1,721,130 research outputs found
New players in the cytokine orchestra of inflammatory bowel disease
No full textIn both Crohn's disease (CD) and ulcerative colitis, the pathologic process is almost certainly driven by an aberrant local immune response directed against normal components of the bacterial microflora. Mucosal immune cells interact with nonimmune cells such as epithelial cells and fibroblasts to promote tissue damage; cytokines are essential mediators of this cross talk. Accumulating evidence now suggests that interleukin-21 (IL-21), the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade. IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with CD, where it contributes to sustaining the ongoing Th1 inflammation. IL-21 also increases the secretion of extracellular matrix-degrading enzymes by fibroblasts and of MIP-3α by epithelial cells. Two other cytokines, IL-27 and IL-32, may also be important in the inflammatory pathways that operate in IBD
IL-21 comes of age as a regulator of effector T cells in the gut
Full text linkIn healthy individuals, antigens from the gut lumen are tolerated by the mucosal immune system. However, a loss of tolerance toward the bacterial microflora probably causes inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis. The abnormal activation of the immune system in the gut of IBD patients is characterized by a cascade of cellular events orchestrated by cytokine cross talk between immune and non-immune cells. Interleukin (IL)-21, the newest member of the common γ-chain-dependent cytokine family, is a key component of the inflammatory cascade in the gut. It is highly expressed in CD and sustains the ongoing T helper type 1 (Th1)-mediated immune response. IL-21 is essential for the differentiation of Th17 cells. IL-21 is also involved in recruiting T cells to the inflamed gut and eliciting the secretion of matrix-degrading enzymes by gut fibroblasts. Overall, there is now sufficient evidence to suggest that targeting IL-21 will be of therapeutic benefit in IBD
Immunopathogenesis of Crohn’s disease
No full textThis review highlights the huge advances made in the understanding of Crohn's disease in the last 15 years. The pathogenic immune response in the gut wall is a highly polarised T helper cell type 1 response, probably directed against antigens of the commensal flora. There is marked over-expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and increased production of matrix degrading enzymes by fibroblasts and macrophages, which are probably responsible for ulceration and fistula formation. Crohn's disease runs in families and the susceptibility genes identified so far are associated with innate recognition of microbial products (Nod2) or epithelial barrier function (OCTN cation transporter genes and DLG5). Endogenous healing pathways mediated by transforming growth factor (TGF)-beta1 are inhibited because mucosal inflammatory cells express Smad7, the endogenous intracellular inhibitor of TGF-beta signalling. This makes it unlikely that enteral feeds containing TFG-beta are therapeutic by means of direct anti-inflammatory effects, however TGF-beta may still be involved because it is a well known epithelial motogen and may promote mucosal healing, in synergy with changes in mucosal bacterial populations as a result of the change in the diet
Reprogramming the immune system in IBD
No full textImmune function in the gut mucosa is tightly regulated to prevent deleterious tissue damaging responses to the indigenous microbiota. In animal models, negative regulatory molecules such as transforming growth factor β1 (TGFβ1) and interleukin (IL)-10 seem to be particularly important. Although IL-10 is made by macrophages, T cells and B cells, TGFβ1 is made by many non-lymphoid/myeloid cells, especially epithelial cells. We have been able to show that in the human gut, neutralization of TGFβ1 increases Th1 and Th17 responses. In IBD, however, especially Crohn's disease, exogenous TGFβ1 cannot inhibit inflammation because of a block in intracellular signalling mediated by Smad7. Knockdown of Smad7 allows endogenous TGFβ1 to dampen inflammation in mucosal tissues from Crohn's patients. We have also generated a mouse which over-expresses Smad7 in T cells. This animal develops more severe colitis in a number of different models, but the inflammation helps protect against colon cancer
Increased expression of mucosal addressin cell adhesion molecule-1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7-positive T cells in blood.
No full textMucosal addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin alpha(4)beta(7), expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal addressin cell adhesion molecule 1/integrin alpha(4)beta(7) pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin alpha(4)beta(7) in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti-interferon alpha neutralizing antibody. Mucosal addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin beta(7)-positive T cells were analyzed by flow cytometry. Mucosal addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal addressin cell adhesion molecule 1 expression. Blocking interferon alpha inhibited the peptic-tryptic digest of gliadin-induced mucosal addressin cell adhesion molecule 1 overexpression. The percentage of circulating beta(7)-positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon alpha and is associated with peripheral depletion of integrin alpha(4)beta(7)-expressing T cells. We conclude that mucosal addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease
The pathophysiologic rationale for biological therapies in inflammatory bowel disease
Full text linkInflammatory bowel disease is driven by an excessive immune response in the gut wall. This review summarises important new developments in understanding this immune response and the downstream mechanisms of intestinal injury, alongside their potential role in opening up new avenues of treatment.
RECENT FINDINGS:
The evidence continues to accumulate that Crohn's disease is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarisation, but IL-21 may also be important. The p40 chain of IL-12 also associates with a novel p19 chain to form IL-23 which is also a potent Th1-inducing cytokine but the expression of IL-23 in Crohn's disease has not been reported. Progress in understanding the immunology of ulcerative colitis remains slow, but IL-13 produced by natural killer T cells may be involved. T-cell resistance to apoptosis occurs in Crohn's disease, and human and mouse studies indicate that the signalling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Fibroblasts and metalloproteinases continue be implicated in ulceration, fibrosis, and fistula formation.
SUMMARY:
Understanding the immunology of inflammatory bowel disease continues to underpin the vast majority of new therapies and identifies new targets. Novel approaches, such as exploiting the antiinflammatory role of cannabinoid receptors, may also prove productive in the future
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