on December 3, 2014
The study published in Immunity describes a mechanism regulating mucosal immune response in the gut, which is important to maintain the physiologic mutualism between our organism and the multitude of bacteria colonizing our intestine. The study was performed by a team of scientists led by Fabio Grassi from the Institute for Research in Biomedicine (IRB), which is affiliated to the Università della Svizzera italiana (USI), in collaboration with the Novartis Institute for Medical Research, the University of Bern, the Fondazione Filarete of Milan, the University of Camerino, the ETH Zurich and the University of Milan. The research was supported by the Swiss National Science Foundation, Nano-Tera.ch, Fondazione Ticinese per la Ricerca sul Cancro, Fondazione per la Ricerca sulla Trasfusione e sui Trapianti, Fondazione Cariplo and Converge Biotech.
Background
Our intestine is colonized by trillions of bacteria, referred to as the microbiome, which condition most pathways affecting our health, diseases and aging. Host physiology and diet influence the composition of the intestinal microbial community. Moreover, gut bacteria promote the development of the gut associated immune system (GALT), which is responsible for the production of immunoglobulin A (IgA), the most abundant antibodies in humans. IgAs are secreted in the gut lumen and ensure controlled mucosal colonization by the microbiome without pathologic invasion of the organism.
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Scanning electron microscopy showing villi of mouse small intestine (terminal ileum) colonized by filamentous bacteria (courtesy of Maura Francolini, Fondazione Filarete, Milan). |
Scanning electron microscopy showing a single villus of mouse small intestine (terminal ileum) colonized by filamentous bacteria (courtesy of Maura Francolini, Fondazione Filarete, Milan). |
The discovery
The results of this study are published in the last issue of Immunity and describe a mechanism regulating the extent of the antibody response to the microbiome and ensuring bacterial commensalism. The principal finding of the study is the identification of the role played by a receptor for adenosine triphosphate (ATP), P2X7, in T follicular helper (Tfh) cells of the Peyer’s patches in the small intestine. These cells are pivotal in controlling the excessive expansion of the microbiome by regulating the secretion of high affinity anti-microbial IgAs. Stimulation of P2X7 by ATP, the universal energy currency of cells that is also released in the extracellular space, results in the death of Tfh cells, thus limiting the secretion of IgA and permitting controlled colonization of the mucosa. Lack of this P2X7 mediated control results in excessive IgA response and depletion of bacteria from the intestine. An important consequence of the reduction of the mucosal bacterial load by P2X7 deficiency is the impairment of basal stimulation of the immune system. In fact, the authors also show that a physiological P2X7-dependent bacterial colonization of the intestinal mucosa determines the absorption of bacterial components into the blood, which tonically stimulate our systemic immune system. This tonic stimulation ensures protection of the organism in case of bacterial spread into the blood or other organs. Accordingly, mice deficient in P2X7 succumb to otherwise innocuous bacteriaemia. “The study also suggests a potential strategy for designing vaccine to elicit enhanced mucosal responses to protect the organism against selected pathogens” comments Fabio Grassi, senior author of the study.
About the Institute for Research in Biomedicine (IRB) and the Università della Svizzera italiana (USI). The Institute for Research in Biomedicine (IRB), founded in 2000 in Bellinzona, has been affiliated to the Università della Svizzera italiana (USI) in 2010. Financed by private and public institutions, and by competitive grants, the IRB currently hosts nine research groups and 95 researchers. Research focuses on the human host defense against infections, tumors and degenerative diseases. With more than 400 publications in leading scientific journals, the IRB has gained an international reputation as a center of excellence in immunology. www.irb.usi.ch
Article Reference:
ATP-Gated Ionotropic P2X7 Receptor Controls Follicular T Helper Cell Numbers in Peyer’s Patches to Promote Host-Microbiota Mutualism. Proietti M. et al. , Immunity, Volume 41, Issue 5, p789–801, 20 November 2014
