Expansion of Interleukin‐22– and Granulocyte–Macrophage Colony‐Stimulating Factor–Expressing, but Not Interleukin‐17A–Expressing, Group 3 Innate Lymphoid Cells in the Inflamed Joints of Patients With Spondyloarthritis

Abstract

Objective Clinical trials of the anti–interleukin‐17A (anti– IL ‐17A) antibody secukinumab have demonstrated a crucial role of the cytokine IL ‐17A in the pathogenesis of spondyloarthritis (SpA); however, its cellular source in this condition remains a matter of controversy. Group 3 innate lymphoid cells ( ILC 3s) have been recently identified as potent producers of proinflammatory cytokines, including IL ‐17A and IL ‐22, in a number of different tissues. This study was undertaken to characterize the presence and composition of ILC s, and investigate whether these cells are an important source of IL ‐17A, in the synovial tissue ( ST ) of patients with SpA. Methods Matched ST , synovial fluid, and peripheral blood ( PB ) samples were obtained from SpA patients with actively inflamed knee joints. ILC subsets were characterized by flow cytometry. Gene expression analysis at the single‐cell level was performed directly ex vivo and after in vitro activation. An IL ‐17A enzyme‐linked immunospot assay was used to detect IL ‐17A–secreting cells. Results ILC s, and particularly NK p44+ ILC 3s, were expanded in inflamed arthritic joints. Single‐cell expression analysis demonstrated that ST ILC s were clearly distinguishable from ST T cells and from their PB counterparts. Expression of the Th17 signature transcripts RORC , AHR , and IL 23R was detected in a large proportion of ST ILC 3s. These cells were capable of inducing expression of IL 22 and CSF 2 , but not IL 17A , in response to in vitro restimulation. Conclusion Our findings demonstrate that absolute and relative numbers of ILC 3s are enriched in the synovial joints of patients with SpA. However, these cells are not a significant source of IL ‐17A in this disease.

Interleukin‐17A Is Produced by CD4+ but Not CD8+ T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis

“…Group 3 ILCs were another cell type that has been reported as a potential source of IL-17A in PsA SF (15). However, a recent study showed that although these group 3 ILCs are expanded in inflamed arthritis joints, they have failed to express IL-17A upon in vitro stimulation (16). These findings are similar to our observations with regard to CD8+ T cells.…”

“…However, it is still not clear which of the above cell types is the main producer of IL-17A in local joints affected with PsA. Recently, it was reported that ILC3s fail to express IL-17A upon in vitro stimulation in joints affected with spondyloarthritis (16). Nevertheless, direct ex vivo comparison of IL-17A production upon T cell receptor (TCR) activation by CD4+ and CD8+ T cells has yet to be performed using PsA SF specimens.…”

Innate lymphoid cells in inflammatory arthritis

“…In addition, GM-CSF-producing ILC3s were also found to be expanded in the synovial tissue of SpA patients [44]. Consistently, a very recent study confirmed NKp44 + ILC3s were accumulated in the inflamed joints of peripheral SpA patients [45]. Although expression of Th17 signature transcripts such as RORC, AHR, and IL-23R were identified in a large proportion of synovial tissue ILC3s, these cells produce IL-22 and GM-CSF but not IL-17, suggesting they are not a significant source of IL-17 in SpA [45].…”

WITHDRAWN: Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cell populations, serum cytokine/chemokines, and treatment response to methotrexate in rheumatoid arthritis and spondyloarthritis

“…The numbers of ILC1 and ILC3 have been reported to be increased in the peripheral blood, synovial uid, and lymph node in patients with RA and juvenile idiopathic arthritis (JIA) [21,22], whereas the number of peripheral ILC2 was decreased [23]. On the other hand, ILC3 has been shown to be present in the healthy entheses and perientheseal bone and expand in the peripheral blood, gut, synovial uid, or bone marrow in SpA patients and produce key in ammatory cytokines related to SpA [24][25][26][27][28][29]. Although these reports indicate that ILCs are involved in the pathophysiology of RA and SpA, the associations between ILCs and the patterns of musculoskeletal in ammation are unknown.…”