Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 212, Issue 11, Pages 1793-1802Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132307
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Funding
- Arthritis Research UK [20770, 20305, 19796, 19381, 18286]
- Wellcome Trust ISSF Seedcorn Award
- Wellcome Trust ISSF Mobility Award
- National Health and Medical Research Council (NHMRC, Australia)
- Operational Infrastructure Support Program by the Victorian Government of Australia
- Senior Medical Research Fellowships - Sylvia and Charles Viertel Foundation
- NHMRC
- MRC [MR/N003063/1, G0800648, MR/K020250/1] Funding Source: UKRI
- Medical Research Council [G0800648, MR/K020250/1, MR/N003063/1] Funding Source: researchfish
- Versus Arthritis [20305, 19381, 20770] Funding Source: researchfish
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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.
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