| 1. |
- Heap, Graham A., et al.
(författare)
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HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:10, s. 1131-1134
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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| 2. |
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| 3. |
- Lindén, Sara K., 1974, et al.
(författare)
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MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy.
- 2009
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- The bacterium Helicobacter pylori can cause peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. The cell-surface mucin MUC1 is a large glycoprotein which is highly expressed on the mucosal surface and limits the density of H. pylori in a murine infection model. We now demonstrate that by using the BabA and SabA adhesins, H. pylori bind MUC1 isolated from human gastric cells and MUC1 shed into gastric juice. Both H. pylori carrying these adhesins, and beads coated with MUC1 antibodies, induced shedding of MUC1 from MKN7 human gastric epithelial cells, and shed MUC1 was found bound to H. pylori. Shedding of MUC1 from non-infected cells was not mediated by the known MUC1 sheddases ADAM17 and MMP-14. However, knockdown of MMP-14 partially affected MUC1 release early in infection, whereas ADAM17 had no effect. Thus, it is likely that shedding is mediated both by proteases and by disassociation of the non-covalent interaction between the alpha- and beta-subunits. H. pylori bound more readily to MUC1 depleted cells even when the bacteria lacked the BabA and SabA adhesins, showing that MUC1 inhibits attachment even when bacteria cannot bind to the mucin. Bacteria lacking both the BabA and SabA adhesins caused less apoptosis in MKN7 cells than wild-type bacteria, having a greater effect than deletion of the CagA pathogenicity gene. Deficiency of MUC1/Muc1 resulted in increased epithelial cell apoptosis, both in MKN7 cells in vitro, and in H. pylori infected mice. Thus, MUC1 protects the epithelium from non-MUC1 binding bacteria by inhibiting adhesion to the cell surface by steric hindrance, and from MUC1-binding bacteria by acting as a releasable decoy.
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| 4. |
- van Asseldonk, Dirk P, et al.
(författare)
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Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease-Proceedings of the first Thiopurine Task Force meeting
- 2011
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Ingår i: DIGESTIVE AND LIVER DISEASE. - : Elsevier Science B.V., Amsterdam. - 1590-8658. ; 43:4, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Background: Thiopurines, such as azathioprine and mercaptopurine, are of pivotal importance in the treatment of inflammatory bowel disease. Although these drugs have been used for several decades, still many questions remain unanswered. Aim: To provide an overview of clinically and scientifically challenging topics concerning thiopurine therapy in inflammatory bowel disease treatment. Methods: The first meeting of the Thiopurine Task Force Interest Group was held during the 2009 United European Gastroenterology Week in London (GASTRO2009). The topics of this meeting were of particular clinical and scientific interest. Additional literature was identified by performing a Pubmed search using the search terms inflammatory bowel disease, azathioprine, 6-mercaptopurine and thioguanine. Results: The following topics were discussed: therapeutic drug monitoring; the synergy of thiopurines with aminosalicylates and allopurinol; serious adverse events such as opportunistic infections, hepatotoxicity, carcinogenicity and pancreatitis; prolongation of thiopurines during clinical remission; indications for thiopurines in the postoperative setting; and the potential use of thioguanine. Specific interesting and clinically relevant topics for potential future research are provided. Conclusions: Thiopurines remain central to inflammatory bowel disease treatment, although future studies are required to substantiate a more personalised medicine approach to their use.
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| 5. |
- Lindén, Sara K., 1974, et al.
(författare)
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Mucin dynamics in intestinal bacterial infection.
- 2008
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 3:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bacterial gastroenteritis causes morbidity and mortality in humans worldwide. Murine Citrobacter rodentium infection is a model for gastroenteritis caused by the human pathogens enteropathogenic Escherichia coli and enterohaemorrhagic E. coli. Mucin glycoproteins are the main component of the first barrier that bacteria encounter in the intestinal tract. METHODOLOGY/PRINCIPAL FINDINGS: Using Immunohistochemistry, we investigated intestinal expression of mucins (Alcian blue/PAS, Muc1, Muc2, Muc4, Muc5AC, Muc13 and Muc3/17) in healthy and C. rodentium infected mice. The majority of the C. rodentium infected mice developed systemic infection and colitis in the mid and distal colon by day 12. C. rodentium bound to the major secreted mucin, Muc2, in vitro, and high numbers of bacteria were found in secreted MUC2 in infected animals in vivo, indicating that mucins may limit bacterial access to the epithelial surface. In the small intestine, caecum and proximal colon, the mucin expression was similar in infected and non-infected animals. In the distal colonic epithelium, all secreted and cell surface mucins decreased with the exception of the Muc1 cell surface mucin which increased after infection (p<0.05). Similarly, during human infection Salmonella St Paul, Campylobacter jejuni and Clostridium difficile induced MUC1 in the colon. CONCLUSION: Major changes in both the cell-surface and secreted mucins occur in response to intestinal infection.
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| 6. |
- Png, Chin Wen, et al.
(författare)
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Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria.
- 2010
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Ingår i: The American journal of gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 1572-0241 .- 0002-9270. ; 105:11, s. 2420-2428
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Mucosa-associated bacteria are increased in inflammatory bowel disease (IBD), which suggests the possibility of an increased source of digestible endogenous mucus substrate. We hypothesized that mucolytic bacteria are increased in IBD, providing increased substrate to sustain nonmucolytic mucosa-associated bacteria. METHODS: Mucolytic bacteria were characterized by the ability to degrade human secretory mucin (MUC2) in pure and mixed anaerobic cultures. Real-time PCR was used to enumerate mucosa-associated mucolytic bacteria in 46 IBD and 20 control patients. Bacterial mucolytic activity was tested in vitro using purified human MUC2. RESULTS: We confirm increased total mucosa-associated bacteria 16S rRNA gene in macroscopically and histologically normal intestinal epithelium of both Crohn's disease (CD) (mean 1.9-fold) and ulcerative colitis (UC) (mean 1.3-fold). We found a disproportionate increase in some mucolytic bacteria. Mean Ruminococcus gnavus were increased >4-fold and Ruminococcus torques ∼100-fold in macroscopically and histologically normal intestinal epithelium of both CD and UC. The most abundantly detected mucolytic bacterium in controls, Akkermansia muciniphila, was reduced many fold in CD and in UC. Coculture of A. muciniphila with MUC2 as the sole carbon source led to reduction in its abundance while it augmented growth of other bacteria. CONCLUSIONS: Mucolytic bacteria are present in healthy humans, where they are an integral part of the mucosa-associated bacterial consortium. The disproportionate increase in R. gnavus and R. torques could explain increased total mucosa-associated bacteria in IBD.
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