Dataset Information

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

ABSTRACT: Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R-deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment.

SUBMITTER: Jones GW

PROVIDER: S-EPMC4612100 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Jones Gareth W GW Bombardieri Michele M Greenhill Claire J CJ McLeod Louise L Nerviani Alessandra A Rocher-Ros Vidalba V Cardus Anna A Williams Anwen S AS Pitzalis Costantino C Jenkins Brendan J BJ Jones Simon A SA

The Journal of experimental medicine 20150928 11

Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the I ...[more]

PMID: 26417004

Similar Datasets

Project description:BACKGROUND: Ectopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive local antigen-dependent B cell development and autoantibody production. This process involves the expression of specific homing chemokines and the development of high endothelial venules (HEV). OBJECTIVE: To investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where autoantibodies have not been described and the organisation and function of B cells is not clear, and to analyse their clinical correlates. METHODS: Arthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis factor alpha blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral lymph node addressin (PNAd)-positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines in relation to the size of lymphoid aggregates. RESULTS: Lymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell segregation was often observed, and was correlated with the size of lymphoid aggregates. A close relationship between the presence of large and highly organised aggregates, the development of PNAd+ HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to treatment was associated with a regression of the LN features. CONCLUSIONS: LN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further investigation.

Project description:OBJECTIVES:National and international guidelines recommend prompt referral of patients presenting with inflammatory arthritis (IA), but general practitioners (GPs) feel uncertain in their proficiency to detect synovitis through joint examination, the method of choice to identify IA. Our objective was to develop and validate a rule composed of clinical characteristics to assist GPs and other physicians in identifying IA when in doubt. DESIGN:Split-sample derivation and validation study. SETTING:The Leiden Early Arthritis Recognition Clinic (EARC), a screening clinic for patients in whom GPs suspected but were unsure of the presence of IA. PARTICIPANTS:1288 consecutive patients visiting the EARC. PRIMARY AND SECONDARY OUTCOME MEASURES:Associations of clinical characteristics with presence of IA were determined using logistic regression in 644 patients, while validating the results in the other 644 patients (split-sample validation). To facilitate application in clinical practice, a simplified rule (with scores ranging from 0 to 7.5) was derived and validated. RESULTS:IA was identified by a rheumatologist in 41% of patients. In univariable analysis, male gender, age ≥60 years, symptom duration <6 weeks, morning stiffness >60 min, a low number of painful joints (1-3 joints), presence of patient-reported joint swelling and difficulty with making a fist were associated with IA in the derivation data set. Using multivariable analysis, a simplified rule consisting of these seven items was derived and validated, yielding an area under the receiver operator characteristic curve (AUC) of 0.74 (95% CI 0.70 to 0.78) in the derivation data set. Validation yielded an AUC of 0.71 (95% CI 0.67 to 0.75). Finally, the model was repeated to study predicted probabilities with a lower prevalence of inflammatory arthritis to simulate performance in primary care settings. CONCLUSIONS:Our rule, composed of clinical parameters, had reasonable discriminative ability for IA and could assist physicians in decision-making in patients with suspected IA, increasing appropriateness of healthcare utilisation.

Project description:BACKGROUND:Previous studies have identified critical roles of IL-27 in the pathological mechanisms of sepsis, and blockade of IL-27 may be a promising alternative therapy for sepsis. The purpose of this study was to evaluate the clinical relevance of IL-27 genetic polymorphisms in sepsis and to further characterize their effect on IL-27 expression and inflammatory processes following sepsis. METHODS:A total of 885 septic patients and 1101 healthy controls were enrolled and genotyped for IL-27 genetic variants (rs153109/-964A?>?G and rs17855750/2905 T?>?G). Quantitative real-time PCR and enzyme-linked immunosorbent assays were performed to detect IL-27 expression and cytokine production. The effect of the rs153109 polymorphism on IL-27 promoter activity was evaluated using a luciferase reporter assay, and THP-1 cell apoptosis was calculated using an annexin V apoptosis assay. RESULTS:No significant differences in the genotype/allele frequencies were observed between patients with sepsis and healthy controls, suggesting that these two IL-27 polymorphisms may not influence susceptibility to sepsis. The -964AA genotype was overrepresented in patients with severe sepsis/septic shock relative to patients with the sepsis subtype, and the A allele was significantly associated with 28-mortality in sepsis. Patients carrying the -964AA genotype exhibited significantly higher expression levels of IL-27 than the GA/GG genotype carriers. The results of an in vitro (lipopolysaccharide (LPS))-stimulated experiment showed that this sepsis-associated high-risk AA genotype significantly increased IL-27 levels and enhanced TNF-? and IL-1? production in the peripheral blood mononuclear cells (PBMCs) upon exposure to LPS in vitro. Furthermore, luciferase reporter assays indicated that the high-risk -964A allele resulted in increased promoter activities compared to the non-risk allele in THP-1 and 293 T cells. Additionally, IL-27 treatment significantly enhanced TNF-? and IL-6 secretion and apoptosis of THP-1 cells upon LPS stimulation. CONCLUSIONS:These results provided evidence that the IL-27 -964A?>?G polymorphism functionally enhanced IL-27 expression and promoted sepsis-induced inflammatory responses, which ultimately resulted in promoting the progression of sepsis and poor prognosis.

Dataset Information

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Publications

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets