Histopathological features of gastrointestinal mucosal biopsies in children with juvenile idiopathic arthritis

Pichler, Judith; Ong, Christina; Shah, Neil; Sebire, Neil J.; Kiparrissi, Fevronia; Borrelli, Osvaldo; Pilkington, Clarissa; Elawad, Mamoun

doi:10.1038/pr.2016.27

Cited by 19 publications

(19 citation statements)

References 35 publications

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“…Given the observed expression of CCR9 and α4β7 on CD161 + Tconv and CD161 + Treg in blood, and the suggested link between arthritis and gut inflammation (50–57), we next examined the expression of these receptors on CD161 + Tconv and CD161 + Treg from patients with autoimmune arthritis. Ex vivo analysis showed significantly higher percentages of CCR9 + and integrin α4 + β7 + cells within CD161 + Tconv (Figure 7A) and CD161 + Treg (Figure 7B) compared to their CD161 − counterparts in blood of JIA patients.…”

Section: Resultsmentioning

confidence: 99%

CD161+ Tconv and CD161+ Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire

et al. 2017

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Human regulatory T cells (Treg) are important in immune regulation, but can also show plasticity in specific settings. CD161 is a lectin-like receptor and its expression identifies an effector-like Treg population. Here, we determined how CD161+ Treg relate to CD161+ conventional T cells (Tconv). Transcriptional profiling identified a shared transcriptional signature between CD161+ Tconv and CD161+ Treg, which is associated with T helper (Th)1 and Th17 cells, and tissue homing, including high expression of gut-homing receptors. Upon retinoic acid (RA) exposure, CD161+ T cells were more enriched for CCR9+ and integrin α4+β7+ cells than CD161− T cells. In addition, CD161+ Tconv and CD161+ Treg were enriched at the inflamed site in autoimmune arthritis, and both CD161+ and CD161− Treg from the inflamed site were suppressive in vitro. CD161+ T cells from the site of autoimmune arthritis showed a diminished gut-homing phenotype and blunted response to RA suggesting prior imprinting by RA in the gut or at peripheral sites rather than during synovial inflammation. TCRβ repertoires of CD161+ and CD161− Tconv and Treg from blood showed limited overlap whereas there was clear overlap between CD161+ and CD161− Tconv, and CD161+ and CD161− Treg from the inflamed site suggesting that the inflamed environment may alter CD161 levels, potentially contributing to disease pathogenesis.

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Section: Resultsmentioning

confidence: 99%

CD161+ Tconv and CD161+ Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire

et al. 2017

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“…Our findings of elevated concentrations of circulating LBP and anti-core LPS antibodies in patients with spondyloarthropathies are also consistent with the observation that many such patients have subclinical intestinal inflammation (30). Also, there are recent reports of histologically determined intestinal inflammation in JIA patients (7). The same finding has been confirmed in patients with spondylarthropathies (31), a group where elevated levels of acute phase reactants and anti-LPS were also observed.…”

Section: Discussionmentioning

confidence: 99%

“…Intestinal immune activation in JIA patients is manifest as lymphonodular hyperplasia and increased tissue γ/δ+ and cytotoxic lymphocyte populations (3,4). Additionally, JIA patients have defective intestinal barrier function (5,6), and many children with JIA and abdominal pain have evidence of microscopic colitis (7). Also, exclusive enteral nutrition, which induces remission in Crohn’s disease, has been beneficial in patients with JIA (8), and associations between gut microbiome alterations and JIA have recently been reported (9–11).…”

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confidence: 99%

Serologic Evidence of Gut-driven Systemic Inflammation in Juvenile Idiopathic Arthritis

et al. 2017

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Objective Accumulating evidence links juvenile idiopathic arthritis (JIA) to non-host factors such as gut microbes. We hypothesize that children with new-onset JIA have increased intestinal bacterial translocation and circulating LPS. Methods We studied systemic treatment-naive JIA patients (poly-articular JIA, n=22, oligo-articular JIA, n=31 and spondyloarthropathies, n=16), patients with established inflammatory bowel disease and arthritis (IBD-RA, n=11), and 34 healthy controls. We determined circulating IgG reactivity against LPS, LPS binding protein (LBP), alpha-1-acid glycoprotein (A1AGP), and C-reactive protein (CRP) in plasma or serum from these patients and controls. JADAS27 scores were calculated for patients with JIA. Results Circulating anti-core LPS antibody concentrations in patients with poly-articular JIA (p=0.001), oligo-articular JIA (p=0.024), and spondyloarthropathies (p=0.001) were significantly greater than in controls, but there were no significant inter-group differences. Circulating LBP concentrations were also significantly greater in patients with poly-articular JIA (p=0.001), oligo-articular JIA (p=0.002), and spondyloarthropathies (p=0.006) than controls, as were A1AGP concentrations (p=0.001, 0.001, and 0.003, respectively). No differences were observed between controls and IBD-RA patients in any of the assays. Circulating concentrations of LBP and A1AGP correlated strongly with CRP concentrations (r=0.787 and r=0.635 respectively). Anti-core LPS antibody levels and CRP (r=0.26), LBP (r=0.24) and A1AGP (r=0.22) concentrations had weaker correlations. JADAS27 scores correlated with LBP (r=0.66) and A1AGP concentrations (r=0.58). Conclusion Children with poly-articular JIA, oligo-articular JIA, and spondylarthropathies have evidence of increased exposure to gut bacterial products. These data reinforce the concept that the intestine is a source of immune stimulation in JIA.

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“…Increases in intestinal permeability have also been reported in children with JIA -it appears to be a common consequence of microscopic colitis 16,17,18 . Lipopolysaccharide (LPS), a potent immune-activating factor from many aerobic gram-negative rods, is known to activate innate cells such as neutrophils and macrophages.…”

Section: Is Gut Microbial Lps a Potential Trigger Of Juvenile Idiopatmentioning

confidence: 95%

Is Gut Microbial LPS a Potential Trigger of Juvenile Idiopathic Arthritis?

Azzouz

Silverman

2017

J Rheumatol

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Histopathological features of gastrointestinal mucosal biopsies in children with juvenile idiopathic arthritis

Cited by 19 publications

References 35 publications

CD161+ Tconv and CD161+ Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire

CD161+ Tconv and CD161+ Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire

Serologic Evidence of Gut-driven Systemic Inflammation in Juvenile Idiopathic Arthritis

Is Gut Microbial LPS a Potential Trigger of Juvenile Idiopathic Arthritis?

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