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

Abstract

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.

Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal

“…In these pilot studies, we foud that 12/61 patients with lupus exceeded the level in any of the tested control subjects (Mann-Whitney, p=0.03) (figure 1G). Furthermore, patients with lupus also displayed raised serum soluble CD14 (Welch test, p=0.0002) and raised α1-acid glycoprotein levels (Welch test, p<0.0001) (figure 1H, I), which in other conditions have been attributed to gut bacterial translocation 28 29. Taken together, these findings suggest that patients with lupus may at times experience impaired gut barrier function, which potentially may enable commensals, or their components, to escape the intestinal lumen.…”

Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects

“…82 By demonstrating the presence of significantly higher levels of circulating gut bacterial products in subjects with juvenile idiopathic arthritis, Fotis et al reinforced the concept that the intestine is a source of immune stimulation in arthritis. 83 Consistent with this hypothesis, Ciccia et al demonstrated increased zonulin expression, damaged intestinal mucosal barrier as well as gut vascular barrier in patients with ankylosing spondylitis. 84 Furthermore, they hypothesized that modulation of monocyte behavior by these bacterial products and zonulin may be the mechanism underlying the disease development.…”

SLE: reconciling heterogeneity

“…Stratification by clinical and serological phenotypes , demography and habits is qualitative, on disease activity measures quantitative 50–57. Stratification on sex, race, socioeconomic status,58–62 access to medical care, medication choice and adherence,63 willingness to participate in clinical trials, doctor–patient interactions,64 patient preferences and perceptions,65 lifestyle choices,66 67 physician choices,68–71 environmental triggers,72–76 poverty,77 social disparities,78 and life events,79 smoking80 and the gut pathobiont81 all affect manifestations and outcomes in ways that dictate who participates in a study on SLE and in ways that cannot be examined in animal models 82. Stratification on gene expression , quantitative, predicts risk and possibly phenotype83–93; SLE-like illnesses (the autoinflammatory diseases),94 Aicardi-Goutières syndrome,95 96 Canale-Smith syndrome97 and SLE associated with immunodeficiency98 suggest mechanisms for primary illness, and for phenotype diversity.…”