Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

Benham, Helen; Rehaume, Linda; Hasnain, Sumaira Z.; Velasco, J. García; Baillet, Athan; Ruutu, Merja; Kikly, Kristine; Wang, Ran; Tseng, Hsu‐Wen; Thomas, Gethin; Brown, Matthew A.; Strutton, Geoffrey; McGuckin, Michael A.; Thomas, Ranjeny

doi:10.1002/art.38638

Cited by 180 publications

(138 citation statements)

References 55 publications

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“…Mice with an activating mutation in the SH2 domain of this molecule develop axial and peripheral arthritis, which is suppressed in the absence of IL17. Furthermore, studies in SKG mice (ZAP-70 knockout model) have demonstrated that the development of the joint, bone, entheseal, and dactylitic inflammation in these mice is IL23 mediated [25]. Thus, emerging data in animal models implicate an important role for the IL17/IL23 axis in the pathophysiology of psoriasis, enthesitis, synovitis, and abnormal bone turnover in PsA.…”

Section: Il23 and Psoriatic Arthritismentioning

confidence: 99%

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Mortezavi

Ritchlin

2015

Curr Treat Options in Rheum

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Section: Il23 and Psoriatic Arthritismentioning

confidence: 99%

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Mortezavi

Ritchlin

2015

Curr Treat Options in Rheum

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“…In the SKG model, mice develop peripheral and axial arthritis, unilateral uveitis, ileitis and psoriasis like skin inflammation in response to intraperitoneal injection of β-1,3-glucan [40]. The severity of peripheral arthritis, spondylitis and enthesitis is significantly reduced in IL-17A−/− SKG mice and SKG mice treated with anti-IL-23 [41].…”

Section: Evidence From Murine Models Of Pso and Psamentioning

confidence: 95%

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

2015

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Investigators have accrued compelling evidence that the IL-17 pathway is central to the pathogenesis of psoriasis and psoriatic arthritis. The evidence comprises genome-wide association studies (GWAS), data from experimental murine models and findings from in vitro studies on patients' cells or tissue biopsies. More recently, the success of drugs blocking the IL-17 pathway in treating both psoriasis (PsO) and psoriatic arthritis (PsA) confirms that IL-17 is a clinically relevant therapeutic target. However, there remain many unanswered questions: is PsA simply an extension of PsO from the skin to the synovial tissue or are there differences in the underlying pathogenesis of these diseases? Which cell type represents the primary source of IL-17 in PsO and PsA? And how are these cells regulated? This review outlines the IL-17 pathway, summarises the evidence supporting its role in PsO and PsA and discusses recent data that may help to address these yet unresolved questions.

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“…(191). An intestinal Th17 response has been shown to trigger inflammatory arthritis with bony spur formation in a spondyloarthritis mouse model (208). Thus the NLRP family are a potential link between innate inflammation and Th17 induced bone formation in AS.…”

Section: Resultsmentioning

confidence: 99%

Determinants of radiographic severity in ankylosing spondylitis

Truong¹

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Ankylosing Spondylitis (AS) is a highly heritable condition characterised by excessive bone formation and stiffness of the spine and pelvis causing functional impairment. Functional impairment is strongly correlated with radiographic signs of bone formation. Clinicians can accurately measure bone formation but have a limited ability to predict or prevent it.A small number of non-genetic factors have been identified that explain approximately one third of the variation in radiographic severity. No genetic predictors of radiographic severity have consistently been identified.This work investigates the contribution of non-genetic and genetic factors to radiographic severity. Knowledge of causal genetic variants could be used to predict prognosis or to design therapeutics. Spinal radiographs were scored using the modified Stoke Ankylosing Spondylitis Severity Score (or a modified version of this score), mostly by a single calibrated reader.Observed modified Stoke Ankylosing Spondylitis Severity Scores were compared between males and females. Cross-sectional modelling was performed on 1392 subjects by comparing previously recorded clinical covariates and demographics with the latest radiographic score for each patient, using a negative binomial model. Residuals from this model were considered to be the phenotype corrected for known covariates. A quantitative Genome Wide Association Study (GWAS) was performed on 1253 cases, comparing the corrected phenotype with millions of genetic markers per subject. Genomewide Complex Trait Analysis (GCTA) was used to estimate the contribution of common variants with small effect sizes to the phenotype. An allelic risk score approach was used to examine the hypothesis that known bone mineral density, height, AS susceptibility and smoking dependence related loci also affect AS radiographic severity.ii Known contributors to radiographic severity -gender, smoking and symptom duration were found to explain approximately one-third of phenotypic variation. GCTA estimated that common variants contribute at least 33% of phenotypic variation. No signal was identified to link known contributors to AS susceptibility, including the MHC region, with radiographic severity. Known AS susceptibility, BMD, height and smoking dependence loci were not associated with severity upon allelic risk score analysis. GWAS suggested that loci involved in bone metabolism and innate inflammation may influence radiographic severity.Some genes in the same pathways as AS susceptibility loci, including the TNF pathway, had a suggestive association with the phenotype. Additionally suggestive associations between loci related to bone formation and immune-microbiota interactions in the gut were present, which, if confirmed, may provide a mechanism for observed patterns of microbiota in human AS cases.This study did not definitively associate any specific loci with the phenotype, probably due to its low power and limitations of the phenotype modelling. Modelling was limited to a cross-sectional analysis, slightl...

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Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

Cited by 180 publications

References 55 publications

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

Determinants of radiographic severity in ankylosing spondylitis

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