The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.
TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.
Summary Intestinal epithelial cells (IECs) and dendritic cells (DCs) play a pivotal role in antigen sampling and the maintenance of gut homeostasis. However, the interaction of commensal bacteria with the intestinal surface remains incompletely understood. Here we investigated immune cell responses to commensal and pathogenic bacteria. HT‐29 human IECs were incubated with Bifidobacterium infantis 35624, Lactobacillus salivarius UCC118 or Salmonella typhimurium UK1 for varying times, or were pretreated with a probiotic for 2 hr prior to stimulation with S. typhimurium or flagellin. Gene arrays were used to examine inflammatory gene expression. Nuclear factor (NF)‐κB activation, interleukin (IL)‐8 secretion, pathogen adherence to IECs, and mucin‐3 (MUC3) and E‐cadherin gene expression were assayed by TransAM assay, enzyme‐linked immunosorbent assay (ELISA), fluorescence, and real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR), respectively. IL‐10 and tumour necrosis factor (TNF)‐α secretion by bacteria‐treated peripheral blood‐derived DCs were measured using ELISA. S. typhimurium increased expression of 36 of the 847 immune‐related genes assayed, including NF‐κB and IL‐8. The commensal bacteria did not alter expression levels of any of the 847 genes. However, B. infantis and L. salivarius attenuated both IL‐8 secretion at baseline and S. typhimurium‐induced pro‐inflammatory responses. B. infantis also limited flagellin‐induced IL‐8 protein secretion. The commensal bacteria did not increase MUC3or E‐cadherin expression, or interfere with pathogen binding to HT‐29 cells, but they did stimulate IL‐10 and TNF‐α secretion by DCs. The data demonstrate that, although the intestinal epithelium is immunologically quiescent when it encounters B. infantis or L. salivarius, these commensal bacteria exert immunomodulatory effects on intestinal immune cells that mediate host responses to flagellin and enteric pathogens.
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