ILC3 in Axial Spondyloarthritis: the Gut Angle


Purpose of Review

A growing body of evidence supports the relevance of the interleukin-23/interleukin-17 (IL-23/IL-17) pathway for the pathogenesis of axial spondyloarthritis (axSpA) and its treatment. Recently, innate lymphoid cells (ILC), a heterogeneous family of immune effector cells, have been identified as a relevant contributor in tissue homeostasis, partially via IL-23/IL-17 axis. This review describes the biology and the origins of the group 3 ILCs (ILC3s) in humans, focusing on their role in the pathogenesis of axSpA.

Recent Findings

Clinical trials showed the effectiveness of IL23/IL-17 axis inhibition in both spondyloarthritis (SpA) and Inflammatory Bowel Disease (IBD). Recent findings confirm the high prevalence of subclinical gut inflammation in patients with SpA. Translational data in humans have demonstrated an increase in the number of ILC3s responsive to IL-23 and producing either IL-22 or IL-17 in the gut of SpA patients. The observation of gut-derived ILC3s in circulation and at inflamed tissues in patients with SpA suggest a recirculation of ILCs from mucosal site to lymphoid tissues and possibly enthesis and joints.


Multiple observations demonstrate the expansion of IL-17- and IL-22-producing ILC3 in the subclinically inflamed gut of SpA patients. These innate immune cells, also observed in normal entheses, seem to be able to re-circulate from the gut to inflamed tissues of SpA patients, thus contributing to the disease perpetuation. The development of tools that can provide access to diseased tissue from sacroiliac joint and spinal entheses will provide valuable knowledge on the role of ILC3 in axSpA pathogenesis.

This is a preview of subscription content, access via your institution.

Fig. 1


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Kenna TJ, Davidson SI, Duan R, Bradbury LA, McFarlane J, Smith M, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis. Arthritis Rheum [Internet]. 2012;64:1420–9.

    CAS  Article  Google Scholar 

  2. 2.

    Gracey E, Qaiyum Z, Almaghlouth I, Lawson D, Karki S, Avvaru N, et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis. 2016;75:2124–32.

    CAS  PubMed  Google Scholar 

  3. 3.

    •• Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, 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 [Internet]. 2011;13:R95. This report demonstrated the prevalence of lL-17 positive cell other than Th17 in spinal facet joints of patients with AS.

    CAS  Google Scholar 

  4. 4.

    Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Caňete JD, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum [Internet]. 2012;64:99–109.

    Google Scholar 

  5. 5.

    •• Ciccia F, Guggino G, Rizzo A, Saieva L, Peralta S, Giardina A, 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 [Internet]. 2015;74:1739–47. This study demonstrated the expansion of gut-derived lL-17+ and lL-22+lLC3s, supporting gut/joint axis theory.

    CAS  PubMed  Google Scholar 

  6. 6.

    Mjösberg J, Spits H. Human innate lymphoid cells. J Allergy Clin Immunol. 2016;138:1265–76.

    PubMed  Google Scholar 

  7. 7.

    Neill DR, Flynn RJ. Origins and evolution of innate lymphoid cells: wardens of barrier immunity. Parasite Immunol. 2018;40:e12436.

    Google Scholar 

  8. 8.

    McKenzie ANJ, Spits H, Eberl G. Innate lymphoid cells in inflammation and immunity. Immunity. 2014;41:366–74.

    CAS  PubMed  Google Scholar 

  9. 9.

    Kiessling R, Klein E, Pross H, Wigzell H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur J Immunol. 1975;5:117–21.

    CAS  PubMed  Google Scholar 

  10. 10.

    Mebius RE, Rennert P, Weissman IL. 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. 1997;7:493–504.

    CAS  PubMed  Google Scholar 

  11. 11.

    • Bernink JH, Krabbendam L, Germar K, de Jong E, Gronke K, Kofoed-Nielsen M, et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity. 2015;43:146–60. Work demonstrating the plasticity of intestinal lLCs controlled by lL-12 and lL-23 in inflamed gut.

    CAS  PubMed  Google Scholar 

  12. 12.

    Zhang K, Xu X, Pasha MA, Siebel CW, Costello A, Haczku A, et al. Cutting edge: notch signaling promotes the plasticity of group-2 innate lymphoid cells. J Immunol. 2017;198:1798–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lim AI, Menegatti S, Bustamante J, Le Bourhis L, Allez M, Rogge L, et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J Exp Med. 2016;213:569–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature. 2010;463:540–4.

    CAS  PubMed  Google Scholar 

  15. 15.

    Vonarbourg C, Diefenbach A. Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells. Semin Immunol. 2012;24:165–74.

    CAS  PubMed  Google Scholar 

  16. 16.

    Nagasawa M, Spits H, Ros XR. Innate lymphoid cells (ILCs): cytokine hubs regulating immunity and tissue homeostasis. Cold Spring Harb Perspect Biol. 2017;10:a030304.

    Google Scholar 

  17. 17.

    Renoux VM, Zriwil A, Peitzsch C, Michaëlsson J, Friberg D, Soneji S, et al. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity. 2015;43:394–407.

    CAS  PubMed  Google Scholar 

  18. 18.

    Scoville SD, Mundy-Bosse BL, Zhang MH, Chen L, Zhang X, Keller KA, et al. A progenitor cell expressing transcription factor RORγt generates all human innate lymphoid cell subsets. Immunity. 2016;44:1140–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    •• Montaldo E, Teixeira-Alves LG, Glatzer T, Durek P, Stervbo U, Hamann W, et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity. 2014;41:988–1000. Seminal work that identified human progenitor cells committed precursor of lLC3s.

    CAS  PubMed  Google Scholar 

  20. 20.

    •• Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, et al. Systemic human ILC precursors provide a substrate for tissue ILC differentiation. Cell. 2017;168:1086–1100.e10. Seminal paper demonstrating circulating progenitor and supporting the theory of in situ “lLC-poiesis”.

    CAS  PubMed  Google Scholar 

  21. 21.

    Boos MD, Yokota Y, Eberl G, Kee BL. Mature natural killer cell and lymphoid tissue–inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med. 2007;204:1119–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Klose CSN, Flach M, Möhle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014;157:340–56.

    CAS  PubMed  Google Scholar 

  23. 23.

    Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature. 2014;508:397–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cherrier M, Sawa S, Eberl G. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J Exp Med. 2012;209:729–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Seillet C, Rankin LC, Groom JR, Mielke LA, Tellier J, Chopin M, et al. Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med. 2014;211:1733–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Geiger TL, Abt MC, Gasteiger G, Firth MA, O’Connor MH, Geary CD, et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med. 2014;211:1723–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Yagi R, Zhong C, Northrup DL, Yu F, Bouladoux N, Spencer S, et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity. 2014;40:378–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012;36:55–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Harmon C, Robinson MW, Fahey R, Whelan S, Houlihan DD, Geoghegan J, et al. Tissue-resident Eomes hi T-bet lo CD56 bright NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol. 2016;46:2111–20.

    CAS  PubMed  Google Scholar 

  30. 30.

    Collins A, Rothman N, Liu K, Reiner SL. Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI Insight. 2017;2:e90063.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12:21–7.

    CAS  PubMed  Google Scholar 

  32. 32.

    Naito T, Shiohara T, Hibi T, Suematsu M, Ishikawa H. RORγt is dispensable for the development of intestinal mucosal T cells. Mucosal Immunol. 2008;1:198–207.

    CAS  PubMed  Google Scholar 

  33. 33.

    Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13:145–9.

    CAS  PubMed  Google Scholar 

  34. 34.

    Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174:1054–66.

    CAS  PubMed  Google Scholar 

  35. 35.

    •• Simoni Y, Fehlings M, Kløverpris HN, McGovern N, Koo SL, Loh CY, et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity. 2017;46:148–61. This report provides a deep phenotyping of lLC subsets via mass cytometry.

    CAS  PubMed  Google Scholar 

  36. 36.

    Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol [Internet]. 2013;14:221–9.

    CAS  Article  Google Scholar 

  37. 37.

    Gebhardt T, Palendira U, Tscharke DC, Bedoui S. Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance. Immunol Rev. 2018;283:54–76.

    CAS  PubMed  Google Scholar 

  38. 38.

    Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity. 2013;38:769–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Camelo A, Rosignoli G, Ohne Y, Stewart RA, Overed-Sayer C, Sleeman MA, et al. IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells. Blood Adv [Internet]. 2017;1:577 LP–589.

    CAS  Article  Google Scholar 

  40. 40.

    Hoyler T, Klose CSN, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 2012;37:634–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Mjösberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B, et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity. 2012;37:649–59.

    PubMed  Google Scholar 

  42. 42.

    Mjösberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12:1055–62.

    PubMed  Google Scholar 

  43. 43.

    Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2015;519:242–6.

    CAS  PubMed  Google Scholar 

  44. 44.

    Spits H. Group 2 innate lymphoid cells show up in the skin. Immunol Cell Biol. 2013;91:390–2.

    CAS  PubMed  Google Scholar 

  45. 45.

    Hashiguchi M, Kashiwakura Y, Kojima H, Kobayashi A, Kanno Y, Kobata T. Peyer’s patch innate lymphoid cells regulate commensal bacteria expansion. Immunol Lett. 2015;165:1–9.

    CAS  PubMed  Google Scholar 

  46. 46.

    Koyasu S, Moro K, Tanabe M, Takeuchi T. Natural Helper Cells. 2010:21–44.

  47. 47.

    Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29–40.

    CAS  PubMed  Google Scholar 

  48. 48.

    Price AE, Liang H-E, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci. 2010;107:11489–94.

    CAS  PubMed  Google Scholar 

  49. 49.

    Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria J-P, O’Byrne PM, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137:75–86.e8.

    CAS  PubMed  Google Scholar 

  50. 50.

    Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al. A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210:2939–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    •• Wang S, Xia P, Chen Y, Qu Y, Xiong Z, Ye B, et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell [Internet] Elsevier Inc. 2017;171:201–216.e18. Identification of lL-10 producing regulatory lLCs termed lLCreg.

    PubMed  Google Scholar 

  52. 52.

    Ciccia F, Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, Peralta S, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64:1869–78.

    CAS  PubMed  Google Scholar 

  53. 53.

    Hoorweg K, Peters CP, Cornelissen F, Aparicio-Domingo P, Papazian N, Kazemier G, et al. Functional differences between human NKp44(−) and NKp44(+) RORC(+) innate lymphoid cells. Front Immunol. 2012;3:72.

  54. 54.

    Victor AR, Nalin AP, Dong W, McClory S, Wei M, Mao C, et al. IL-18 drives ILC3 proliferation and promotes IL-22 production via NF-κB. J Immunol [Internet]. 2017;199:ji1601554.

    CAS  Article  Google Scholar 

  55. 55.

    Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–9.

    CAS  PubMed  Google Scholar 

  56. 56.

    Longman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, et al. CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med [Internet]. 2014;211:1571–83.

    CAS  Article  Google Scholar 

  57. 57.

    Mebius RE, Rennert P, Weissman IL. Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity [Internet]. 1997;7:493–504.

    CAS  Article  Google Scholar 

  58. 58.

    Forkel M, Mjösberg J. Dysregulation of group 3 innate lymphoid cells in the pathogenesis of inflammatory bowel disease. Curr Allergy Asthma Rep. 2016;16:73.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10:66–74.

    CAS  PubMed  Google Scholar 

  60. 60.

    Shikhagaie MM, Björklund ÅK, Mjösberg J, Erjefält JS, Cornelissen AS, Ros XR, et al. Neuropilin-1 is expressed on lymphoid tissue residing LTi-like group 3 innate lymphoid cells and associated with ectopic lymphoid aggregates. Cell Rep. 2017;18:1761–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Sawa S, Cherrier M, Lochner M, Satoh-Takayama N, Fehling HJ, Langa F, et al. Lineage relationship analysis of RORγt + innate lymphoid cells. Science. 2010;330(80):665–9.

    CAS  PubMed  Google Scholar 

  62. 62.

    Constantinides MG. Interactions between the microbiota and innate and innate-like lymphocytes. J Leukoc Biol. 2018;103:409–19.

    CAS  PubMed  Google Scholar 

  63. 63.

    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.

    CAS  PubMed  Google Scholar 

  64. 64.

    Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M, Sawa S, et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J Exp Med. 2011;208:125–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Satoh-Takayama N, Vosshenrich CAJ, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity. 2008;29:958–70.

    CAS  PubMed  Google Scholar 

  66. 66.

    Melo-Gonzalez F, Kammoun H, Evren E, Dutton EE, Papadopoulou M, Bradford BM, et al. Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria. J Exp Med [Internet]. 2019;216:jem.20180871.

    CAS  Article  Google Scholar 

  67. 67.

    Kim S-H, Cho B-H, Kiyono H, Jang Y-S. Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer’s patches. Sci Rep. 2017;7:3980.

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    van de Pavert SA, Ferreira M, Domingues RG, Ribeiro H, Molenaar R, Moreira-Santos L, et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature. 2014;508:123–7.

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Li S, Bostick JW, Zhou L. Regulation of innate lymphoid cells by aryl hydrocarbon receptor. Front Immunol. 2018;8.

  70. 70.

    Kim CH, Hashimoto-Hill S, Kim M. Migration and tissue tropism of innate lymphoid cells. Trends Immunol. 2016;37:68–79.

    CAS  PubMed  Google Scholar 

  71. 71.

    Deshayes P, Houdent C, Hecketsweiler P. Rheumatic manifestations of Crohn’s disease. A national survey. Rev Rhum Mal Osteoartic. 1976;43:541–51.

    CAS  PubMed  Google Scholar 

  72. 72.

    De Vos M, Mielants H, Cuvelier C, Elewaut A, Veys E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology. 1996;110:1696–703.

    PubMed  Google Scholar 

  73. 73.

    • Van Praet L, Jans L, Carron P, Jacques P, Glorieus E, Colman R, et al. Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort. Ann Rheum Dis. 2014;73:1186–9. This clinical study demonstrated the association between gut and joint inflammation in a large cohort.

    PubMed  Google Scholar 

  74. 74.

    Dunn ETJ, Taylor ES, Stebbings S, Schultz M, Butt AG, Kemp RA. Distinct immune signatures in the colon of Crohn’s disease and ankylosing spondylitis patients in the absence of inflammation. Immunol Cell Biol. 2016;94:421–9.

    CAS  PubMed  Google Scholar 

  75. 75.

    Mielants H, Veys EM, Cuvelier C, De Vos MD. Ileocolonoscopic findings in seronegative spondylarthropathies. Rheumatology. 1988;XXVII:95–105.

  76. 76.

    Ciccia F, Bombardieri M, Rizzo A, Principato A, Giardina AR, Raiata F, et al. Over-expression of paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation. Rheumatology. 2010;49:2076–83.

    CAS  PubMed  Google Scholar 

  77. 77.

    De Vos M, Cuvelier C, Mielants H, Veys E, Barbier F, Elewaut A. Ileocolonoscopy in seronegative spondylarthropathy. Gastroenterology. 1989;96:339–44.

    PubMed  Google Scholar 

  78. 78.

    Tito RY, Cypers H, Joossens M, Varkas G, Van Praet L, Glorieus E, et al. Brief report: dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheum. 2017;69:114–21.

    CAS  Google Scholar 

  79. 79.

    Stoll ML, Kumar R, Morrow CD, Lefkowitz EJ, Cui X, Genin A, et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res Ther. 2014;16:486.

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Costello M-E, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, et al. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol [Internet]. 2015;67:686–91.

    Article  Google Scholar 

  81. 81.

    Ciccia F, Guggino G, Rizzo A, Alessandro R, Luchetti MM, Milling S, et al. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis [Internet]. 2017;76:1123–32.

    CAS  Article  Google Scholar 

  82. 82.

    Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, Stauffer P, et al. HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats. Bereswill S, editor. PLoS One. 2014;9:e105684.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Gill T, Asquith M, Brooks SR, Rosenbaum JT, Colbert RA. Effects of HLA–B27 on gut microbiota in experimental spondyloarthritis implicate an ecological model of dysbiosis. Arthritis Rheum. 2018;70:555–65.

    CAS  Google Scholar 

  84. 84.

    Thjodleifsson B, Geirsson ÁJ, Björnsson S, Bjarnason I. A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. Arthritis Rheum. 2007;56:2633–9.

    PubMed  Google Scholar 

  85. 85.

    Ciccia F, Guggino G, Rizzo A, Alessandro R, Luchetti MM, Milling S, et al. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis. 2017;76:1123–32.

    CAS  PubMed  Google Scholar 

  86. 86.

    Neerinckx B, Elewaut D, Lories RJ. Spreading spondyloarthritis: are ILCs cytokine shuttles from base camp gut? Ann Rheum Dis. 2015;74:1633–5.

    CAS  PubMed  Google Scholar 

  87. 87.

    Eberl G, Sawa S. Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010;31:50–5.

    CAS  PubMed  Google Scholar 

  88. 88.

    Varol C, Zigmond E, Jung S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nat Rev Immunol. 2010;10:415–26.

    CAS  PubMed  Google Scholar 

  89. 89.

    Varol C, Landsman L, Jung S. Probing in vivo origins of mononuclear phagocytes by conditional ablation and reconstitution. Methods Mol Biol. 2009;531:71–87.

  90. 90.

    Schulz O, Jaensson E, Persson EK, Liu X, Worbs T, Agace WW, et al. Intestinal CD103 + , but not CX3CR1 + , antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med. 2009;206:3101–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M, et al. Origin of the lamina propria dendritic cell network. Immunity. 2009;31:513–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Denning TL, Wang Y, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. Nat Immunol. 2007;8:1086–94.

    CAS  PubMed  Google Scholar 

  93. 93.

    Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10:1178–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Diehl GE, Longman RS, Zhang J-X, Breart B, Galan C, Cuesta A, et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature. 2013;494:116–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    • Ciccia F, Guggino G, Zeng M, Thomas R, Ranganathan V, Rahman A, et al. Proinflammatory CX3CR1+CD59+tumor necrosis factor–like molecule 1A+interleukin-23+ monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions. Arthritis Rheum. 2018;70:2003–13. This work demonstrated the expansion of lL23 producing CX3CR1+ mononuclear phagocytes, supporting lLC3 expansion in the gut of AS patients.

    CAS  Google Scholar 

  96. 96.

    Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014;15:929–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Savino B, Castor MG, Caronni N, Sarukhan A, Anselmo A, Buracchi C, et al. Control of murine Ly6Chigh monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6. Blood. 2012;119:5250–60.

    CAS  PubMed  Google Scholar 

  98. 98.

    Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, Pabst O, et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci. 2007;104:6347–52.

    CAS  PubMed  Google Scholar 

  99. 99.

    Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nat Med. 2012;18:1069–76.

    CAS  PubMed  Google Scholar 

  100. 100.

    •• Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo-Ortega H, et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheum. 2017;69:1816–22. Unique report investigating the presence of lLC3 in human spinal enthesis.

    CAS  Google Scholar 

  101. 101.

    Soare A, Weber S, Maul L, Rauber S, Gheorghiu AM, Luber M, et al. Cutting edge: homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. J Immunol [Internet]. 2018;200:1249–54.

    CAS  Article  Google Scholar 

  102. 102.

    Leijten EFA, van Kempen TS, Boes M, Michels-van Amelsfort JMR, Hijnen D, Hartgring SAY, et al. Brief report: enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid. Arthritis Rheumatol (Hoboken, NJ). 2015;67:2673–8.

    Google Scholar 

  103. 103.

    Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, Alexander K, et al. β-glucan triggers spondylarthritis and Crohn’s disease-like ileitis in SKG mice. Arthritis Rheum [Internet]. 2012;64:2211–22.

    CAS  Article  Google Scholar 

  104. 104.

    Rehaume LM, Mondot S, Aguirre de Cárcer D, Velasco J, Benham H, Hasnain SZ, et al. ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol [Internet]. 2014;66:2780–92.

    CAS  Article  Google Scholar 

  105. 105.

    Rehaume LM, Matigian N, Mehdi AM, Lachner N, Bowerman KL, Daly J, et al. IL-23 favours outgrowth of spondyloarthritis-associated pathobionts and suppresses host support for homeostatic microbiota. Ann Rheum Dis [Internet]. 2019;78:494–503.

    Article  Google Scholar 

  106. 106.

    Yin J, Sternes PR, Wang M, Morrison M, Song J, Li T, et al. Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy and the host’s genotype upon microbiome composition. bioRxiv [Internet]. 2019;571430.

Download references

Author information



Corresponding author

Correspondence to Francesco Ciccia.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Spondyloarthritis

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mauro, D., Macaluso, F., Fasano, S. et al. ILC3 in Axial Spondyloarthritis: the Gut Angle. Curr Rheumatol Rep 21, 37 (2019).

Download citation


  • Group 3 innate lymphoid cells
  • Lymphoid tissue inducer cells
  • Gut inflammation
  • Spondyloarthritis
  • Ankylosing spondylitis
  • IL-17
  • IL-23/IL-17 axis