Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling.
We used capture/recapture methods to test the responses of two small mammal species (Peromyscus leucopus and Microtus pennsylvanicus) to small- (microhabitat) and large- (patch) scale habitat variation. Analyses examined the responses of individuals to microhabitat variation among trap stations as well as differences in the density and persistence time of adults and juveniles, and the proportion of reproductive females on experimentally created patches of three sizes (0.0625, 0.25, and 1.0 ha). With the exception of transient P. leucopus, all groups shared significant correlations with microhabitat at the scale of trap stations. By contrast, only juvenile P. leucopus exhibited a response to patch-size (i.e., higher densities on small relative to larger patches). Microhabitat differences among patches also accounted for variation in M. pennsylvanicus densities (but not P. leucopus) in analyses of covariance. Our results suggest that both individuals and populations of M. pennsylvanicus responded to habitat variation at the microhabitat scale, while P. leucopus appeared to respond to both microhabitat and patch scale habitat variation. We note that species characteristics (particularly relative dispersal ability) may prove critical in predicting the scale of habitat responses. We conclude by noting that current theory that assumes uniform responses of population to homogeneous patches is too simplistic to be of much predictive value in field tests.
Regulatory T cells (Tregs) control inflammation and maintain immune homeostasis. The well-characterised circulatory population of CD4+Foxp3+ Tregs is effective at preventing autoimmunity and constraining the immune response, through direct and indirect restraint of conventional T cell activation. Recent advances in Treg cell biology have identified tissue-resident Tregs, with tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair. A population of brain-resident Tregs, characterised as CD69+, has recently been identified in the healthy brain of mice and humans, with rapid population expansion observed under a number of neuroinflammatory conditions. During neuroinflammation, brain-resident Tregs have been proposed to control astrogliosis through the production of amphiregulin, polarize microglia into neuroprotective states, and restrain inflammatory responses by releasing IL-10. While protective effects for Tregs have been demonstrated in a number of neuroinflammatory pathologies, a clear demarcation between the role of circulatory and brain-resident Tregs has been difficult to achieve. Here we review the state-of-the-art for brain-resident Treg population, and describe their potential utilization as a therapeutic target across different neuroinflammatory conditions.
Abstract Although thymic ectopy has long been recognized in humans, the functional activity or potential immunological significance of this thymic tissue is unknown. In this study, we describe murine thymic ectopy, cervical thymic tissue that possesses the same general organization as the thoracic thymus, that is able to support T cell differentiation, and that can export T cells to the periphery. Unexpectedly, the pattern of autoantigen expression by ectopic thymic tissue differs from that of the thoracic thymus, raising the possibility that these two thymic environments may project different versions of self.
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