Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate‐like T Cell Signature

Abstract

ObjectiveSpA patients often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate‐like T‐cells are involved in dysregulated interleukin (IL)‐23/IL‐17 responses in the gut‐joint axis in SpA.MethodsIleal and colonic intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL), and paired peripheral blood mononuclear cells (PBMC), were isolated from treatment‐naive non‐radiographic axial (nr‐ax)SpA patients with (n=11) and without (n=14) microscopic gut inflammation, and healthy controls (n=15), undergoing ileocolonoscopy. Presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate‐like T‐cells and conventional T‐cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL‐17A levels were measured via Luminex.ResultsMicroscopic gut inflammation in nr‐axSpA was characterized by increased ileal intraepithelial γδ‐hi‐T cells. γδ‐hi T cells were also increased in PBMC of nr‐axSpA patients versus healthy controls, and were strongly associated with ASDAS. The abundance of mucosal associated invariant T (MAIT)‐cells and invariant natural killer T (iNKT)‐cells was unaltered. Innate‐like T‐cells in the inflamed gut showed increased RORγt, IL‐17A and IL‐22 levels with loss of Tbet, a signature that was less pronounced in conventional T‐cells. Presence of gut inflammation was associated with higher serum IL‐17A levels. In patients treated with TNF blockade, the proportion of γδ‐hi cells and RORγt expression in blood was completely restored.ConclusionIntestinal innate‐like T‐cells display marked type 17 skewing in the inflamed gut mucosa of nr‐axSpA patients. γδ‐hi T cells are linked to intestinal inflammation and disease activity in SpA.This article is protected by copyright. All rights reserved.

Innate‐like T Cells: Connecting the Dots Linking Microscopic Intestinal Inflammation to Spondyloarthritis

“…A similar enrichment in the inflamed joints of patients with SpA of IL-17-producing innate-like T cells provides support for the existence of a "gut-synovial axis" (2,4). Intestinal dysbiosis, an imbalance of the microbiota, leads to increases in intestinal permeability, which has been implicated in the pathogenesis of several autoimmune conditions, such as type I diabetes, celiac disease, and inflammatory bowel disease (8).…”

“…Furthermore, we have shown that, although IFN γ-producing iNKT cells are protective against severe arthritis development in SKG mice, over time, the increased prevalence of NKT17 cells in the arthritic joints and draining lymph node positively correlates with disease severity (18). Unlike in synovial fluid, iNKT cells are too infrequent in the intestine of the patients with SpA to characterize them for transcription factor expression or function (2). Like γδT cells, MAIT cells in the intestine also are affected in patients with nonradiographic axial SpA (2), and increases in MAIT cells are found in synovial fluid of patients with SpA and patients with rheumatoid arthritis (19).…”

“…Axial SpA mainly affects the axial skeleton and is currently subdivided into two subtypes: radiographic and nonradiographic SpA (1). Mortier et al report in this issue of Arthritis & Rheumatology that γδT cells are selectively enriched in the ileal intraepithelial compartment from a subset of patients with nonradiographic axial SpA also displaying gut inflammation (2).…”

“…Given the enrichment of innate-like T cells in the intestine, it is plausible that these cells are associated with microscopic gut inflammation in axial SpA. Indeed, with a cohort of 25 patients and controls, Mortier et al show that γδT cells are selectively enriched in the ileal intraepithelial compartment from patients with nonradiographic axial SpA displaying gut inflammation (2). They further identify increases in a subset of gamma delta cells in both the circulation and intestine with higher expression of the T cell antigen receptor (TCR) γδ.…”