Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007570 (celiac disease)
 13,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Celiac Sprue, or gluten-sensitive enteropathy, is an inheritable human disease of the small intestine that is triggered by the dietary intake of gluten. Recently, several Pro- and Gln-rich peptide sequences (most notably PQPQLPY and analogs) have been identified from gluten with potent immunogenic activity toward CD4(+) T cells from small intestinal biopsies of Celiac Sprue patients. These peptides have three unusual properties. First, they are relatively stable toward further proteolysis by gastric, pancreatic, and intestinal enzymes. Second, they are recognized and deamidated by human tissue transglutaminase (tTGase) with high selectivity. Third, tTGase-catalyzed deamidation enhances their affinity for HLA-DQ2, the disease-specific class II major histocompatibility complex heterodimer. In an attempt to seek a mechanistic explanation for these properties, we undertook secondary structural studies on PQPQLPY and its analogs. Circular dichroism studies on a series of monomeric and dimeric analogs revealed a strong polyproline II helical propensity in a subset of them. Two-dimensional nuclear magnetic resonance spectroscopic analysis confirmed a polyproline II conformation of PQPQLPY, and was also used to elucidate the secondary structure of the most helical variant, (D-P)QPQLPY. Remarkably, a strong correlation was observed between polyproline II content of naturally occurring gluten peptides and the specificity of human tTGase toward these substrates. Analogs with up to two D-amino acid residues retained both polyproline II helical content and transglutaminase affinity. Since the Michaelis constant (K(m)) is the principal determinant of tTGase specificity for naturally occurring gluten peptides and their analogs, our results suggest that the tTGase binding site may have a preference for polyproline II helical substrates. If so, these insights could be exploited for the design of selective small molecule inhibitors of this pharmacologically important enzyme.
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PMID:Circular dichroism and nuclear magnetic resonance spectroscopic analysis of immunogenic gluten peptides and their analogs. 1232 65

The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA-HLA-DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA-DRB1*0301 was associated with an increased risk for CD, while HLA-DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1-DRB1*0301 (associated with risk for disease), A4-DRB1*0301 and A6-DRB1*07. In view of our results, both HLA-DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA-DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.
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PMID:HLA-DRB1 and MHC class 1 chain-related A haplotypes in Basque families with celiac disease. 1236 85

Recent evidence from several studies has suggested a genetic predisposition in the pathogenesis of ulcerative colitis (UC), which is especially related with major histocompatibility complex (MHC) genes. The aim of this study was to investigate the possible association of human leukocyte antigen (HLA-B, HLA-DR) and MHC class I chain-related-transmembrane (MICA-TM) polymorphism with the behavior and extension of UC. We selected 121 unrelated patients with UC. These were divided into two groups according to the extension of the disease: 31 patients with distal UC and 90 with wide extension UC; 116 blood donors were also selected as healthy controls, all of whom were typed for HLA-B, HLA-DR, and MICA-TM alleles. HLA-B7 was found to be overrepresented in distal UC patients compared with those with extensive UC (p(c) = 0.007, OR = 5.33) and healthy controls (p(c) = 0.03, OR = 4.09). The MICA-A5.1 allele was also increased in distal UC (p(c) = 0.015, OR = 3.82) when compared with extensive forms. These alleles are in strong linkage disequilibrium in our population. The MICA-A5 allele was significantly increased in extensive forms when compared with healthy controls(p(c) = 0.02, OR = 2.4). According to our results, MICA-A5.1 allele seems to be protective against extensive forms of UC, and MICA-A5 may condition a worse progression of the disease. These results are in agreement with other studies that suggest a similar role of such alleles in other diseases, such as insulin-dependent diabetes mellitus and celiac disease.
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PMID:MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis. 1287 61

Celiac sprue (CS) is defined as a chronic small bowel malabsorption disorder caused by ingestion of gluten, affecting those genetically predisposed individuals. It is characterized by intestinal villi atrophy, increased number of intraepithelial lymphocytes and extense inflammatory infiltrate in the intestinal lamina propria. The role of gluten as responsible for the intestinal damage seen in CS patients is clear, however, the physiopathological mechanisms involved are still unknown. Several factors and theories have been proposed: 1) Genetic predisposition, based on the association to mendelian factors as well to the presence of particular major histocompatibility complex (MHC) haplotypes in CS patients; 2) Immunological factors, that consider the derangements that occur in the immune response of CS patients, and 3) Gliadin partial deamination by the tissular transglutaminase (tTG). In an effort to explain all these complex mechanisms, recently, all these theories have been unified, yielding one complex physiopathogenic mechanism that we tray to explain in the present review.
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PMID:[Current concepts on celiac disease physiopathology]. 1496 78

The development of transgenic mice expressing human DR and DQ major histocompatibility complex (MHC) class II molecules has been of value in studying the immunopathology of human MHC class II-associated autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus and celiac disease. Such mice have been used to identify the target antigens that are involved in the initiation of these diseases. Many of the mice develop aspects of the human diseases, either spontaneously or following immunization with the relevant antigen, thus providing an in vivo disease model, which may be used as a tool for further understanding the disease mechanisms and testing novel immunotherapies.
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PMID:Humanized animal models for autoimmune diseases. 1510 70

Coeliac disease (CD) is an intestinal disorder caused by intolerance to dietary gluten in susceptible individuals. The HLA-DQ genes are major risk factors for CD, but other genes also play an important role in the disease susceptibility. Immune-mediated mechanisms are known to underlie the pathogenesis of CD. We studied single-nucleotide polymorphisms in transforming growth factor (TGF)-beta1, interleukin (IL)-10, IL-6, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha genes in the Finnish population using family-based association approach. In addition, we genotyped a trinucleotide repeat polymorphism in the major histocompatibility complex (MHC) class I chain-related protein A (MICA) gene, located in the human leucocyte antigen (HLA) region in the vicinity of TNF-alpha. To control the effect of linkage disequilibrium between HLA-DQ genes and MICA and TNF-alpha, an HLA-stratified association analysis was performed. We did not find evidence of association between TGF-beta1, IL-10, IL-6 and IFN-gamma polymorphisms and CD susceptibility. No association was found for any of the MICA alleles independently of DQ genes, whereas TNF-alpha-308 A allele was slightly overrepresented on chromosomes carried by CD patients compared with control chromosomes, indicating that either TNF-alpha, or another gene in linkage disequilibrium with it, could confer increased susceptibility to CD. This result supports the earlier findings that the HLA region harbours a novel susceptibility factor in addition to HLA-DQ.
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PMID:Cytokine gene polymorphisms and genetic association with coeliac disease in the Finnish population. 1564 22

Genetic predisposition to coeliac disease (CD) is determined primarily by alleles at the HLA-DQB locus, and evidence exists implicating other major histocompatibility complex-linked genes (6p21) and the CTLA4 locus on chromosome 2q33. In addition, extensive family studies have provided strong, reproducible evidence for a susceptibility locus on chromosome 5q (CELIAC2). However, the gene responsible has not been identified. We have assayed genetic variation at the IL4, IL5, IL9, IL13, IL17B and NR3C1 (GR) loci, all of which are present on chromosome 5q and have potential or demonstrated involvement in autoimmune and/or inflammatory disease, in a sample of 409 CD cases and 355 controls. Thirteen single nucleotide polymorphisms were chosen on the basis of functional relevance, prior disease association and, where possible, prior knowledge of the haplotype variation present in European populations. There were no statistically significant allele or haplotype frequency differences between cases and controls. Therefore, these results provide no evidence that these loci are associated with CD in this sample population.
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PMID:Chromosome 5q candidate genes in coeliac disease: genetic variation at IL4, IL5, IL9, IL13, IL17B and NR3C1. 1571 13

Binding of peptide epitopes to major histocompatibility complex proteins involves multiple hydrogen bond interactions between the peptide main chain and major histocompatibility complex residues. The crystal structure of HLA-DQ2 complexed with the alphaI-gliadin epitope (LQPFPQPELPY) revealed four hydrogen bonds between DQ2 and peptide main chain amides. This is remarkable, given that four of the nine core residues in this peptide are proline residues that cannot engage in amide hydrogen bonding. Preserving main chain hydrogen bond interactions despite the presence of multiple proline residues in gluten peptides is a key element for the HLA-DQ2 association of celiac disease. We have investigated the relative contribution of each main chain hydrogen bond interaction by preparing a series of N-methylated alphaI epitope analogues and measuring their binding affinity and off-rate constants to DQ2. Additionally, we measured the binding of alphaI-gliadin peptide analogues in which norvaline, which contains a backbone amide hydrogen bond donor, was substituted for each proline. Our results demonstrate that hydrogen bonds at P4 and P2 positions are most important for binding, whereas the hydrogen bonds at P9 and P6 make smaller contributions to the overall binding affinity. There is no evidence for a hydrogen bond between DQ2 and the P1 amide nitrogen in peptides without proline at this position. This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease.
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PMID:Main chain hydrogen bond interactions in the binding of proline-rich gluten peptides to the celiac disease-associated HLA-DQ2 molecule. 1582 53

Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P<10(-14)). DRB1*14 showed striking under-transmission (P=0.000032) to affected offspring newly establishing this allele as a broadly acting resistance factor. Trans interactions were seen in both DRB1*15 and non-DRB1*15 bearing genotype combinations. DRB1*08 was transmitted preferentially with DRB1*15 (P=0.0114) and, in the presence of DRB1*08, the transmission of DRB1*15 was almost invariable (37 transmissions to one non-transmission). DRB1*01 was under-transmitted to offspring in the presence of DRB1*15 (P=0.019). Both DRB1*01 and DRB1*14 haplotypes carry DQA1*01-DQB1*05 alleles, suggesting a common DQ-related mechanism for the protection mediated by these haplotypes. These studies demonstrate that it is the Class II genotype that determines susceptibility and resistance to MS. By analogy with celiac disease and type I diabetes, the pattern of susceptibility strongly supports an autoimmune aetiology.
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PMID:Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. 1593 13

Transglutaminase 2 (TG-ase 2) is one of the enzymes which catalyzes the deamination and transacylation of proteins. The transfer of a glutamine acyl residue to a lysine amine group of the acceptor protein is one of the posttranslational covalent modifications regulating some polypeptide activities. The control of protein oligomerization by TG-ase 2 is a cause of the formation of detergent-insoluble macromolecular aggregates. These inclusions are present in degenerating cells during, for example, Alzheimer's and Parkinson's disease. Overexpression of TG-ase 2 has been noted in apoptotic cells. Protein reserves in cereals are rich in glutamine, a substrate of TG-ase 2. Deamination of glutamine is the most important reaction for the initiation of the inflammatory process during gluten-dependent disease of the gut (celiac disease). Grains that contain gliadin are a cause of inflammatory reaction in children with intolerance to glutene. Interactions of the TG-ase product-glutamate with antigens of the major histocompatibility complex type II (MHC II, or HLA DQ) cause autoimmunological reaction by CD4+ T lymphocytes. Knowledge of the kinetic and molecular character of TG-ase 2 has contributed to finding peptides to replace gliadin. These molecules do not evoke immunological events.
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PMID:[The involvement of transglutaminase 2 in autoimmunological diseases]. 1601 94


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