Innate Lymphoid Cells and T Cells Contribute to the Interleukin‐17A Signature Detected in the Synovial Fluid of Patients With Juvenile Idiopathic Arthritis

Abstract

Objective Evidence suggests that aberrant function of innate lymphoid cells (ILCs), whose functional and transcriptional profiles overlap with those of Th cell subsets, contributes to immune‐mediated pathologies. To date, analysis of juvenile idiopathic arthritis (JIA) immune pathology has concentrated on the contribution of CD4+ T cells; we have previously identified an expansion of Th17 cells within the synovial fluid (SF) of JIA patients. We undertook this study to extend this analysis to further investigate the role of ILCs and other interleukin‐17 (IL‐17)–producing T cell subsets in JIA. Methods ILCs and CD3+ T cell subsets were defined in peripheral blood mononuclear cells (PBMCs) from healthy adults, healthy children, and JIA patients and in SF mononuclear cells (SFMCs) from JIA patients using flow cytometry. Defined subsets in SFMCs were correlated with clinical measures including physician's global assessment of disease activity on a visual analog scale, number of joints with active disease, and erythrocyte sedimentation rate. Transcription factor and cytokine profiles of sorted ILCs were assessed by quantitative reverse transcriptase–polymerase chain reaction. Results Group 1 ILCs (ILC1s), NKp44− group 3 ILCs (natural cytotoxicity receptor–negative [NCR−] ILC3s), and NKp44+ ILC3s (NCR+ ILC3s) were enriched in JIA SFMCs compared to PBMCs, which corresponded to an increase in transcripts for TBX21, IFNG, and IL17A. Of the ILC subsets, the frequency of NCR− ILC3s in JIA SFMCs displayed the strongest positive association with clinical measures, which was mirrored by an expansion in IL‐17A+CD4+, IL‐17A+CD8+, and IL‐17A+ γδ T cells. Conclusion We demonstrate that the strength of the IL‐17A signature in JIA SFMCs is determined by multiple lymphoid cell types, including NCR− ILC3s and IL‐17A+CD4+, IL‐17A+CD8+, and IL‐17A+ γδ T cells. These observations may have important implications for the development of stratified therapeutics.

Association between the polymorphism of IL-17A and IL-17F gene with knee osteoarthritis risk: a meta-analysis based on case-control studies

“…Recent studies have suggested that knee OA might be considered a chronic inflammatory disorder, elevated levels of IL-1, IL-6, IL-17,TNF-α, and other acute-phase proteins that are found in patients with cartilage degradation [25]. A kind of conventional viewpoint is that inflammatory mechanism plays a crucial role in the pathogenesis and evolution of cartilage degeneration and expression of inflammatory reaction [26][27][28]. IL-17 is one of the most important regulators of innate and adaptive immune responses, and it is expressed in synovial tissues, and could contribute to cartilage degeneration and synovial infiltration in joint by inducing the release of chemokines by chondrocytes [29,30].…”

The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases

“…When patients were divided according to treatment, DN and γδ T cell levels were significantly lower (p = 0.001, p = 0.02, respectively) in patients receiving methotrexate (MTX) than in patients not receiving MTX [71]. However, in another study of JIA, 80% of CD4 -CD8of T cells were γδ T cells and γδ cells secreting IL-17 were positively correlated with innate lymphoid cells (ILC) type 3 secreting IL-17, which in turn correlated with disease severity by physician visual analogue score (VAS) [72]. In another study, when analyzed in relation to subsets of JIA, an elevated percentage of γδ T cells in PB was found in quiescent systemic JIA which decreased in active disease [73].…”

Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

“…Once it occurs in the joint, inflammatory Th cell activation can occur independent of conventional TCR signaling . Thinking along such lines may also explain recent findings in patients with oligoarticular or polyarticular JIA, in whom an IL‐17 signature in synovial fluid is driven by a whole potpourri of contributors comprising γδ T lymphocytes and receptor‐negative innate lymphoid cells, but also CD4+ and CD8+ lymphocytes .…”