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Dennis Mcgonagle - One of the best experts on this subject based on the ideXlab platform.
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Interleukin‐23 pathway at the Enthesis: The emerging story of enthesitis in spondyloarthropathy
Immunological Reviews, 2020Co-Authors: Charlie Bridgewood, Kassem Sharif, Jonathan P Sherlock, Abdulla Watad, Dennis McgonagleAbstract:The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R-expressing cells were ensconced in healthy murine Enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R-expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human Enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human Enthesis and highlight the remarkable emerging story of this unique skeletal tissue.
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interleukin 23 pathway at the Enthesis the emerging story of enthesitis in spondyloarthropathy
Immunological Reviews, 2020Co-Authors: Charlie Bridgewood, Kassem Sharif, Jonathan P Sherlock, Abdulla Watad, Dennis McgonagleAbstract:: The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R-expressing cells were ensconced in healthy murine Enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R-expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human Enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human Enthesis and highlight the remarkable emerging story of this unique skeletal tissue.
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Group 3 Innate Lymphoid Cells in Human Enthesis
2017Co-Authors: Richard Cuthbert, Evangelos M. Fragkakis, Robert Dunsmuir, Mark Coles, Helena Marzo-ortega, Peter V. Giannoudis, Elena Jones, Yasser M. El-sherbiny, Dennis McgonagleAbstract: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 spondyloarthropathy (SpA). It was investigated whether normal and injured human Enthesis, the key target tissue in early SpA, harboured ILC3s in entheseal soft tissue (EST) and adjacent peri-entheseal bone (PEB). Methods Interspinous ligament and spinous process bone was collected from donors with no systemic inflammatory disease, enzymatically digested and immunophenotyped. The immunological profile of entheseal cells was examined and the transcriptional profile of sorted ILC3s was compared to those isolated from SpA synovial fluid. To assess the ability of entheseal tissue to produce IL-17 and IL-22 entheseal digests were stimulated with IL-23 and IL-1β. Osteoarthritic and ruptured Achilles tissue was examined histologically. Results Compared to peripheral blood, human EST had a higher proportion of ILCs (p=0.008), EST and PEB both had a higher proportion of NKp44+ ILC3s (p=0.001 and p=0.043). RORγt, STAT3 and IL-23R transcript expression validated the entheseal ILC3 phenotype. Cytokine transcript expression was similar in ILC3s isolated from Enthesis and SpA synovial fluid. Normal entheseal digests stimulated with IL-23/IL-1β upregulated IL17A transcript and histological examination of injured/damaged entheses showed RORγt expressing cells. Conclusion This work shows that human Enthesis harbours a resident population of ILC3s, with the potential to participate in spondyloarthropathy pathogenesis. This article is protected by copyright. All rights reserved.
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brief report group 3 innate lymphoid cells in human Enthesis
Arthritis & Rheumatism, 2017Co-Authors: Richard Cuthbert, Evangelos M. Fragkakis, Robert Dunsmuir, Mark Coles, Peter V. Giannoudis, Elena Jones, Helena Marzoortega, Yasser M Elsherbiny, Dennis McgonagleAbstract: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.
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Human Enthesis Group 3 Innate Lymphoid Cells
Arthritis & Rheumatism, 2017Co-Authors: Richard Cuthberd, Mark Coles, Dennis McgonagleAbstract: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.
Olivier Hauger - One of the best experts on this subject based on the ideXlab platform.
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Early Achilles Enthesis Involvement in a Murine Model of Spondyloarthropathy: Morphological Imaging with Ultrashort Echo-Time Sequences and Ultrasmall Superparamagnetic Iron Oxide (USPIO) Particle Evaluation in Macrophagic Detection
Hindawi-Wiley, 2019Co-Authors: Benjamin Dallaudiere, Aurelien J. Trotier, Emeline J. Ribot, Stéphane Loubrie, Sylvain Miraux, Olivier HaugerAbstract:Purpose. To confirm the interest of 3-dimensional ultrashort echo-time (3D-UTE) sequences to assess morphologic aspects in normal and pathological Achilles entheses in a rat model of spondyloarthropathy (SpA) with histological correlations, in comparison with conventional RARE T2 Fat-Sat sequences, and, furthermore, to evaluate the feasibility of a 3D multiecho UTE sequence performed before and after the intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles to assess macrophagic involvement in the Achilles Enthesis in the same rat model of SpA. Materials and Methods. Fourteen rats underwent in vivo MRI of the ankle at 4.7 T, including a 3D RARE T2 Fat-Sat sequence and a 3D ultrashort echo-time (UTE) sequence for morphologic assessment at baseline and day 3 after induction of an SpA model, leading to Achilles enthesopathy in the left paw (right paw serving as a control). A 3D multiecho UTE sequence was also performed at day 3 before and then 24 (4 rats) and 48 (2 rats) hours after intravenous injection of USPIO. Visual analysis and signal intensity measurements of all images were performed at different locations of the Achilles Enthesis and preinsertional area. Visual analysis and T2∗ measurements were performed before and after USPIO injection, on the 3D multiecho UTE sequence in the same locations. Normal and pathological values were compared by Wilcoxon signed-rank tests. MR findings were compared against histological data. Results. 3D-UTE sequences enabled morphologic identification of the anterior fibrocartilage and posterior collagenic areas of the Achilles Enthesis. Visual analysis and signal intensity measurements distinguished SpA-affected entheses from healthy ones at day 3 (P=0.02). After administration of USPIO, no differences in signals were detected. Similarly, both visual analysis and signal T2∗ measurements in the Enthesis were unable to distinguish the SpA-affected tendons from healthy ones (P=0.914). Neither the normal anatomy of the Enthesis nor its pathological pattern could be distinguished using the standard RARE sequence. Histology confirmed the absence of USPIO in Achilles entheses, despite marked signs of inflammation. Conclusion. Unlike conventional RARE T2 Fat-Sat sequences, 3D-UTE sequences enable morphologic assessment of normal Enthesis anatomy and early detection of abnormalities in pathological conditions. However, 3D multiecho UTE sequences combined with USPIO injections with T2∗ measurements were unable to detect macrophagic involvement in these pathological conditions
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Three‐dimensional ultrashort echo time (3D UTE) MRI of Achilles tendon at 4.7T MRI with comparison to conventional sequences in an experimental murine model of spondyloarthropathy
Journal of Magnetic Resonance Imaging, 2019Co-Authors: Benjamin Dallaudiere, Aurelien J. Trotier, Emeline J. Ribot, Sylvain Miraux, D. Verdier, S. Lepreux, Olivier HaugerAbstract:Background: Due to the very short T2 of its components, the normal anatomy of Achilles Enthesis is impossible to define with “conventional” long echo time (TE) T2 sequences. However, this is a common site affected by rheumatologic disease. Early abnormalities related to inflammatory processes are impossible to detect in this location. Purpose: To assess the feasibility of a 3D‐UTE (ultrashort echo time) sequence to evaluate normal and pathological Achilles entheses, determining both anterior fibrocartilaginous and posterior collagenic portions at 4.7T, in a rat model of spondyloarthropathy (SpA) with histological correlation. To assess whether this sequence detects SpA enthesopathy prior to long TE T2 sequences, enabling disease monitoring. Study Type: Prospective case–control study. Animal Model: Twelve immunocompetent Wistar male rats imaged before (controls); the model was induced in eight rats (16 tendons) imaged at day 6, day 13, and day 21 with regular sacrifice for ex vivo imaging and histological correlation. Field Strength 4.7T Bruker Biospec Systems. 3D balanced steady‐state free precession (bSSFP) and 3D‐UTE sequences, performed at baseline (day 0, n = 12 animals / 24 tendons), day 6 (n = 8/16), 13 (n = 4/8), and day 21 (n = 2/4). Assessment: Visual analysis and signal intensity measurements (signal to noise ratio, SNR) of both bSSFP and UTE images were performed by two independent musculoskeletal radiologists at different locations of the Achilles Enthesis and preinsertional area. Statistical Tests: Normal and pathological rat values were compared by Wilcoxon signed‐rank tests, as well as interobserver differences. MRI findings were compared against histological data. Results: The 3D‐UTE sequence identified the anterior fibrocartilage and posterior collagenic areas of Achilles entheses in all cases. Visual analysis and signal intensity measurements distinguished SpA‐affected entheses from healthy ones at days 6 and 13 (P = 0.002 and P = 0.006, respectively). Neither the normal anatomy of the Enthesis nor its pathological pattern could be identified on T2 bSSFP sequences. Data Conclusion: Unlike bSSFP T2 sequences, 3D‐UTE sequences enable visualization of normal Enthesis anatomy and early detection of abnormalities in pathological conditions.
Bimin Chen - One of the best experts on this subject based on the ideXlab platform.
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evaluation of normal cadaveric achilles tendon and Enthesis with ultrashort echo time ute magnetic resonance imaging and indentation testing
NMR in Biomedicine, 2019Co-Authors: Bimin Chen, Xin Cheng, Erik W Dorthe, Yinghua Zhao, Darryl D Dlima, G M Bydder, Sirun LiuAbstract:Entheses are regions where tendons and ligaments attach to bone, and are the primary target in seronegative and other diseases of the musculoskeletal (MSK) system. MRI has been widely used for visualizing features of inflammatory and degenerative MSK disease; however, normal tendons and entheses have short transverse relaxation times (T2 ), and show little or no signal with conventional clinical MRI pulse sequences, making it difficult to investigate their MR properties. In this study we examined the normal MR morphology of the cadaveric Achilles tendon and Enthesis at 3 T using novel three-dimensional ultrashort echo time (3D UTE) Cones sequences, and at 11.7 T using conventional MRI sequences. We also studied the MR properties of the Achilles tendon and Enthesis including T2 *, T1 , and magnetization transfer ratio (MTR). In addition, MT modeling of macromolecular proton fractions was investigated using 3D UTE Cones sequences at 3 T. Indentation testing was performed to investigate the mechanical properties of the tendons and entheses, and this was followed by histological examination. In total five specimens (<50 years) were investigated. On average, tendons and entheses respectively had T2 * values of 0.93 ± 0.48 ms and 2.77 ± 0.79 ms, T1 values of 644 ± 22 ms and 780 ± 55 ms, MTRs of 0.373 ± 0.03 and 0.244 ± 0.009 with an MT power of 1000° and frequency offset of 2 kHz, and macromolecular proton fractions of 18.0 ± 2.2% and 13.9 ± 1.9%. Compared with the tendon, the Enthesis generally had a longer T2 *, a longer T1 , a lower MTR, and a lower macromolecular proton fraction as well as both a higher Young's modulus and stiffness. Results from this study are likely to provide a useful baseline for identifying deviations from the normal in seronegative arthritis and other disease of the entheses.
Benjamin Dallaudiere - One of the best experts on this subject based on the ideXlab platform.
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Early Achilles Enthesis Involvement in a Murine Model of Spondyloarthropathy: Morphological Imaging with Ultrashort Echo-Time Sequences and Ultrasmall Superparamagnetic Iron Oxide (USPIO) Particle Evaluation in Macrophagic Detection
Hindawi-Wiley, 2019Co-Authors: Benjamin Dallaudiere, Aurelien J. Trotier, Emeline J. Ribot, Stéphane Loubrie, Sylvain Miraux, Olivier HaugerAbstract:Purpose. To confirm the interest of 3-dimensional ultrashort echo-time (3D-UTE) sequences to assess morphologic aspects in normal and pathological Achilles entheses in a rat model of spondyloarthropathy (SpA) with histological correlations, in comparison with conventional RARE T2 Fat-Sat sequences, and, furthermore, to evaluate the feasibility of a 3D multiecho UTE sequence performed before and after the intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles to assess macrophagic involvement in the Achilles Enthesis in the same rat model of SpA. Materials and Methods. Fourteen rats underwent in vivo MRI of the ankle at 4.7 T, including a 3D RARE T2 Fat-Sat sequence and a 3D ultrashort echo-time (UTE) sequence for morphologic assessment at baseline and day 3 after induction of an SpA model, leading to Achilles enthesopathy in the left paw (right paw serving as a control). A 3D multiecho UTE sequence was also performed at day 3 before and then 24 (4 rats) and 48 (2 rats) hours after intravenous injection of USPIO. Visual analysis and signal intensity measurements of all images were performed at different locations of the Achilles Enthesis and preinsertional area. Visual analysis and T2∗ measurements were performed before and after USPIO injection, on the 3D multiecho UTE sequence in the same locations. Normal and pathological values were compared by Wilcoxon signed-rank tests. MR findings were compared against histological data. Results. 3D-UTE sequences enabled morphologic identification of the anterior fibrocartilage and posterior collagenic areas of the Achilles Enthesis. Visual analysis and signal intensity measurements distinguished SpA-affected entheses from healthy ones at day 3 (P=0.02). After administration of USPIO, no differences in signals were detected. Similarly, both visual analysis and signal T2∗ measurements in the Enthesis were unable to distinguish the SpA-affected tendons from healthy ones (P=0.914). Neither the normal anatomy of the Enthesis nor its pathological pattern could be distinguished using the standard RARE sequence. Histology confirmed the absence of USPIO in Achilles entheses, despite marked signs of inflammation. Conclusion. Unlike conventional RARE T2 Fat-Sat sequences, 3D-UTE sequences enable morphologic assessment of normal Enthesis anatomy and early detection of abnormalities in pathological conditions. However, 3D multiecho UTE sequences combined with USPIO injections with T2∗ measurements were unable to detect macrophagic involvement in these pathological conditions
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Three‐dimensional ultrashort echo time (3D UTE) MRI of Achilles tendon at 4.7T MRI with comparison to conventional sequences in an experimental murine model of spondyloarthropathy
Journal of Magnetic Resonance Imaging, 2019Co-Authors: Benjamin Dallaudiere, Aurelien J. Trotier, Emeline J. Ribot, Sylvain Miraux, D. Verdier, S. Lepreux, Olivier HaugerAbstract:Background: Due to the very short T2 of its components, the normal anatomy of Achilles Enthesis is impossible to define with “conventional” long echo time (TE) T2 sequences. However, this is a common site affected by rheumatologic disease. Early abnormalities related to inflammatory processes are impossible to detect in this location. Purpose: To assess the feasibility of a 3D‐UTE (ultrashort echo time) sequence to evaluate normal and pathological Achilles entheses, determining both anterior fibrocartilaginous and posterior collagenic portions at 4.7T, in a rat model of spondyloarthropathy (SpA) with histological correlation. To assess whether this sequence detects SpA enthesopathy prior to long TE T2 sequences, enabling disease monitoring. Study Type: Prospective case–control study. Animal Model: Twelve immunocompetent Wistar male rats imaged before (controls); the model was induced in eight rats (16 tendons) imaged at day 6, day 13, and day 21 with regular sacrifice for ex vivo imaging and histological correlation. Field Strength 4.7T Bruker Biospec Systems. 3D balanced steady‐state free precession (bSSFP) and 3D‐UTE sequences, performed at baseline (day 0, n = 12 animals / 24 tendons), day 6 (n = 8/16), 13 (n = 4/8), and day 21 (n = 2/4). Assessment: Visual analysis and signal intensity measurements (signal to noise ratio, SNR) of both bSSFP and UTE images were performed by two independent musculoskeletal radiologists at different locations of the Achilles Enthesis and preinsertional area. Statistical Tests: Normal and pathological rat values were compared by Wilcoxon signed‐rank tests, as well as interobserver differences. MRI findings were compared against histological data. Results: The 3D‐UTE sequence identified the anterior fibrocartilage and posterior collagenic areas of Achilles entheses in all cases. Visual analysis and signal intensity measurements distinguished SpA‐affected entheses from healthy ones at days 6 and 13 (P = 0.002 and P = 0.006, respectively). Neither the normal anatomy of the Enthesis nor its pathological pattern could be identified on T2 bSSFP sequences. Data Conclusion: Unlike bSSFP T2 sequences, 3D‐UTE sequences enable visualization of normal Enthesis anatomy and early detection of abnormalities in pathological conditions.
Sirun Liu - One of the best experts on this subject based on the ideXlab platform.
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evaluation of normal cadaveric achilles tendon and Enthesis with ultrashort echo time ute magnetic resonance imaging and indentation testing
NMR in Biomedicine, 2019Co-Authors: Bimin Chen, Xin Cheng, Erik W Dorthe, Yinghua Zhao, Darryl D Dlima, G M Bydder, Sirun LiuAbstract:Entheses are regions where tendons and ligaments attach to bone, and are the primary target in seronegative and other diseases of the musculoskeletal (MSK) system. MRI has been widely used for visualizing features of inflammatory and degenerative MSK disease; however, normal tendons and entheses have short transverse relaxation times (T2 ), and show little or no signal with conventional clinical MRI pulse sequences, making it difficult to investigate their MR properties. In this study we examined the normal MR morphology of the cadaveric Achilles tendon and Enthesis at 3 T using novel three-dimensional ultrashort echo time (3D UTE) Cones sequences, and at 11.7 T using conventional MRI sequences. We also studied the MR properties of the Achilles tendon and Enthesis including T2 *, T1 , and magnetization transfer ratio (MTR). In addition, MT modeling of macromolecular proton fractions was investigated using 3D UTE Cones sequences at 3 T. Indentation testing was performed to investigate the mechanical properties of the tendons and entheses, and this was followed by histological examination. In total five specimens (<50 years) were investigated. On average, tendons and entheses respectively had T2 * values of 0.93 ± 0.48 ms and 2.77 ± 0.79 ms, T1 values of 644 ± 22 ms and 780 ± 55 ms, MTRs of 0.373 ± 0.03 and 0.244 ± 0.009 with an MT power of 1000° and frequency offset of 2 kHz, and macromolecular proton fractions of 18.0 ± 2.2% and 13.9 ± 1.9%. Compared with the tendon, the Enthesis generally had a longer T2 *, a longer T1 , a lower MTR, and a lower macromolecular proton fraction as well as both a higher Young's modulus and stiffness. Results from this study are likely to provide a useful baseline for identifying deviations from the normal in seronegative arthritis and other disease of the entheses.