134: Interleukin-27 as a novel antagonist of ectopic lymphoid-like structure development in early inflammatory arthritis

Abstract

Evaluation of joint tissue from early inflammatory arthritis patients through ultrasound-guided synovial biopsy has enabled disease classification based on local pathology. For example, the disease can be classed as fibroblast-, myeloid- or lymphoid-driven. Lymphoid histopathology can be further divided into patients displaying either diffuse infiltrates, or ectopic lymphoid-like structures (ELS) reminiscent of the follicular compartments in secondary lymphoid organs. Approximately 25% of rheumatoid arthritis (RA) patients develop ELS and display severe symptoms associated with local immune cell priming and autoantibody production. However, cytokine control of ELS development in inflammatory arthritis is poorly defined. Interleukin (IL)-27 is a negative regulator of adaptive immune responses. To investigate the role of IL-27 in inflammatory arthritis, wild type (WT) and IL-27 receptor (IL-27R)-deficient mice were exposed to antigen-induced arthritis. IL-27R-deficient mice developed exacerbated inflammatory arthritis, displaying increased synovial infiltrate, hypertrophy and bone erosions. Heightened peripheral T H 17- and B-cell responses in IL-27R-deficiency were reflected in increased serum IL-17 levels and antigen-specific IgG titers. Strikingly, IL-27R-deficient mice developed synovial histopathology reminiscent of RA patients with ELS, comprising synovial lymphoid aggregates with distinct T-cell (CD3 + ), B-cell (B220 + ) and DC (F/480 + , CD21 + ) areas that were absent in WT mice. Development of lymphoid aggregates was associated with elevated synovial expression of homeostatic chemokines that promote ectopic lymphoneogenesis (e.g. Cxcl13, Ccl21 ) and the transcriptional regulator Bcl-6 , which is involved in germinal center organization and functional regulation. Ectopic lymphoneogenesis in IL-27R-deficient mice was not associated with an increase in synovial IL-6 or IL-21 expression. Studies in clinical RA patients reflect our experimental outcomes and reveal reduced synovial IL-27 expression in patients with joint histopathology comprising ELS compared to patients with diffuse lymphocytic infiltrates. Thus, IL-27 may negatively regulate the formation of ELS in human pathologies such as RA and represents a potential biomarker of synovial histopathology in early RA.