Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiopathogenesis of primary sclerosing cholangitis (PSC) remains undefined. Immunopathogenetic mechanisms appear to be involved, based on human leukocyte antigen complex susceptibility associations, existence of multiple autoantibodies, and presence of inflammatory bowel disease in > 75% of patients. PSC may represent an autoimmune disease with atypical features or an immune-mediated inflammatory disease, similar to inflammatory bowel disease itself. Immunogenetic susceptibility is closely linked to ligands for innate immune cells and capacity for sustained production of proinflammatory cytokines. Immunopathogenesis involves a multistep process initiated by the activation of cholangiocyte by bacterial pathogen-associated molecular patterns (stimuli of innate immunity) and proinflammatory cytokines in conjunction with aberrant expression of gut-specific chemokines and endothelial cell adhesion molecules in the liver. After recruitment of gut-primed memory T cells into the portal tracts and peribiliary space, additional mechanisms produce focal, fibrous, obliterative lesions. Progressive periductal fibrosis, chronic inflammation, and ischemic atrophy of biliary epithelia result in ductopenia, cholestasis, and obstructive strictures, culminating in secondary biliary cirrhosis.
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PMID:Etiopathogenesis of primary sclerosing cholangitis. 1649 29

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have inflammatory bowel disease (IBD), the majority ulcerative colitis (UC). An inherent problem in interpreting positive findings in genetic association studies of PSC is thus to distinguish between factors associated with hepatobiliary versus intestinal pathology. We aimed to clarify to what extent human leukocyte antigen (HLA) class II associations in UC patients with and without PSC differ. High-resolution DRB1 and DQB1 typing was performed in 365 Scandinavian PSC patients, an independent cohort of 330 Norwegian UC patients and 368 healthy controls. HLA associations found in PSC were mostly distinct from those seen in UC, and no significant differences were noted between PSC patients with concurrent UC and PSC patients without IBD. This suggests different HLA associated genetic susceptibility to PSC and UC, and supports notions that UC in PSC may represent a distinct UC phenotype.
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PMID:Different HLA class II associations in ulcerative colitis patients with and without primary sclerosing cholangitis. 1730 27

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-gamma, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-gamma indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.
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PMID:Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma. 1734 51

Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn's disease (CD), shows a multifactorial origin, with genetic and environmental factors involved. Although the genetic influence is clear for both diseases, the genetics involved is complex and epistatic interactions with other genes probably exist. The Fc receptor-like 3 gene (FCRL3) maps to the human chromosome 1q21-22 and certain single nucleotide polymorphisms (SNPs) in its promoter have been associated with some autoimmune diseases. Our aim was to study the role of two promoter SNPs of the FCRL3 gene (-169A>G, rs7528684 and -110C>T, rs11264799) in patients with IBD and their interaction with HLA-DRB1 and CARD15 in patients with UC and CD, respectively. A case-control study with 311 patients with CD, 324 patients with UC and 497 healthy controls was performed. All the individuals were White Spaniards. No significant associations were found between any FCRL3 SNP and CD or UC, but the stratification in patients with UC by human leukocyte antigen (HLA) showed a significant increase in heterozygosity at the FCRL3 locus, especially -169 AG (AG vs AA+GG, P= 0.0027, odds ratio = 3.6, 95% confidence interval 1.4-2.9), when HLA-DRB1*0103 carrier patients were compared with HLA-DRB1*0103 noncarriers. Our data suggest an epistatic interaction between genes in chromosomes 6p21 and 1q21-22, marked, respectively, by HLA-DRB1*0103 and FCRL3-169 AG.
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PMID:Epistatic interaction between FCRL3 and MHC in Spanish patients with IBD. 1738 14

The human leukocyte antigen (HLA) region has been implicated in the pathogenesis of inflammatory bowel disease (IBD), which is classified into Crohn's disease (CD) and ulcerative colitis (UC). Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene was reported. BTNL2 is located in the HLA region and its messenger RNA is expressed most abundantly in the intestine. In this study, we performed a case-control association study of BTNL2 in the Japanese patients with IBD and performed linkage disequilibrium (LD) analysis between BTNL2 and HLA-DRB1. We analyzed eight polymorphisms selected after direct sequencing and found that none of the polymorphisms were associated with the Japanese CD cohort. In contrast, five polymorphisms were significantly associated with UC, especially three single nucleotide polymorphisms (BTNL2_19, BTNL2_22 and BTNL2_23) were associated as a haplotype. The most frequent haplotype (GGC haplotype) was a low-risk haplotype (P= 0.000052), whereas the other TCT haplotype was a high-risk haplotype (P= 0.0000085). Among the eight polymorphisms, the strongest association with UC was found in BTNL2_19 (OR = 1.92, P= 0.0000035). As expected, the BTNL2_19-T allele showed strong LD with DRB1*1502 (D'= 0.92). When BTNL2_19 was tested as conditional on the DRB1*1502 carrier status, the significant association disappeared, suggesting that the association was because of its strong LD with DRB1*1502. We conclude that BTNL2 does not contribute to the susceptibility to Japanese CD but is associated with Japanese UC because of the strong LD with HLA-DRB1*1502. The strong LD between BTNL2 and HLA-DRB1 raises another issue about the potential role of BTNL2 in other diseases associated with HLA-DRB1.
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PMID:Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502. 1761 Apr 17

The aetiology of primary sclerosing cholangitis (PSC) is not known. A more than 80-fold increased risk of PSC among first-degree relatives emphasizes the importance of genetic factors. Genetic associations within the human leukocyte antigen (HLA) complex on chromosome 6p21 were detected in PSC 25 years ago. Subsequent studies have substantiated beyond doubt that one or more genetic variants located within this genetic region are important. The true identities of these variants, however, remain to be identified. Several candidate genes at other chromosomal loci have also been investigated. However, according to strict criteria for what may be denominated a susceptibility gene in complex diseases, no such gene exists for PSC today. This review summarises present knowledge on the genetic susceptibility to PSC, as well as genetic associations with disease progression and clinical subsets of particular interest (inflammatory bowel disease and cholangiocarcinoma).
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PMID:Genetic epidemiology of primary sclerosing cholangitis. 1790 84

Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
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PMID:Novel genetic markers in inflammatory bowel disease. 1794 29

The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.
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PMID:HLA-DRB1 alleles influence clinical phenotypes in Japanese patients with ulcerative colitis. 1841 74

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease histologically characterized by the presence of intrahepatic and/or extrahepatic biliary duct concentric, obliterative fibrosis, eventually leading to cirrhosis. Approximately 75% of patients with PSC have inflammatory bowel disease. The male predominance of PSC, the lack of a defined, pathogenic autoantigen, and the potential role of the innate immune system suggest that it may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC is associated with several classic autoimmune diseases, and the strongest genetic link to PSC identified to date is with the human leukocyte antigen DRB01*03 haplotype. The precise immunopathogenesis of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Currently, there is no effective therapy for PSC and developing a rational therapeutic strategy demands a better understanding of the disease.
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PMID:The immunobiology of primary sclerosing cholangitis. 1946 33

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the bowel, of unknown origin. Exposure to specific environmental factors by genetically susceptible individuals, leading to an inadequate response of the immune system, is one of the potential explanations for the occurrence of these diseases. Natural killer cells are part of the innate immune system recognizing class I HLA (human leukocyte antigen) molecules on target cells through their membrane receptors. The main receptors of the natural killer cells are the killer immunoglobulinlike receptors (KIRs). Our study aimed to evaluate the association between the KIR genes in patients with inflammatory bowel diseases and healthy controls. We typed 15 KIR genes and HLA class I ligands in 248 unrelated Brazilian Caucasians, of which 111 had UC and 137 had CD, and 250 healthy controls by polymerase chain reaction using sequence-specific oligonucleotides and sequence-specific primers. We found an increase in KIR2DL2 in controls (inflammatory bowel disease [IBD]: p < 0.001; UC: p = 0.01; CD: p = not significant [NS]). The genotype 2DL2+/HLA-C lys(80)+ was also more common in controls (IBD: p = 0.005; UC: p = 0.01; CD: p = NS); as well as 2DL1+/HLA-C Asn(80)+ (IBD: p = 0.026; UC: p = NS;CD: p = NS). The imbalance between activating and inhibitory KIR and HLA ligands may explain, at least in part, the pathogenesis of these inflammatory bowel diseases.
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PMID:Study of killer immunoglobulin-like receptor genes and human leukocyte antigens class I ligands in a Caucasian Brazilian population with Crohn's disease and ulcerative colitis. 2003 5


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