Ramnik xavier biography of mahatma gandhi
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Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase () expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased and decreased gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model usi
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Mahatma Gandhi
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Published in final edited form as: Cell Rep. Oct 2;9(1)– doi: /
Summary
Deficiencies in DNA degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease, Dnase2a, and observed elevated levels of undegraded DNA in both phagocytic and non-phagocytic cells. In non-phagocytic cells, the excess DNA originated from damaged DNA in the nucleus based on co-localization studies, live cell imaging and exacerbation by DNA-damaging agents. Removal of damaged DNA by Dnase2a required nuclear export and autophagy-mediated delivery of the DNA to lysosomes. Finally, DNA was found to accumulate in Dnase2a−/− or autophagy-deficient cells and induce inflammation via the Sting cytosolic DNA-sensing pathway. Our results reveal a cell-autonomous process for removal of damaged nuclear DNA with implications for conditions with elevated DNA damage, such as inflammation, cancer and chemotherapy.
Introduction
Mammalian cells express numerous nucleic sensors that detect and induce responses to invading viruses and other microbes (Barb