Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Soluble CD23 (sCD23) is increased by interleukin-4 (IL-4) and decreased by interferon-gamma (IFN-gamma). On the basis of cytokine profiles T-helper (Th) cells may be functionally divided into IL-2- and IFN-gamma-secreting Th1 cells, which are involved in cell-mediated immunity (CMI), and IL-4- and IL-5-producing Th2 cells, which are involved in humoral immunity. Compared with sex-matched controls (median 8.5) we found significantly elevated levels of serum sCD23 in patients with rheumatoid arthritis (median 22.7, P < 0.0002), with the highest levels detected in patients fulfilling an increasing number of the American Association revised criteria for rheumatoid arthritis. Soluble CD23 levels were also significantly raised in autoimmune thyroiditis (median 11.7, P < 0.02) and myasthenia gravis (median 10.4, P < 0.05). In contrast patients with either coeliac (median 6.5) or Crohn's disease (median 5.8) had reduced levels of sCD23 compared to appropriate controls (median 11.8), in both cases significant at P < 0.01. Variations in sCD23 may, therefore, reflect enhanced Th1 activity in the two later conditions in contrast to heightened Th2 activity within the three classical autoimmune conditions.
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PMID:Variations in serum sCD23 in conditions with either enhanced humoral or cell-mediated immunity. 834 6

Cytokines play an important role in the pathology of inflammatory bowel disease by determining the nature of the mucosal immune response. One way of establishing whether CD and UC are causally related to a defect in the host immune response is to look for polymorphisms that are over-represented in these populations. This is being carried out at great pace both for the cytokine genes and for some other immune response genes. A number of gene expression studies have established that those cytokines produced by activated macrophages such as IL-1, IL-6 and TNF are significantly elevated in both diseases. Differences between the two diseases are less clear, and, where they have been found, they probably reflect the accuracy and sensitivity of quantification. The picture is less clear for the T-cell-derived cytokines, which are generally expressed at a lower copy number in intestinal tissue compared to the monokines. For Crohn's disease, the TH1 cytokines IL-2 and IFN may be abnormally elevated or decreased. In contrast, the TH1/TH2 profile in UC is not significantly different from normal controls. Further work is required to confirm these findings.
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PMID:Cytokines and inflammatory bowel disease. 873 6

Monoclonal populations of mucosal T cells were established from the earliest visible lesions in eight patients with well defined Crohn's disease. The FACS phenotype of all the mucosal derived clones to date are TCR alpha/beta+, CD3+, CD4+, and CD45RO+ memory cells. TCR variable region Beta chain analysis revealed predominantly V beta families 1, 2, 5.1, 5.2, 6, 7 and 8, with V beta family analysis supporting antigen expansion in the diseased mucosa. Putative autoreactivity was evaluated by stimulating individual clones with a battery of antigens and determining proliferation and IL-2 production by thymidine incorporation at 72 h. Antigens tested included crude Crohn's diseased (CD) colon and small bowel homogenates, CD brush border preparations, crude CD colon and small bowel mucin, and purified CD small bowel mucin. Controls included clone, APC, tetanus toxoid and either PHA or Staphylococcus enterotoxin B. A total of 200 clones were studied with 29.5% or 59 clones demonstrating proliferation and/or IL-2 production. T cell receptor V beta gene usage evaluated in a small number of reactive clones correlated with the expanded patient families. Seven of the fifteen represented families revealed diverse T cell receptor gene use and no disease overlap.
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PMID:Analysis of function, specificity and T cell receptor expression of cloned mucosal T cell lines in Crohn's disease. 873 63

In this study, we investigate whether human inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is associated with altered lymphokine secretion profiles, as recently found in various animal models of chronic intestinal inflammation. In initial studies, we determined the proliferative responses of purified lamina propria (LP) CD4+ T cells from patients with IBD under defined conditions of T cell stimulation. We found that IBD LP CD4+ T cells in comparison with control LP CD4+ T cells have diminished TCR/CD3 pathway proliferative responses, whereas CD2/CD28 accessory pathway proliferative responses are relatively preserved. In further studies centering on lymphokine production, we showed that LP T cells from inflamed Crohn's disease mucosa manifest increased IFN-gamma secretion compared with control LP T cells, particularly when stimulated via the CD2/CD28 pathway. Subsequent ELISPOT analysis indicated that this was due to an increased number of IFN-gamma-secreting CD4+ T cells. In contrast, IL-4 and IL-5 production by Crohn's disease LP T cells was decreased compared with that of control LP T cells. Of interest, IL-2 production by Crohn's disease LP T cells was also reduced, as was IL-2 production by peripheral blood T cells. In parallel studies, LP T cells from inflamed ulcerative colitis mucosa stimulated via either the TCR/CD3/CD28 or CD2/CD28 produced increased amounts of IL-5, again when measured either as secreted IL-5 or by ELISPOT analysis. Such increased IL-5 production was not associated with increased IL-4 secretion and, in contrast to Crohn's disease, ulcerative colitis LP T cell production of IL-2 and IFN-gamma was normal. Taken together, these studies provide strong evidence that the immunopathologic process characteristic of the two major forms of IBD is associated with very different cytokine secretion patterns. These different patterns may determine the type of inflammatory process present.
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PMID:Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. 875 34

Lymphocyte-mediated inflammation is a hallmark of autoimmune diseases, such as multiple sclerosis. Crohn's disease, rheumatoid arthritis and sarcoidosis. However, this type of inflammation probably developed under evolutionary pressure from pathogenic microorganisms, such as mycobacteria and other intracellular infective agents. One such pathogen, the gram-positive bacterium Listeria monocytogenes (L. monocytogenes), induces a cascade of tissue alterations that ultimately results in the eradication of the bacteria associated with a granulomatous response. Consequently, murine listeriosis has been established as a model to analyze not only T-cell-dependent antibacterial protection but also T-cell-mediated mononuclear inflammation in parenchymal organs. Extensive studies of the molecular basis of the latter phenomenon led to the conclusion that the most decisive step from non-specific microabscess formation to granulomatous inflammation is the activation of non-specifically invading CD4+ T cells, which results in high local concentrations of TNF-alpha and IFN-gamma in the presence of IL-2. This in turn induces CD11b-independent mechanisms of intraparenchymal monocyte accumulation. Because any attempt to neutralize the effects of TNF-alpha and IFN-gamma to modulate T-cell-mediated inflammation will also dramatically decrease host resistance, other anti-inflammatory strategies based on the modulation of TNF-alpha and IFN-gamma-induced mechanisms of monocyte accumulation must be developed. Recalling the classical work by Dienes & Schoenheit on the induction of bacterial allergies (1), the cytokine phenotype of granuloma formation also has implications as regards the most potent adjuvant environment for the development of a T-cell response. The murine listeriosis model is the basis for all conclusions in this article on the role of cytokines in the induction and expression of T-cell-mediated inflammation and, as we will show, promises to yield still more insights into the rational design of vaccines.
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PMID:Cytokines in the induction and expression of T-cell-mediated granuloma formation and protection in the murine model of listeriosis. 931 76

The aim of this study was to identify molecular mechanisms involved in transcriptional regulation of IL-2 expression following CD2 and CD3 activation in lamina propria (LP) T cells. Studies used T cells from normal, ulcerative colitis, and Crohn's disease mucosa and freshly isolated PBMC, PBMC stimulated with IL-2 alone, and PBMC stimulated with IL-2 and cocultured with B cell lines (LP-like T cells). Electrophoretic mobility shift assays were performed with nuclear extracts from cells activated with either anti-CD2 or anti-CD3 Abs. CD2 signaling in LPMC and LP-like T cells led to a pattern of sustained up-regulation of AP-1-binding complexes, whereas CD3 activation resulted in only transient up-regulation. While the pattern of regulation of AP-1 binding observed in normal, uninflamed, or inflamed Crohn's disease LPMC is similar, differences in intensity of AP-1 binding were observed. Activation of LP-like T cells mimics the up-regulation of AP-1 with a kinetic profile similar to that observed with freshly isolated LPMC from Crohn's disease-inflamed tissue. The AP-1 complex formed following CD2 activation is composed of jun/fos heterodimers. The CD2-enhanced responsiveness is reflected in functional analysis experiments utilizing transfection of both multimeric-TRE or IL-2 promoter-luciferase constructs directly into normal, ulcerative colitis, or Crohn's disease LPMC. Our data suggest that activation of LP T cells from normal, ulcerative colitis, or Crohn's disease mucosa through the CD2 pathway leads to induction of AP-1 complexes that bind to the IL-2 promoter, and may play a pivotal role in modulating IL-2 production in the gut.
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PMID:Activation of the CD2 pathway in lamina propria T cells up-regulates functionally active AP-1 binding to the IL-2 promoter, resulting in messenger RNA transcription and IL-2 secretion. 959 Feb 39

Although the importance of genetic susceptibility to IBD has been established by epidemiological studies, the genes involved remain poorly characterized. Important candidate genes include those encoding the immunoregulatory cytokines IL-2 and IL-10. The aim of this study was to assess the contribution of the IL-2 and IL-10 genes to IBD susceptibility. One hundred and ninety-eight pairs of siblings with IBD were genotyped at dinucleotide repeat polymorphisms within the IL-2 and IL-10 genes, and data analysed by the affected sib-pair method of linkage analysis and the transmission disequilibrium test (TDT). A subset of 89 affected sibling pairs was genotyped at markers flanking the IL-2 gene as part of a genome-wide search. The IL-2 polymorphism showed no linkage to IBD overall, but modest evidence for linkage to the ulcerative colitis (UC) data set (P = 0.028). A microsatellite 4 cM distal to the IL-2 gene showed a similar distortion in the ulcerative colitis subgroup (P = 0.006). The TDT showed some distortion of allelic transmission for the IL-2 polymorphism in the UC group, but this did not reach statistical significance (P = 0.09). Results for the IL-10 polymorphism were not significant. Thus the gene encoding IL-2 may contribute to UC susceptibility, but the effect is modest and must await replication in other data sets. The IL-10 gene does not appear to contribute to the risk of developing UC or Crohn's disease.
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PMID:Contribution of the IL-2 and IL-10 genes to inflammatory bowel disease (IBD) susceptibility. 969 79

Inflammatory bowel disease (IBD) denotes chronic inflammatory disorders of gastrointestinal tract of unknown etiology that comprises 2 major groups: ulcerative colitis (UC) and Crohn's disease (CD). Disregulation of the intestinal immune system both at humoral and cellular level constitutes an important element in the multifactorial pathogenesis of IBD. The expression of pro-inflammatory cytokines, most notably IL-1, IL-6, TNF-alpha and chemokines (IL-8, ENA-78, MCP-1, RANTES) in intestinal mucosa from IBD patients is markedly enhanced, however, it is not always accompanied by increases in cytokines' serum levels. In IBD also significant changes occur in the tissue expression of immunoregulatory cytokines: increased levels of IL-2 mRNA and IFN-gamma mRNA, and decreased expression of IL-4 were found in affected intestinal mucosa. Chronic intestinal lesions of patients with Crohn's disease are associated with a Th1 type cytokine profile. The clinical effectiveness of anti-TNF-alpha antibodies and of IL-10 has been demonstrated in steroid-refractory Crohn's disease patients. The data demonstrating the role of cytokines in the pathogenesis of IBD should be carefully analyzed because of limitations imposed by the patient- and sample-related parameters. Further investigations will clarify the significance of the impairments in cytokine network for the initiation and progression of the IBD.
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PMID:Cytokines in inflammatory bowel disease. 970 46

This study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.
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PMID:Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients. 993 22

We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2-/- mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn's disease. The integrin alpha E beta 7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of alpha E beta 7 in colitis, we administered a mAb against alpha E beta 7 to IL-2-/- mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0-2 vs 3-4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 +/- 0.6 x 107 vs 1.2 +/- 0.2 x 107; p < 0.05). Similarly, functional studies revealed that IFN-gamma production by lamina propria lymphocytes isolated from IL-2-/- TNP-OVA-immunized mice treated with anti-alpha E beta 7 was significantly lower than in untreated IL-2-/- TNP-OVA-immunized mice. In contrast, IFN-gamma production by splenic cells isolated from treated IL-2-/- TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2-/- mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after alpha E beta 7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing alpha E beta 7.
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PMID:Administration of mAb against alpha E beta 7 prevents and ameliorates immunization-induced colitis in IL-2-/- mice. 1020 45


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