/C mice by enhancing polarization of APC to inflammatory phenotype. PLoS ONE 7, e45225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jiang, H. R. et al. IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages. Eur. J. Immunol. 42, 1804–1814 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. van Nieuwenhuijze, A. et al. GM-CSF as a therapeutic target in inflammatory diseases. Mol. Immunol. 56, 675–682 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Greven, D. E. et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann. Rheum. Dis. 74, 1 924–1930 (2015).

    Article  CAS  Google Scholar 

  114. 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 

  115. van der Heijde, D. et al. Brief report: secukinumab provides significant and sustained inhibition of joint structural damage in a phase III study of active psoriatic arthritis. Arthritis Rheumatol. 68, 1914–1921 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Fava, R. A. et al. Lymphotoxin-β receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome. Arthritis Res. Ther. 13, R182 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fuchs, A. & Colonna, M. Innate lymphoid cells in homeostasis, infection, chronic inflammation and tumors of the gastrointestinal tract. Curr. Opin. Gastroenterol. 29, 581–587 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

H.S. is supported by an advanced European Research Council grant (341038).

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Authors and Affiliations

  1. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam,

    Medya M. Shikhagaie, Suzanne M. Bal, Xavier Romero Ros & Hergen Spits

  2. Department of Clinical Immunology and Rheumatology Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, the Netherlands

    Kristine Germar

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  1. Medya M. Shikhagaie
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  2. Kristine Germar
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Contributions

All authors contributed to the writing of this article. H.S. and M.S. researched data for the article and K.G., S.B. and X.R. provided substantial contributions to the discussion of its content. M.S., X.R. and S.B. undertook review and/or editing of the manuscript before submission.

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Correspondence to Hergen Spits.

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Shikhagaie, M., Germar, K., Bal, S. et al. Innate lymphoid cells in autoimmunity: emerging regulators in rheumatic diseases. Nat Rev Rheumatol 13, 164–173 (2017). https://doi.org/10.1038/nrrheum.2016.218

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