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

A13D8 is a monoclonal IgM antibody that identifies an as yet unknown antigen that is expressed intensely and ubiquitously in enterocytes. Immunohistochemically, it was shown that A13D8 has a granular supranuclear staining pattern in columnar epithelial cells of normal small intestine and the colon. In ulcerative colitis, this staining pattern was retained. However, during active inflammation, staining also was evident in goblet cells. To test whether this feature of goblet cell staining was unique to ulcerative colitis, tissue sections from a variety of colitides were examined. Crohn's disease, infectious colitis, and ischemic colitis had similar staining patterns to that seen with ulcerative colitis. There was significantly more inflammation in the biopsies from patients with ulcerative colitis and Crohn's disease with positive goblet cell staining than in the biopsies from those patients with negative goblet cell staining. Almost all positive goblet cell staining in ulcerative colitis and Crohn's disease occurred in biopsies that were actively inflamed, whereas there was rare staining in biopsies that were noninflamed (regardless of whether or not there was active inflammation elsewhere in the colon). Ileal goblet cells stained positively with A13D8 only in cases of active ileitis. In cases of collagenous colitis, with comparable degrees of inflammation to that seen in ulcerative colitis and Crohn's disease, there was rarely goblet cell staining and in graft-versus-host disease goblet cell staining of A13D8 was not observed. The binding of A13D8 to tissue sections was completely inhibited by N-acetyl-D-galactosamine. These results, in conjunction with immunochemical studies, suggest that the antibody recognizes an N-acetyl-D galactosamine-containing epitope on a glycoprotein(s). In conclusion, these data suggest that A13D8 recognizes a glycoprotein expressed by intestinal columnar epithelial cells and during specific inflammatory states, particularly those associated with a neutrophilic infiltrate, becomes evident in goblet cells. Further work is required to establish the exact nature of this molecule and whether it is a pro- or anti-inflammatory factor.
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PMID:The differential expression of a novel intestinal epithelial glycoprotein in various forms of inflammatory bowel disease. 870 31

CD11/CD18 leucocyte glycoprotein deficiency is a rare, congenital adhesion molecule disorder which, in its severe form, is usually fatal. Leucocytes in affected subjects have abnormal migration and adherence, rendering patients susceptible to life threatening infections. The CD11/CD18 integrins, and other adhesion molecules, are considered essential to the normal inflammatory response. It has been postulated that adhesion molecules may be responsible for mediating in part, the inflammatory changes observed in inflammatory bowel diseases and related disorders. This report describes the first case of CD11/CD18 deficiency characterised by a chronic ileocolitis. Bone marrow transplantation completely resolved the gastrointestinal symptoms, supporting a role for neutrophil dysfunction in the pathogenesis of the gut lesions. This case suggests that specific blockade of CD11/CD18 integrins alone may not halt the chronic inflammatory response observed in immune mediated bowel disorders, and that abnormalities of leucocyte function must be included in the differential diagnosis of paediatric Crohn's disease.
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PMID:Leucocyte adhesion deficiency presenting as a chronic ileocolitis. 894 73

Previous studies support a role for intestinal epithelial cells (IEC) as antigen-presenting cells in mucosal immune responses. T cells activated by IEC are CD8+, suppressor in function, and dependent upon CD8-associated p56lck activation. A 180-kD glycoprotein (gp180) recognized by mAbs B9 and L12 has been identified and shown to be important in CD8+ T cell activation by IEC. Since IEC derived from patients with inflammatory bowel disease (IBD) are incapable of activating CD8+ T cells, we asked whether this correlated with gp180 expression. While frozen sections of normal bowel revealed bright gp180 staining on all IEC, both inflamed and uninflamed ulcerative colitis (UC) specimens showed patchy staining. In Crohn's disease (CD), staining was faint to absent. Flow cytometry confirmed immunohistochemical data. The staining patterns correlated with the ability of IEC to activate CD8-associated p56lck. Normal IEC induced phosphorylation of p56lck in CD8alpha but not CD4+ transfectants. In contrast, both UC and CD IEC activated CD4 and, to a much lesser extent, CD8-associated p56lck. Thus, gp180 expression by IBD IEC appears to be altered, and correlates with a functional alteration of lck activation. This defect may reflect a more proximal event in the pathogenesis of IBD.
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PMID:Defective expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease. 932 71

Many attempts have been made over recent years to assess accurately disease activity in Crohn's disease. We review some of these attempts, giving particular emphasis to the combination of serum levels of proinflammatory cytokines (interleukin-6, tumour necrosis factor alpha, recombinant interleukin-2 and acid alpha-1-glycoprotein).
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PMID:Assessing disease activity in Crohn's disease--are we there yet? 939 81

According to Heelan et al. patients suffering from Crohn's disease (CD) produce antibodies against a cell wall associated glycoprotein antigen gp200 of the yeast Saccharomyces cerevisiae, while healthy people do not. Here the authors show, that antibodies against this glycoprotein gp200 can also be detected in the sera of healthy humans. The intensity of the antibody titer which is measured by immunoblot experiments is independent from the state of health. The Saccharomyces cerevisiae specific gp200 is a highly glycosylated protein localized not only in the cell wall but also accumulated in the culture medium. Some of the tested sera from CD patients, as well as from healthy adults, also reacted with a 120-kDa glycoprotein which is to be found in preparations containing secreted proteins. Because the binding of antibodies is greatly reduced by periodate treatment of gp200 and by the 120-kDa polypeptide, it is very likely that their carbohydrate moieties are the antigenic determinants against which the specific human antibodies are directed. The human humoral immune response applies only to Saccharomyces cerevisiae antigens, because no analogous immune responses could be detected against antigens derived from the yeast Arxula adeninivorans.
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PMID:Humoral immune response to a 200-kDa glycoprotein antigen of Saccharomyces cerevisiae is common in man. 965 63

We examined immune and inflammatory activation during remission in patients with Crohn's disease who presented with various clinical profiles (prolonged remission vs. relapsing disease). Thirty-six patients with at least 3 years' follow-up starting from a remission period were studied retrospectively. Relapses were defined by a retrospective calculation of the Crohn's disease activity index or by the clinical judgement of the physicians in charge of the patients. Disease course over the study period was assessed by the mean number of annual relapses. Analysis used measurements during remission of the following: erythrocytes sedimentation rate, relative lymphocytosis, acid alpha1-glycoprotein, interleukin-6 (IL-6), and soluble interleukin-2 receptor (sIL-2R) serum levels. During the study period 21 patients experienced at least one relapse and 15 did not. Mean serum levels of sIL-2R and mean relative lymphocytosis in remission significantly discriminated between relapsing and nonrelapsing patients. Only the mean sIL-2R serum level was selected by multivariate analysis, with a cutoff value of 82 pM/1 (sensitivity of 76% and specificity of 80%). The only features correlated with mean number of annual relapses in the relapsing patients were mean serum levels of sIL-2R (r=0.58, P=0.015) and IL-6 in remission (r=0.45, P=0.039). Multivariate analysis demonstrated statistical significance only for the mean serum level of IL-6 (P=0.014). In Crohn's disease the persistent elevation in sIL-2R serum levels during remission corresponds to chronic active disease, while high serum levels of IL-6 in these patients is associated with a high frequency of relapse.
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PMID:Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. 1100 19

SPARC is a glycoprotein of the extracellular matrix that exhibits a number of biological functions such as disruption of cell adhesion and modulation of matrix metalloprotease expression. These properties, in concert with the expression of the molecule during development, repair, and neoplastic progression, suggest that SPARC has an important role in remodeling in a variety of tissues. However, the role of SPARC in the intestine is unclear since the development expression and tissular origin of SPARC in this organ appears to be species-dependent. As a first step to investigate the function of SPARC in the tissues of the intestine, we have analyzed its expression at the protein and mRNA levels in the human fetal and adult small intestinal and colonic mucosa as well as in intestinal cell models. Our results show that SPARC expression is differentially regulated during development and along the length of the human intestine. In the colon, SPARC was predominantly found at the epithelial-mesenchymal interface at the fetal stage, below detection levels in the normal adult, but re-expressed in the stroma of colonic tumors. In the small intestine, low levels of SPARC expression were observed at an early stage of morphogenesis (between 9 and 11 weeks) but expression was not detected at subsequent developmental stages nor was it induced in the mucosa of Crohn's disease. While SPARC appeared to be produced mainly by mesenchymal and stromal cells in the intact intestine it was not detected in colon cancer cells. Taken together, these results indicate that SPARC is subject to an onco-fetal pattern of expression in the stroma of the colonic mucosa while its expression is much more restricted in the small intestine, suggesting a differential involvement of this molecule in the extracellular matrix remodeling occurring along the length of the developing and diseased human intestinal mucosa.
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PMID:Expression of SPARC/osteonectin/BM4O in the human gut: predominance in the stroma of the remodeling distal intestine. 1125 29

The heat-stable and soluble glycoprotein gp200 (molecular weight 200 kDa) is part of the cell wall of S. cerevisiae. Recently, an association was shown between IgA and IgG against gp200 and inflammation in Crohn's disease. Gp200 is able to induce a proliferation of human lymphocytes in vitro, together with a natural killer cell associated cytotoxicity. Specific IgE against Saccharomyces cerevisiae (baker's or brewer's yeast) may be detected in approximately 73%, against Candida albicans in 68% of those patients suffering from severe atopic dermatitis. The aim of this study was to elucidate the possible role of an anti-gp200 immune response for the pathogenesis of atopic dermatitis by immunoblot analysis. Anti-gp200 IgE was found in 55% of healthy individuals, in 67% of individuals with atopic predisposition without eczema, in 63% of the patients with mild atopic dermatitis, and in 86% of patients with severe atopic dermatitis, respectively. On the contrary, anti-gp200 IgG could be shown in 55% of healthy individuals, in 89% of individuals with atopic predisposition but without eczema, in 100% of patients with mild atopic dermatitis, and in 79% with severe atopic dermatitis, respectively. No immunoreactivity was found when an extract of Arxula adeninivorans was used as antigen. These results underline the specificity of the immunoblot results with gp200 from Saccharomyces cerevisiae. It can be concluded that occurrence of specific IgE against Saccharomyces cerevisiae cannot be explained by a cross reactivity, e.g., against Candida albicans allergens. Further investigations with the recombinant gp200 will give information on the role of this glycoprotein both in atopic dermatitis and Morbus Crohn.
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PMID:IgG and IgE immune response against the surface glycoprotein gp200 of Saccharomyces cerevisiae in patients with atopic dermatitis. 1169 91

Splice variants of the glycoprotein CD44 are transiently expressed on lymphocytes during T cell activation. Increased expression of CD44v6 on peripheral blood lymphocytes (PBL) of patients with inflammatory bowel disease (IBD) was described recently. The aim of this study was therefore to characterize CD44v6 expression on CD4(+) lamina propria lymphocytes (LPL) of patients with active IBD in comparison to controls. CD44v6 expression on CD4(+) LPL (n = 19) of controls and patients with active IBD (Crohn's disease n = 14, ulcerative colitis n = 15) was analyzed by flow cytometry and compared to that on autologous PBL. Thereby, in vitro regulation of CD44v6 on LPL and PBL via CD3 and CD2 and the costimulatory signal B7-1 was examined. In addition, the role of protein kinase C (PKC) in CD44v6 expression was tested. CD44v6 expression was increased in CD4(+) LPL (median, 45%) compared to PBL (median, 38%). Surprisingly, in IBD CD44v6 was downregulated on CD4(+) lamina propria T cells, irrespective of their state of inflammation (median, 28%). CD44v6 expression on LPL was not upregulated upon CD3 activation alone but following costimulation with B7-1. However, CD2-mediated T cell activation sufficiently induced upregulation of CD44v6 on LPL and PBL. In our study, downregulation of CD44v6 on LPL of patients with IBD was not due to defective PKC activation. Taken together, these data indicate that decreased CD44v6 expression on LPL in IBD might be a feature of an inappropriate costimulatory signal in T cell activation.
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PMID:Decreased CD44v6 expression in lamina propria lymphocytes of patients with inflammatory bowel disease. 1173 44

The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn s disease, ulcerative colitis, hepatitis C, and multiple sclerosis. The inflammatory processes leading to tissue damage and disease are mediated in part by the alpha4 integrins, alpha4beta1 and alpha4beta7, expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands, vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM), expressed in the affected tissue. Upon binding, the combined integrin/CAM interactions at the cell surface result in firm adhesion of the leukocyte to the vessel wall followed by entry into the affected tissue. Elevated cell adhesion molecule (CAM) expression in various organs has been linked with several autoimmune diseases. Monoclonal antibodies specific for alpha4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The alpha4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing alpha4 integrin antagonists have recently appeared. This article discusses the rationale for targeting alpha4 integrins for the treatment of autoimmune disorders and reviews some currently known antagonists. The methods used to identify lead molecules and the progress of selected antagonists toward becoming new drugs will is also discussed. (131 references).
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PMID:Alpha 4 integrin antagonists. 1205 18


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