| 1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
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| 3. |
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| 4. |
- Akiba, K., et al.
(author)
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LHC forward physics
- 2016
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In: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 43:11
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Journal article (peer-reviewed)
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| 5. |
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| 6. |
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| 7. |
- Bellenguez, C, et al.
(author)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Journal article (peer-reviewed)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 8. |
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| 9. |
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| 10. |
- Fernandez, J. L. Abelleira, et al.
(author)
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A Large Hadron Electron Collider at CERN
- 2012
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In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Journal article (peer-reviewed)
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| 11. |
- Alic, I., et al.
(author)
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Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
- 2021
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10, s. 5766-5788
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Journal article (peer-reviewed)abstract
- A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of beta-amyloid-(A beta)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A beta deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical beta and gamma-secretase inhibition. We found that T21 organoids secrete increased proportions of A beta-preventing (A beta 1-19) and A beta-degradation products (A beta 1-20 and A beta 1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in similar to 30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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| 12. |
- Escott-Price, Valentina, et al.
(author)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 13. |
- Angeles-Martinez, R., et al.
(author)
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Transverse Momentum Dependent (TMD) Parton Distribution Functions: Status and Prospects
- 2015
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In: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 46:12, s. 2501-2534
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Journal article (peer-reviewed)abstract
- We review transverse momentum dependent (TMD) parton distribution functions, their application to topical issues in high-energy physics phenomenology, and their theoretical connections with QCD resummation, evolution and factorization theorems. We illustrate the use of TMDs via examples of multi-scale problems in hadronic collisions. These include transverse momentum q(T) spectra of Higgs and vector bosons for low q(T), and azimuthal correlations in the production of multiple jets associated with heavy bosons at large jet masses. We discuss computational tools for TMDs, and present the application of a new tool, TMDLIB, to parton density fits and parameterizations.
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| 14. |
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| 15. |
- Jones, Lesley, et al.
(author)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Journal article (peer-reviewed)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 16. |
- Wallon, Conny, et al.
(author)
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Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro
- 2008
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In: Gut. - London UK : BMJ Group. - 0017-5749 .- 1468-3288. ; 57:1, s. 50-58
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Journal article (peer-reviewed)abstract
- Objective: Persistent stress and life events affect the course of ulcerativecolitis and irritable bowel syndrome by largely unknown mechanisms.Corticotropin-releasing hormone (CRH) has been implicated asan important mediator of stress-induced abnormalities in intestinalmucosal function in animal models, but to date no studies inhuman colon have been reported. The aim was to examine the effectsof CRH on mucosal barrier function in the human colon and toelucidate the mechanisms involved in CRH-induced hyper-permeability.Design: Biopsies from 39 volunteers were assessed for macromolecularpermeability (horseradish peroxidise (HRP), 51Cr-EDTA), andelectrophysiology after CRH challenge in Ussing chambers. Thebiopsies were examined by electron and confocal microscopy forHRP and CRH receptor localisation, respectively. Moreover, CRHreceptor mRNA and protein expression were examined in the humanmast cell line, HMC-1.Results: Mucosal permeability to HRP was increased by CRH (2.8±0.5pmol/cm2/h) compared to vehicle exposure (1.5±0.4 pmol/cm2/h),p = 0.032, whereas permeability to 51Cr-EDTA and transmucosalelectrical resistance were unchanged. The increased permeabilityto HRP was abolished by -helical CRH (9-41) (1.3±0.6pmol/cm2/h) and the mast cell stabiliser, lodoxamide (1.6±0.6pmol/cm2/h). Electron microscopy showed transcellular passageof HRP through colonocytes. CRH receptor subtypes R1 and R2were detected in the HMC-1 cell line and in lamina propria mastcells in human colon.Conclusions: Our results suggest that CRH mediates transcellular uptake ofHRP in human colonic mucosa via CRH receptor subtypes R1 andR2 on subepithelial mast cells. CRH-induced macromolecular uptakein human colon mucosa may have implications for stress-relatedintestinal disorders.
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| 17. |
- Keita, Åsa V, et al.
(author)
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Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum
- 2006
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In: Laboratory investigation. - : Elsevier BV. - 0023-6837 .- 1530-0307. ; 86:5, s. 504-516
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Journal article (peer-reviewed)abstract
- The follicle-associated epithelium (FAE), covering Peyer's patches, provides a route of entry for antigens and microorganisms. Animal studies showed enhanced antigen and bacterial uptake in FAE, but no study on barrier function of human FAE has been reported. Our aim was to characterize the normal barrier properties of human FAE. Specimens of normal ileum were taken from 30 patients with noninflammatory colonic disease. Villus epithelium (VE) and FAE were identified and mounted in Ussing chambers. Permeability to 51Cr-EDTA, transmucosal flux of the protein antigen, horseradish peroxidase (HRP), and transport of fluorescent Escherichia coli (chemically killed K-12 and live HB101) were measured. Uptake mechanisms were studied by confocal- and transmission electron microscopy, and by using pharmacological inhibitors in an in vitro coculture model of FAE and in human ileal FAE. HRP flux was substantially higher in FAE than in VE, and was reduced by an amiloride analog. Electron microscopy showed HRP-containing endosomes. Transport of E. coli K-12 and HB101 was also augmented in FAE and was confirmed by confocal microscopy. In vitro coculture experiments and electron microscopy revealed actin-dependent, mainly transcellular, uptake of E. coli K-12 into FAE. 51Cr-EDTA permeability was equal in FAE and VE. Augmented HRP flux and bacterial uptake but similar paracellular permeability, suggest functional variations of transcellular transport in the FAE. We show for the first time that FAE of human ileum is functionally distinct from regular VE, rendering the FAE more prone to bacterial–epithelial cell interactions and delivery of antigens to the mucosal immune system.
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| 18. |
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| 19. |
- Münch, Andreas, 1970-, et al.
(author)
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Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, and after loop ileostomy
- 2005
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In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 54:8, s. 1126-1128
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Journal article (peer-reviewed)abstract
- Collagenous colitis has become a more frequent diagnosis but the aetiology of this disease is still unknown. We describe a female patient with intractable collagenous colitis who was treated with a temporary loop ileostomy. She was followed clinically, histopathologically, and functionally by measuring mucosal permeability before surgery, after ileostomy, and after bowel reconstruction. In our case report, active collagenous colitis was combined with increased transcellular and paracellular mucosal permeability. Diversion of the faecal stream decreased inflammation of the mucosa and normalised epithelial degeneration and mucosal permeability. After restoration of bowel continuity, mucosal permeability was altered prior to the appearance of a collagenous layer.
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| 20. |
- Persborn, Mats, et al.
(author)
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Effects of probiotics (Ecologic 825) on barrier function during maintenance treatment for severe pouchitis
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Other publication (other academic/artistic)abstract
- Background : About 10-15% of patients with an ileoanal pouch develop a severe, form of pouchitis that necessitates long and/or frequent use of antibiotics and in rare cases even pouch excision. Probiotics have been shown to reduce the risk of recurrence after induction treatment with antibiotics. The mechanisms behind the positive effects of probiotics are not fully understood. The aim of our study was to examine the mucosal barrier function in relation to pouchitis, before and after treatment with probiotics. Methods: 16 patients with a history of severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: Once during active pouchitis, second after 4 weeks of treatment with antibiotics until clinical remission and third after eight weeks of probiotic treatment. 13 controls with an ileoanal pouch with no recent history of pouchitis were used. The biopsies were mounted in Ussing chambers and mucosal barrier function was assessed by electrophysiology, transmucosal uptake of E coli K12, permeability to Cr-EDTA and Horseradish peroxidase (HRP). Pouchitis Disease Activity Index (PDAI) was used in all subjects. Results: PDAI was significantly improved after treatment with antibiotics and probiotics. There was a significant difference in E. coli K12 passage before treatment compared to controls (3.7 units (3.4-8.5) vs 1.7 units (1.0-2.4) p< 0.01). E. coli K12 passage did not change after antibiotic treatment (5.0 units (3.3-7.1) p = ns vs controls). In contrast a significant reduction in bacterial uptake was seen after probiotics (2.2 units (1.8-3.3) p< 0.05). Likewise, a significant normalization of HRP flux was seen after probiotic treatment. Pouchitis did not affect paracellular permability or electrophysiology. Conclusion: Probiotic treatment restored the increased permeation to E. coli and HRP in patients with chronic pouchitis. This could be an important factor behind the positive effects of probiotics in patients with chronic pouchitis.
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| 21. |
- Persborn, Mats, et al.
(author)
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The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis
- 2013
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In: Alimentary Pharmacology and Therapeutics. - : Wiley-Blackwell. - 0269-2813 .- 1365-2036. ; 38:7, s. 772-783
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Journal article (peer-reviewed)abstract
- Background less thanbrgreater than less thanbrgreater thanA total of 10-15% of patients with an ileoanal pouch develop severe pouchitis necessitating long-term use of antibiotics or pouch excision. Probiotics reduce the risk of recurrence of pouchitis, but mechanisms behind these effects are not fully understood. less thanbrgreater than less thanbrgreater thanAim less thanbrgreater than less thanbrgreater thanTo examine mucosal barrier function in pouchitis, before and after probiotic supplementation and to assess composition of mucosal pouch microbiota. less thanbrgreater than less thanbrgreater thanMethods less thanbrgreater than less thanbrgreater thanSixteen patients with severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: during active pouchitis; clinical remission by 4 weeks of antibiotics; after 8 weeks of subsequent probiotic supplementation (Ecologic 825, Winclove, Amsterdam, the Netherlands). Thirteen individuals with a healthy ileoanal pouch were sampled once as controls. Ussing chambers were used to assess transmucosal passage of Escherichia coli K12, permeability to horseradish peroxidase (HRP) and Cr-51-EDTA. Composition and diversity of the microbiota was analysed using Human Intestinal Tract Chip. less thanbrgreater than less thanbrgreater thanResults less thanbrgreater than less thanbrgreater thanPouchitis Disease Activity Index (PDAI) was significantly improved after antibiotic and probiotic supplementation. Escherichia coli K12 passage during active pouchitis [3.7 (3.4-8.5); median (IQR)] was significantly higher than in controls [1.7 (1.0-2.4); P andlt; 0.01], did not change after antibiotic treatment [5.0 (3.3-7.1); P = ns], but was significantly reduced after subsequent probiotic supplementation [2.2 (1.7-3.3); P andlt; 0.05]. No significant effects of antibiotics or probiotics were observed on composition of mucosal pouch microbiota; however, E. coli passage correlated with bacterial diversity (r = -0.40; P = 0.018). Microbial groups belonging to Bacteroidetes and Clostridium clusters IX, XI and XIVa were associated with healthy pouches. less thanbrgreater than less thanbrgreater thanConclusions less thanbrgreater than less thanbrgreater thanProbiotics restored the mucosal barrier to E. coli and HRP in patients with pouchitis, a feasible factor in prevention of recurrence during maintenance treatment. Restored barrier function did not translate into significant changes in mucosal microbiota composition, but bacterial diversity correlated with barrier function.
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| 22. |
- Saddiki, H., et al.
(author)
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Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study
- 2020
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In: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:8
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Journal article (peer-reviewed)abstract
- Background The epsilon 4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association betweenAPOEgenotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of beta-amyloid peptide (A, beta-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated withAPOEgenotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least oneAPOE epsilon 4 allele. Compared with non-epsilon 4 carriers, heterozygous epsilon 4 carriers had a 4.6 (95% confidence interval 4.1-5.2;p< 0.001) and epsilon 4/epsilon 4 homozygotes a 25.4 (20.4-31.2;p< 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (pfor interaction < 0.001). The PAF associated with carrying at least one epsilon 4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect ofAPOE epsilon 2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE epsilon 4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect ofAPOE epsilon 4 at the population level. Author summaryWhy was this study done? The epsilon 4 allele of apolipoprotein E () gene () and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The recent development of diagnostic criteria based on biomarkers that reflect brain beta-amyloid and tau lesions (beta-amyloid deposition, pathologic tau, neurodegeneration [A/T/N] classification]) increases homogeneity in diagnosed cases. The strength of association of AD with risk factors can be better determined using biomarker-based AD compared with AD diagnosis based only on clinical criteria because the latter are known to lack specificity as a result of difficulties in ruling out other causes of dementia. What did the researchers do and find? We compared the overall and age-specific association between and AD using a case-control study that included 1,593 AD cases from memory clinics with positive cerebrospinal fluid biomarkers and 11,723 dementia-free controls drawn from two longitudinal cohort studies. The use of a large number of cases and controls allows assessment of whether the association between and AD is dependent on age. Compared with controls, patients with AD were more likely to carry one (odds ratio [OR] = 4.6) or two (OR = 25.3). This association was significantly modified by age, with the strongest association seen between 65 and 70 years of age and weaker associations at the two tails of the age distribution. What do these findings mean? Incorporating biomarkers for diagnosis of AD identified an association with that is apparently greater than has been previously reported using clinical diagnosis of the disease. The impact of on the risk of AD was strongest between the 65 and 70 years of age, earlier than the mean age at diagnosis in this study, which was 72.8 years.
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| 23. |
- Velin Keita, Åsa, et al.
(author)
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Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats
- 2004
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In: Gut. - : BMJ. - 0017-5749. ; 53:4, s. 494-500
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Journal article (peer-reviewed)abstract
- Background: Chronic stress affects the course of inflammatory bowel disease and experimental colitis, and may also initiate intestinal inflammation in rats. Aim: To investigate the effects of stress on the M cell containing follicle associated epithelium, specialised in antigen uptake. Subjects and methods: Wistar rats were submitted to acute water avoidance stress for one hour or chronic water avoidance stress for 1 hour/day for 10 consecutive days. Permeability to 51Cr-EDTA, horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied in both villus and follicle associated epithelium in Ussing chambers. Segments were further examined by light, electron, and confocal microscopy. Results: Acute stress increased horseradish peroxidase flux in villus as well as in follicle associated epithelium. Chronic stress further increased permeability to horseradish peroxidase in villus and follicle associated epithelium, in the latter by almost fourfold. Moreover, chronic stress induced over 30 times increased E coli passage in follicle associated epithelium whereas there was no significant increase in villus epithelium. Bacterial uptake was confirmed by confocal microscopy showing fluorescent bacteria penetrating and passing through the epithelial surface. Conclusions: These results show that the barrier function of follicle associated epithelium can be modulated, and that chronic stress enhances the uptake of luminal antigens and bacteria via the follicle associated epithelium. This can increase antigen exposure in Peyer’s patches thereby having implications in the initiation of proinflammatory immune responses within the intestinal mucosa.
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| 24. |
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| 25. |
- Wallon, Conny, et al.
(author)
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Corticotropin-Releasing Hormone and Mast Cells in the Regulation of Mucosal Barrier Function in the Human Colon
- 2009
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In: MOLECULAR STRUCTURE AND FUNCTION OF THE TIGHT JUNCTION: FROM BASIC MECHANISMS TO CLINICAL MANIFESTATIONS. - : Wiley. - 0077-8923. ; 1165, s. 206-210
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Journal article (peer-reviewed)abstract
- Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.
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| 26. |
- Wallon, Conny, et al.
(author)
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Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon
- 2005
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 40:5, s. 586-595
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Journal article (peer-reviewed)abstract
- Objective Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine. Material and methods Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions. Results In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP. Conclusions Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.
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| 27. |
- Wallon, Conny, et al.
(author)
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Eosinophils Express Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier in Ulcerative Colitis
- 2011
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In: Gastroenterology. - : Elsevier Science B.V. Amsterdam. - 0016-5085 .- 1528-0012. ; 140:5, s. 1597-1607
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Journal article (peer-reviewed)abstract
- BACKGROUND andamp; AIMS: Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropinreleasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS: Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers (51Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS: Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), alpha-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS: We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.
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| 28. |
- Yakymenko, Olena, 1988-, et al.
(author)
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Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
- 2018
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In: Scandinavian Journal of Gastroenterology. - Oxfordshire, United Kingdom : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 53:6, s. 677-684
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Journal article (peer-reviewed)abstract
- Objective: Infliximab is important in the therapeutic arsenal of Crohn’s disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.Materials and methods: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.Results: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450–3000); controls 1163(225–1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8–1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.Conclusion: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab’s clinical efficacy in colonic CD.
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