Richard J Cuthbert1, Evangelos M Fragkakis2, Robert Dunsmuir3, Zhi Li4, Mark Coles4, Helena Marzo-Ortega5, Peter V Giannoudis1, Elena Jones1, Yasser M El-Sherbiny6, Dennis McGonagle5. 1. University of Leeds, Leeds, UK. 2. University of Leeds and The Leeds Teaching Hospitals NHS Trust, Leeds, UK. 3. The Leeds Teaching Hospitals NHS Trust, Leeds, UK. 4. University of York, York, UK. 5. University of Leeds and NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Leeds Teaching Hospital Trust, Leeds, UK. 6. University of Leeds and NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Leeds Teaching Hospital Trust, Leeds, UK, and Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
Abstract
OBJECTIVE: Group 3 innate lymphoid cells (ILC3s) play a pivotal role in barrier tissues such as the gut and the skin, two important sites of disease in spondyloarthritis (SpA). This study was undertaken to investigate whether normal or injured human enthesis, a key target tissue in early SpA, harbors ILC3s in entheseal soft tissue and adjacent perientheseal bone. METHODS: Interspinous ligament and spinous process bone from donors with no systemic inflammatory disease were collected, enzymatically digested, and immunophenotyped. The immunologic profile of entheseal cells was examined, and the transcriptional profile of sorted ILC3s was compared to that of ILC3s isolated from SpA synovial fluid (SF). To assess the ability of entheseal tissue to produce interleukin-17 (IL-17) and IL-22, entheseal digests were stimulated with IL-23 and IL-1β. Osteoarthritic and ruptured Achilles tendon tissue was examined histologically. RESULTS: The proportion of ILCs in human entheseal soft tissue was higher than that in peripheral blood (P = 0.008); entheseal soft tissue and perientheseal bone both had a higher proportion of NKp44+ ILC3s (P = 0.001 and P = 0.043, respectively). Studies of retinoic acid receptor-related orphan nuclear receptor γt (RORγt), STAT3, and IL-23 receptor transcript expression validated the entheseal ILC3 phenotype. Cytokine transcript expression was similar in ILC3s isolated from enthesis and from SpA SF. Stimulation of normal entheseal digests with IL-23/IL-1β led to up-regulation of IL-17A transcript, and histologic examination of injured/damaged entheses revealed the presence of RORγt-expressing cells. CONCLUSION: This work shows that human enthesis harbors a resident population of ILC3s, with the potential to participate in the pathogenesis of SpA.
OBJECTIVE: Group 3 innate lymphoid cells (ILC3s) play a pivotal role in barrier tissues such as the gut and the skin, two important sites of disease in spondyloarthritis (SpA). This study was undertaken to investigate whether normal or injured human enthesis, a key target tissue in early SpA, harbors ILC3s in entheseal soft tissue and adjacent perientheseal bone. METHODS: Interspinous ligament and spinous process bone from donors with no systemic inflammatory disease were collected, enzymatically digested, and immunophenotyped. The immunologic profile of entheseal cells was examined, and the transcriptional profile of sorted ILC3s was compared to that of ILC3s isolated from SpA synovial fluid (SF). To assess the ability of entheseal tissue to produce interleukin-17 (IL-17) and IL-22, entheseal digests were stimulated with IL-23 and IL-1β. Osteoarthritic and ruptured Achilles tendon tissue was examined histologically. RESULTS: The proportion of ILCs in human entheseal soft tissue was higher than that in peripheral blood (P = 0.008); entheseal soft tissue and perientheseal bone both had a higher proportion of NKp44+ ILC3s (P = 0.001 and P = 0.043, respectively). Studies of retinoic acid receptor-related orphan nuclear receptor γt (RORγt), STAT3, and IL-23 receptor transcript expression validated the entheseal ILC3 phenotype. Cytokine transcript expression was similar in ILC3s isolated from enthesis and from SpA SF. Stimulation of normal entheseal digests with IL-23/IL-1β led to up-regulation of IL-17A transcript, and histologic examination of injured/damaged entheses revealed the presence of RORγt-expressing cells. CONCLUSION: This work shows that human enthesis harbors a resident population of ILC3s, with the potential to participate in the pathogenesis of SpA.
Authors: Eric Gracey; Lars Vereecke; Dermot McGovern; Mareike Fröhling; Georg Schett; Silvio Danese; Martine De Vos; Filip Van den Bosch; Dirk Elewaut Journal: Nat Rev Rheumatol Date: 2020-07-13 Impact factor: 20.543
Authors: Lu Yang; Melania H Fanok; Aranzazu Mediero-Munoz; Laura K Fogli; Carmen Corciulo; Shahla Abdollahi; Bruce N Cronstein; Jose U Scher; Sergei B Koralov Journal: Arthritis Rheumatol Date: 2018-04-18 Impact factor: 10.995