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Gut reactions: immune pathways in the intestine in health and disease.

Powrie F - EMBO Mol Med (2012)

View Article: PubMed Central - PubMed

Affiliation: Experimental Medicine Division, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. fiona.powrie@path.ox.ac.uk

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How in the vast majority of us it steadfastly protects from pathogens but in others, it turns on our own tissues or innocuous environmental antigens leading to autoimmune and chronic inflammatory diseases... As Th2 cells had been shown to reciprocally regulate the Th1 response, it seemed likely that differential activation of Th2 responses might explain Treg activity... However, we found that Treg function was IL-4-independent but required TGF-β production (Powrie et al, )... Key advances in the molecular control of Treg function have shown that Treg cells adapt to environmental conditions and utilize a range of suppressive mechanisms that are tuned to the inflammatory responses they control. »…Treg cells adapt to environmental conditions and utilize a range of suppressive mechanisms that are tuned to the inflammatory responses they control. « The T-cell transfer model of colitis together with a number of genetic models of chronic intestinal inflammation, illustrated the importance of balance between inflammatory and regulatory pathways for intestinal health... The complex and poorly characterized interactions between the intestinal immune system and commensal bacteria captivated me and this area has become the focus of my current research... Our results have shown that Foxp3+ Treg cells are abundant in the intestine and produce high levels of the immune suppressive cytokine interleukin 10 (IL-10), which is required for the control of intestinal homeostasis (Asseman et al, )... We also found that the intestine is a specific site for the generation of Treg cells reactive with intestinal antigens through the actions of specialized dendritic cells, the vitamin A metabolite retinoic acid and TGF-β (Coombes and Powrie, )... Indeed the capacity of the intestinal immune system to favour Treg induction and production of IL-10 may be an important component of host commensal mutualism, preventing deleterious inflammatory responses to intestinal bacteria... Like Th17 cells, IL-23-driven ILC are dependent on the transcription factor retinoic acid receptor related orphan receptor gamma t (RORγt) indicating striking functional parallels between innate and adaptive lymphoid populations in the gut (Buonocore et al, )... Together these results highlight the multiple activities of IL-23 that mediate tissue inflammatory responses (Fig 1)... In IBD, genetically controlled malfunctions in a number of different pathways including intestinal barrier function, host defence and innate and adaptive inflammatory pathways, predispose to a dysregulated interplay between the microbiota and the intestinal immune system... The complex clinical and genetic subtypes in IBD, taken together with the individuality of the intestinal microbiota, raise formidable challenges ahead as we try to apply findings from experimental models to the development of novel therapies for IBD... Further understanding of individuality and commonality in IBD aetiology and pathogenesis is required to identify subgroups of patients that may benefit from more tailored therapeutic approaches... Towards this goal, in 2009 I was appointed as the Sidney Truelove Professor of Gastroenterology at Oxford to translate findings from fundamental mucosal immunology to the study of IBD... Advances in molecular microbiology, genetics and analysis of human clinical samples offer great hope that we can apply our growing knowledge of immune system bacterial interactions towards enhanced therapies for these devastating clinical conditions.

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Intestinal homeostasis and its breakdown in chronic colitisUnder homeostatic conditions RORγt expressing lymphoid cells including Th17 cells, γδ T cells and innate lymphoid cells promote host defence and repair. IL-10 secreting Treg cells are abundant and prevent pathological inflammatory responses. In colitis, sustained IL-23 production in response to colitogenic bacteria promote pathological Type 17 responses with elaboration of inflammatory cytokines and repression of the Treg response.
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fig01: Intestinal homeostasis and its breakdown in chronic colitisUnder homeostatic conditions RORγt expressing lymphoid cells including Th17 cells, γδ T cells and innate lymphoid cells promote host defence and repair. IL-10 secreting Treg cells are abundant and prevent pathological inflammatory responses. In colitis, sustained IL-23 production in response to colitogenic bacteria promote pathological Type 17 responses with elaboration of inflammatory cytokines and repression of the Treg response.

Mentions: Deficiencies in regulatory pathways in the presence of triggering intestinal bacteria can lead to chronic intestinal inflammation. Initially thought to be driven by an interleukin 12 (IL-12)-dependent Th1 response, Kevin Maloy and I made the unanticipated observation in collaboration with Dan Cua and colleagues at DNAX, of a functional role for the IL-12 family cytokine, interleukin 23 (IL-23), as key driver of T-cell transfer colitis (Ahern et al, 2008). Further analysis of this pathway led to the identification of a novel population of innate lymphoid cells (ILC) that mediate colitis through the production of Type-17 associated cytokines. Like Th17 cells, IL-23-driven ILC are dependent on the transcription factor retinoic acid receptor related orphan receptor gamma t (RORγt) indicating striking functional parallels between innate and adaptive lymphoid populations in the gut (Buonocore et al, 2010). Together these results highlight the multiple activities of IL-23 that mediate tissue inflammatory responses (Fig 1). Further understanding of the molecular signatures associated with interleukin 23 receptor (IL-23R) signalling in lymphoid cells may provide novel therapies in inflammatory disease.


Gut reactions: immune pathways in the intestine in health and disease.

Powrie F - EMBO Mol Med (2012)

Intestinal homeostasis and its breakdown in chronic colitisUnder homeostatic conditions RORγt expressing lymphoid cells including Th17 cells, γδ T cells and innate lymphoid cells promote host defence and repair. IL-10 secreting Treg cells are abundant and prevent pathological inflammatory responses. In colitis, sustained IL-23 production in response to colitogenic bacteria promote pathological Type 17 responses with elaboration of inflammatory cytokines and repression of the Treg response.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376842&req=5

fig01: Intestinal homeostasis and its breakdown in chronic colitisUnder homeostatic conditions RORγt expressing lymphoid cells including Th17 cells, γδ T cells and innate lymphoid cells promote host defence and repair. IL-10 secreting Treg cells are abundant and prevent pathological inflammatory responses. In colitis, sustained IL-23 production in response to colitogenic bacteria promote pathological Type 17 responses with elaboration of inflammatory cytokines and repression of the Treg response.
Mentions: Deficiencies in regulatory pathways in the presence of triggering intestinal bacteria can lead to chronic intestinal inflammation. Initially thought to be driven by an interleukin 12 (IL-12)-dependent Th1 response, Kevin Maloy and I made the unanticipated observation in collaboration with Dan Cua and colleagues at DNAX, of a functional role for the IL-12 family cytokine, interleukin 23 (IL-23), as key driver of T-cell transfer colitis (Ahern et al, 2008). Further analysis of this pathway led to the identification of a novel population of innate lymphoid cells (ILC) that mediate colitis through the production of Type-17 associated cytokines. Like Th17 cells, IL-23-driven ILC are dependent on the transcription factor retinoic acid receptor related orphan receptor gamma t (RORγt) indicating striking functional parallels between innate and adaptive lymphoid populations in the gut (Buonocore et al, 2010). Together these results highlight the multiple activities of IL-23 that mediate tissue inflammatory responses (Fig 1). Further understanding of the molecular signatures associated with interleukin 23 receptor (IL-23R) signalling in lymphoid cells may provide novel therapies in inflammatory disease.

View Article: PubMed Central - PubMed

Affiliation: Experimental Medicine Division, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. fiona.powrie@path.ox.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

How in the vast majority of us it steadfastly protects from pathogens but in others, it turns on our own tissues or innocuous environmental antigens leading to autoimmune and chronic inflammatory diseases... As Th2 cells had been shown to reciprocally regulate the Th1 response, it seemed likely that differential activation of Th2 responses might explain Treg activity... However, we found that Treg function was IL-4-independent but required TGF-β production (Powrie et al, )... Key advances in the molecular control of Treg function have shown that Treg cells adapt to environmental conditions and utilize a range of suppressive mechanisms that are tuned to the inflammatory responses they control. »…Treg cells adapt to environmental conditions and utilize a range of suppressive mechanisms that are tuned to the inflammatory responses they control. « The T-cell transfer model of colitis together with a number of genetic models of chronic intestinal inflammation, illustrated the importance of balance between inflammatory and regulatory pathways for intestinal health... The complex and poorly characterized interactions between the intestinal immune system and commensal bacteria captivated me and this area has become the focus of my current research... Our results have shown that Foxp3+ Treg cells are abundant in the intestine and produce high levels of the immune suppressive cytokine interleukin 10 (IL-10), which is required for the control of intestinal homeostasis (Asseman et al, )... We also found that the intestine is a specific site for the generation of Treg cells reactive with intestinal antigens through the actions of specialized dendritic cells, the vitamin A metabolite retinoic acid and TGF-β (Coombes and Powrie, )... Indeed the capacity of the intestinal immune system to favour Treg induction and production of IL-10 may be an important component of host commensal mutualism, preventing deleterious inflammatory responses to intestinal bacteria... Like Th17 cells, IL-23-driven ILC are dependent on the transcription factor retinoic acid receptor related orphan receptor gamma t (RORγt) indicating striking functional parallels between innate and adaptive lymphoid populations in the gut (Buonocore et al, )... Together these results highlight the multiple activities of IL-23 that mediate tissue inflammatory responses (Fig 1)... In IBD, genetically controlled malfunctions in a number of different pathways including intestinal barrier function, host defence and innate and adaptive inflammatory pathways, predispose to a dysregulated interplay between the microbiota and the intestinal immune system... The complex clinical and genetic subtypes in IBD, taken together with the individuality of the intestinal microbiota, raise formidable challenges ahead as we try to apply findings from experimental models to the development of novel therapies for IBD... Further understanding of individuality and commonality in IBD aetiology and pathogenesis is required to identify subgroups of patients that may benefit from more tailored therapeutic approaches... Towards this goal, in 2009 I was appointed as the Sidney Truelove Professor of Gastroenterology at Oxford to translate findings from fundamental mucosal immunology to the study of IBD... Advances in molecular microbiology, genetics and analysis of human clinical samples offer great hope that we can apply our growing knowledge of immune system bacterial interactions towards enhanced therapies for these devastating clinical conditions.

Show MeSH
Related in: MedlinePlus