Loss of transforming growth factor β signalling in the intestine contributes to tissue injury in inflammatory bowel disease

Kb, Hahm; Im, Y-H.; Tw, Parks; Park, Sang Hoon; Markowitz, Sanford D.; Hy, Jung; Green, J; Sj, Kim

doi:10.1136/gut.49.2.190

Cited by 173 publications

(146 citation statements)

References 33 publications

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“…It is also important in maintaining or healing the epithelial structure (45)(46)(47). Recent work with another mouse model wherein TGF-␤ receptor signaling has been rendered defective in the gut mucosa results in an inflammatory enteropathy that has histologic features which mimic the enteropathy of celiac disease (48). These mice also have circulating Abs to tTG (49).…”

Section: Discussionmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

137

107

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We have investigated the genetic basis of the immune response to dietary gluten in HCD4/DQ8 and HCD4/DQ6 double transgenic mice. Mice were immunized with gluten i.p. or individual peptides s.c. and spleen or draining lymph node T cells were challenged in vitro. Strong proliferative responses to gluten were seen in the HCD4/DQ8 mice, whereas the HCD4/DQ6 mice responded to gluten poorly. A series of overlapping peptides spanning gliadin were synthesized. The HCD4/DQ8 mice reacted to many of the individual peptides of gliadin, while the HCD4/DQ6 mice were relatively unresponsive. T cells isolated from HCD4/DQ8 mice also responded well to modified (deamidated) versions of the gliadin peptides, whereas HCD4DQ6 mice did not. The T cell response to gluten was CD4 dependent and DQ restricted and led to the production of cytokines IL-6, TGF-β, and IL-10. Finally, intestinal lymphocytes isolated from gluten-fed HCD4/DQ8 mice displayed an activated phenotype. These data suggest that this HLA class II transgenic murine model of gluten sensitivity may provide insight into the initiation of the MHC class II-restricted gluten sensitivity in celiac disease.

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Section: Discussionmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

137

107

View full text Add to dashboard Cite

show abstract

“…In this context, abnormalities of the IEL population have been reported in a number of human inflammatory bowel diseases (IBD) [1][2][3][4]. Immunoregulatory cytokines, in particular IL-10 and TGF-g , are also important in the control of chronic gut inflammation [5][6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

et al. 2004

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Intraepithelial lymphocytes (IEL) play a key role in gut homeostasis and are critical effector cells preventing the inflammatory intestinal lesions induced in mice following oral infection with Toxoplasma gondii. In this intestinal inflammatory model, CD4 + T lymphocytes from the lamina propria (LP) synergize with the infected enterocytes to secrete pro-inflammatory chemokines and cytokines. In this study, we assessed the mechanisms accounting for the ability of IEL to modulate the inflammatory activity of these cells. Adoptive transfer of IEL purified from wild-type mice, or CD154-,CD95L-or IL-10-deficient mice infected with T. gondii completely impairs the development of the lethal ileitis in recipient mice orally infected with T. gondii. Compared with unprimed IEL isolated from naive mice, the CD8 § g TCR § g subset of primed IEL, isolated from T. gondii-infected mice, secretes increased amount of TGF-g . IEL interact with the LP CD4 + T lymphocytes, down-regulate their production of inflammatory cytokines such as IFN-+ and reduce their proliferative activity. These effects are linked to the secretion of TGF-g and are correlated with a shift in the balance between Smad7/T-bet down-regulation and Smad2/Smad3 up-regulation in LP CD4 + T lymphocytes.

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“…3a, b). The importance of the functional adaptations of the local intestinal immune system to its unique environment is best illustrated during failure of these mechanisms, e.g., during the development of chronic intestinal inflammation, either in patients with celiac disease, inflammatory bowel diseases (IBD), or in various mouse strains deficient for genes involved in the control of immune responses such as IL-10 and TGFβ [73][74][75][76]. Deregulated immune response(s) against an otherwise harmless luminal microflora in susceptible individuals is now generally recognized as a key factor in the pathogenesis of IBD.…”

Section: Macrophage Subsets In the Normal And Inflamed Intestinal Mucosamentioning

confidence: 99%

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

2009

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Intestinal macrophages, preferentially located in the subepithelial lamina propria, represent the largest pool of tissue macrophages in humans. As an adaptation to the local antigen-and bacteria-rich environment, intestinal macrophages exhibit several distinct phenotypic and functional characteristics. Notably, microbe-associated molecular pattern receptors, including the lipopolysaccharide (LPS) receptors CD14 and TLR4, and also the Fc receptors for IgA and IgG are absent on most intestinal macrophages under homeostatic conditions. Moreover, while macrophages in the intestinal mucosa are refractory to the induction of proinflammatory cytokine secretion, they still display potent phagocytic activity. These adaptations allow intestinal macrophages to comply with their main task, i.e., the efficient removal of microbes while maintaining local tissue homeostasis. In this paper, we review recent findings on the functional differentiation of monocyte subsets into distinct macrophage populations and on the phenotypic and functional adaptations that have evolved in intestinal macrophages in response to their antigen-rich environment. Furthermore, the involvement of intestinal macrophages in the pathogenesis of celiac disease and inflammatory bowel diseases is discussed.

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Loss of transforming growth factor β signalling in the intestine contributes to tissue injury in inflammatory bowel disease

Abstract: Maintenance of TGF-signalling may be important in regulating immune homeostasis in the intestine (Gut 2001;49:190-198)

Cited by 173 publications

References 33 publications

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

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Loss of transforming growth factor β signalling in the intestine contributes to tissue injury in inflammatory bowel disease

Abstract: Maintenance of TGF-signalling may be important in regulating immune homeostasis in the intestine (Gut 2001;49:190-198)

Cited by 173 publications

References 33 publications

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4+ T cells

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

Contact Info

Product

Resources

About

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells