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Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production., Introduction It is widely believed that the innate immune system mediates the acute response to an infectious agent, but recent work shows that this response can also translate acute infection [...]

The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic [Foxp3.sup.+] regulatory T ([T.sub.reg]) cells (1). However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease (2-4). Here we show that encounter with commensal microbiota results in the peripheral generation of [T.sub.reg] cells rather than pathogenic effectors. We observed that colonic [T.sub.reg] cells used T-cell antigen receptors (TCRs) different from those used by [T.sub.reg] cells in other locations, implying an important role for local antigens in shaping the colonic [T.sub.reg]-cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon [T.sub.reg] TCRs. These TCRs did not facilitate thymic [T.sub.reg]-cell development, implying that many colonic [T.sub.reg] cells arise instead by means of antigen-driven peripheral [T.sub.reg]-cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimaeras and a TCR transgenic line revealed that microbiota indigenous to our mouse colony was required for the generation of colonic [T.sub.reg] cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo [T.sub.reg]-cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of [T.sub.reg] cells in response to an individual's microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota., Although [T.sub.reg] cells are required for the maintainenance of gut tolerance (3), commensal bacteria are not necessary for colonic [T.sub.reg]-cell generation (5,6 ) (Supplementary Fig. 1). Moreover, [T.sub.reg] cells from [...]

Associations between the dynamic community of microbes (the microbiota) and the host they colonize appear to be vital for ensuring host health. Microbe-host communication is actively maintained across physiological barriers of various body sites and is mediated by a range of bidirectional secreted proteins and small molecules. So far, a range of “omics” methods have succeeded in revealing the multiplicity of associations between members of a microbiota and a wide range of host processes and diseases. Although these advances point to possibilities for treating disease, there has not been much translational success thus far. We know little about which organisms are key contributors to host health, the importance of strain differences, and the activities of much of the chemical “soup” that is produced by the microbiota. Adding to this complexity are emerging hints of the role of interkingdom interactions between bacteria, phages, protozoa, and/or fungi in regulating the microbiota-host interactions. Functional approaches, although experimentally challenging, could be the next step to unlocking the power of the microbiota. [ABSTRACT FROM AUTHOR]

Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci (1). One Crohn's disease risk allele is in ATG16L1, a gene homologous [...]

Background The constellation of human inflammatory bowel disease (1131D) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of 1131D. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human 1131D have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe 1131D models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. Methods and Findings We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflarnmatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics. Conclusions Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflarnmatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease. The Editors' Summary of this article follows the references., Introduction Inflammatory bowel disease JBD) is an idiopathic disease of the intestinal tract with the hallmark features of mucosal inflammation and loss of barrier function. Although the exact mechanisms for [...]

We identified cellular and molecular mechanisms within the stem cell niche that control the activity of colonic epithelial progenitors (ColEPs) during injury. Here, we show that while WT mice maintained [...]