Publications
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Molinaro, Antonio; Braadland, Peder Rustøen; Carpino, Guido; Carreras, Alba; Nikolaidis, Marios & Hanzely, Petra
[Show all 40 contributors for this article]
(2026).
Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling.
Nature Metabolism.
8(9),
p. 1910–1925.
doi:
10.1038/s42255-026-01600-1.
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Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut–liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.
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Gaddipati, Sirisha; Varsani, Anika; Rosa, Gloria de La; Dominguez-Gil, Beatriz; Colmenero, Jordi & Mendizabal, Manuel
[Show all 17 contributors for this article]
(2025).
Age-stratified Data Highlight Worldwide Variability in Organ Donation Rates and the Potential Increase in Organ Donation.
Transplantation.
ISSN 0041-1337.
110(3),
p. e707–e714.
doi:
10.1097/tp.0000000000005564.
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Background. Ongoing shortages of organs for transplantation have prompted the critical question of which countries have the highest organ donation rates and how each can increase those rates. The existing metric of donors per million population is flawed because it does not sufficiently account for important differences in the underlying population, including age distributions of deaths in the population. Methods. We sought to develop a better approach to analyze country-specific data on organ donation, including deaths stratified by age, to allow assessment of performance across the world. We used death data from the World Health Organization and donation data from 17 countries across 3 continents. We calculated age group-stratified organ donation rates as donors per 1000 deaths and estimated each country’s potential to increase donation if the age group-specific donation rate mirrored that of the highest-performing country in each age group. Results. There was a 4-fold difference in overall donation rates, with far greater variability within age strata, including a 10-fold difference in donation rates for the oldest age group (70 y and older). The United States showed the greatest potential to increase donations in absolute terms (>8000 increased donors per year), whereas Argentina, Germany, and Hungary had the greatest potential in relative terms. Conclusions. Although countries may have similar overall donation rates, the breakdown within specific age groups varies widely. Examining age-specific donation rates is a necessary step for accurate international comparisons of transplant systems and can enable targeted interventions to augment donation.
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ElAbd, Hesham; Pesesky, Mitchell; Innocenti, Gabriel; Chung, Brian K.; Mahdy, Aya K.H. & Kriukova, Valeriia
[Show all 40 contributors for this article]
(2025).
T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis.
Nature Medicine.
ISSN 1078-8956.
31(7),
p. 2306–2316.
doi:
10.1038/s41591-025-03692-w.
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Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC.
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Vestad, Beate; Hanzely, Petra; Karaliūtė, Indrė; Ramberg, Oda Helgesen; Skiecevičienė, Jurgita & Lukoševičius, Rokas
[Show all 12 contributors for this article]
(2025).
Modulation of Dextran Sodium Sulfate-Induced Colitis in Germ-Free Mice by Enterococcus faecalis Monocolonization.
Microorganisms.
13(12).
doi:
10.3390/microorganisms13122864.
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Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis (UC), are characterized by chronic gastrointestinal inflammation and involve complex interactions of genetic, environmental, and immune factors. Enterococcus faecalis, a gut commensal bacterium, has been implicated in IBD pathogenesis. This study investigated the effects of monocolonization with a UC-derived E. faecalis strain on acute dextran sulfate sodium (DSS)-induced colitis in germ-free (GF) mice, focusing on epithelial injury, inflammatory markers, hematologic indices, and bacterial translocation. In DSS-treated mice, monocolonization was associated with modest and mixed effects, including a higher colitis-related disease activity score, reduced anemia, increased fecal albumin and a trend towards reduced fecal calprotectin. Despite translocation of E. faecalis to mesenteric lymph nodes, no systemic dissemination was observed. Histological analysis revealed broadly similar inflammatory patterns between DSS-treated groups, with slightly more epithelial injury observed in colonized mice. These findings suggest that E. faecalis may influence discrete aspects of DSS injury in a strain-dependent and context-specific manner, rather than broadly altering overall disease severity. This study highlights the utility of GF models for examining strain-specific host–microbe interactions and underscores that individual bacterial isolates may exert heterogeneous and selective effects on acute colitis. Further research is needed to elucidate these complex mechanisms.
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Chung, Brian K.; Jordens, Markus S.; Øgaard, Jonas Daniel Sjøberg; Reims, Henrik Mikael; Flateland, Benedicte & Luedde, Tom
[Show all 9 contributors for this article]
(2025).
Multimodal transcriptomics identifies metallothionein as a novel pathway in primary sclerosing cholangitis.
Hepatology.
ISSN 0270-9139.
doi:
10.1097/HEP.0000000000001432.
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Background and Aims:
Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disorder of unknown etiology characterized by uneven peribiliary infiltration and liver fibrosis. To localize potential disease pathways to specific microanatomical liver regions, we combined spatial and single-nuclei transcriptomics (snRNA-seq) to analyze biopsies from a spectrum of PSC and disease control explants.
Approach and Results:
Liver specimens from 23 PSC (transplant indications: 4 recurrent cholangitis, 7 dysplasia, 12 cirrhosis) and 7 disease controls with cirrhosis (4 metabolic dysfunction–associated steatohepatitis, MASH; 3 alcohol-associated liver disease, ALD) were analyzed by spatial transcriptomics (76,664 spots) and 16 of the same explants were also assessed by snRNA-seq (12 PSC, 2 MASH, 2 ALD; 91,891 nuclei). PSC livers expressed a robust signature of metallothionein (MT1E, MT1G, MT1H) and acute inflammation markers (SAA1, SAA2) at the parenchyma–fibrosis interface compared to disease controls. SnRNA-seq showed that the strongest metallothionein signal originated from a subtype of APOE+ hepatocytes that, by spatial transcriptomics and immunohistochemistry, were consistently localized to the edge of fibrotic lesions in PSC explants. Biliary inflammation induced by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding in mice resulted in significant Mt1 liver expression and liver MT1G expression correlated with AST, ALT, ALP, and bilirubin levels at the time of liver transplantation.
Conclusions:
Combinatorial spatial and high-resolution single-nuclei transcriptomics on the largest number of PSC liver explants to date revealed metallothionein as a novel PSC pathway that could be interrogated in future studies aiming to develop effective therapeutic interventions for PSC.
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Hanzely, Petra; Holm, Kristian; Bjørnholt, Jørgen Vildershøj; Melum, Espen; Hov, Johannes Espolin Roksund & Rasmussen, Henrik
(2025).
Efficacy of oral and rectal administration of human faecal microbiota transplant (FMT) in human microbiota-associated mouse models.
Scientific Reports.
15(1),
p. 1–10.
doi:
10.1038/s41598-025-32072-0.
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The gut microbiome has gained significant interest due to its association with immune dysregulation, allergies, autoimmune conditions, metabolic disorders, and inflammation-associated malignancies. Understanding underlying mechanisms requires appropriate in vivo models, such as human microbiota-associated mouse models to study the microbiota–host interactions. This study compared the efficacy of oral and rectal administration of human faecal microbiota transplant (FMT) from a single donor in C57BL/6J germ-free mice as these methods are often used interchangeably. Using 16S rRNA sequencing, we quantified colonisation efficacy in luminal and tissue samples from orally- (n = 6) and rectally- (n = 6) colonised mice. We detected 84 genera in the FMT sample, 17 of which were not transferred at all, while additional 7 genera were found exclusively in rectally-colonised mice. A significantly higher proportion of amplicon sequence variants (ASVs) (33% vs. 26%; P < 0.05) and genera (32% vs. 25%; P < 0.05) were absent in orally- compared to rectally-colonised group. Some taxa showed different relative abundances in human vs. mouse samples (e.g. Alistipes and Bacteroides relatively more abundant in mice while Faecalibacterium considerably decreased). Beta diversity analysis revealed greater similarity between FMT and tissue samples irrespective of the administration route, with distinct separation of the tissue and luminal samples. Overall, rectal administration yielded more overlapping genera and ASVs with FMT, highlighting that it could have advantages compared with oral administration for microbiota establishment studies
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Song, Hui; Goknil, Arda; Xiaojun, Jiang; Melum, Espen; Joe, Hyunwhan & Gazzotti, Caterina
[Show all 9 contributors for this article]
(2025).
Developing Multi-Agent LLM Applications Through Continuous Human-LLM Co-Programming.
In Lewis, Grace & Muccini, Henry (Ed.),
Proceedings of the 2025 IEEE/ACM 4th International Conference on AI Engineering – Software Engineering for AI (CAIN), Ottawa, Ontario, Canada, 27–28 April 2025.
IEEE (Institute of Electrical and Electronics Engineers).
ISSN 9798331502195.
doi:
10.1109/cain66642.2025.00013.
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The rapid advancement of Large Language Models (LLMs) has opened new possibilities for intelligent multi-agent systems capable of autonomously performing complex tasks. To build such systems, LLMs can be leveraged for task-solving, tool interaction, and code generation but at the same time their costs and unpredictability have to be properly managed. To do so this paper introduces COPMA, a model-based approach to enabling continuous human-LLM co-programming of multi-agent LLM applications. COPMA uses feature-block models to track application features and their implementations as agents and code blocks. Supported by co-programming patterns, de-velopers are guided in constructing, refining, and refactoring feature implementations via trial-and-errors with LLM agents, leveraging their feedback, suggestions, and code examples. The patterns guide the shift of feature implementations between agents and code to balance flexibility, predictability, and cost. Our experience in developing LLM agents for collecting and reviewing medical research papers demonstrates that human-LLM co-programming can reduce development effort to enable rapid prototyping of multi-agent LLM applications.
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Breder, Sigurd; Villard, Christina; Eide, Emma; Wang, Benny; Engesæter, Lise Katrine & Reims, Henrik Mikael
[Show all 15 contributors for this article]
(2025).
A retrospective evaluation of preemptive liver transplantation for bile duct dysplasia in primary sclerosing cholangitis: Balancing risks and benefits.
JHEP Reports.
7(12),
p. 1–11.
doi:
10.1016/j.jhepr.2025.101598.
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Background & Aims
Liver transplantation (LT) to prevent cholangiocarcinoma (CCA) in individuals with primary sclerosing cholangitis (PSC) and bile duct dysplasia was introduced in Norway and Sweden in the early 2000s. We aimed to evaluate this practice to potentially improve future selection of candidates for LT.
Methods
We conducted a retrospective study of 512 adults with PSC who underwent first-time LT between 2000–2021 at Oslo and Karolinska University Hospitals. Pre-LT findings in bile duct brush cytology and/or biopsy of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) were compared with histological findings in the explanted livers and survival rates were assessed.
Results
Bile duct dysplasia, low-grade (LGD) or high-grade (HGD), was the primary LT indication in 17% (88/512). Among individuals transplanted for LGD, only 10% (3/29) had HGD or CCA in the explant, compared to 48% (28/59) in the HGD group. No neoplasia was found in 42% (12/29) of LGD and 24% (14/59) of HGD cases, meaning nearly one-third of patients transplanted for suspected bile duct dysplasia had no histological evidence of neoplasia in the explant. Five-year post-transplant survival according to the explant histology was 95% for no neoplasia, 89% for LGD, 85% for HGD, decreasing to 33% in those with CCA in the explant.
Conclusions
While favorable survival in confirmed dysplasia supports the role of preemptive LT, the absence of neoplasia in a substantial proportion of explants, particularly in suspected LGD, calls for a cautious, individualized approach. LT appears more clearly justified in accurately diagnosed HGD, given its strong association with early malignancy and the poor prognosis of advanced CCA.
Impact and implications
Individuals with primary sclerosing cholangitis (PSC) are at increased risk of developing bile duct cancer. In precancerous stages (bile duct dysplasia), liver transplantation (LT) may prevent progression to advanced, incurable cancer. In our evaluation of 512 patients with PSC who underwent LT, we found that the low diagnostic accuracy and unpredictable detection of mild dysplasia support a cautious, individualized approach to LT in precancerous stages of PSC, while more advanced dysplasia remains a valid indication for LT.
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Kopcil, Pavel; Ervik, Carolina W.; Reint, Ganna; Mamia, Katariina; Szymanska, Monika & Dahal-Koirala, Shiva
[Show all 17 contributors for this article]
(2025).
Editing of ADA2 Point Mutation in Human Hematopoietic Stem Cells.
bioRxiv (preprint article).
doi:
10.1101/2025.08.14.670303.
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Abstract Background The homozygous ADA2 : c.506G>A (p.Arg169Gln; p.R169Q) variant accounts for majority of Deficiency in Adenosine Deaminase 2 (DADA2). This monogenic disorder may be amenable to ex vivo gene therapy by correcting the pathogenic mutation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Objective To apply CRISPR-Cas9 and homology-directed repair (HDR) as a surrogate strategy to model correction of the pathogenic ADA2 c.506G>A variant in healthy cord blood HSPCs. Methods HSPCs were electroporated with optimised CRISPR-Cas9 editing reagents, and editing outcomes, including HDR and on-target deletions, were quantified by ddPCR. Cell functionality was assessed through colony-forming unit (CFU) assays and by xenotransplantation into NOD SCID Gamma (NSG) mice. Two HDR enhancement strategies were tested: (1) genetic inhibitors of p53 and non-homologous end joining (NHEJ) pathways, and (2) pharmacological NHEJ inhibition. Results Small-molecule NHEJ inhibitors increased HDR efficiency approximately two-fold (from ∼40 % to ∼80 %). Edited HSPCs retained normal CFU capacity and successfully engrafted in NSG mice. However, up to 8 % of edited cells exhibited on-target chromosome loss, though this declined over time. Up to 40 % of T cells and fibroblasts demonstrated similar losses under NHEJ inhibitors treatment. In contrast, genetically encoded inhibitors did not improve HDR. Conclusion The ADA2 p. c.506G>A variant can be effectively edited employing surrogate strategy in HSPCs without impairing functionality. Although pharmacological inhibition of NHEJ enhances HDR efficiency, it also increases the risk of on-target chromosome aberrations, highlighting the need for careful consideration of the associated risks and benefits in therapeutic gene editing. Key messages 1) The ADA2 p.R169Q variant can be efficiently corrected via HDR, and the edited CD34+ HSPCs retain their engraftment capability in NSG mice. 2) Pharmacological inhibition of NHEJ using small-molecule inhibitors increases HDR efficiency but is associated with significant on-target deletions and chromosomal arm loss, particularly in differentiated cell types, and in a donor-dependent manner. Capsule summary The ADA2 p.R169Q variant is a viable target for precision gene editing in hematopoietic stem cells. Although inhibition of NHEJ improves HDR efficiency, it concomitantly increases the risk of large on-target deletions, particularly in differentiated cells.
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Haaker, Maya W.; Chang, Jung-Chin; Chung, Brian K.; Pieper, Tobias S.; Noé, Falko & Wang, Tongtong
[Show all 13 contributors for this article]
(2025).
Cellular Crosstalk Promotes Hepatic Progenitor Cell Proliferation and Stellate Cell Activation in 3D Co-culture.
Cellular and Molecular Gastroenterology and Hepatology (CMGH).
19(5).
doi:
10.1016/j.jcmgh.2025.101472.
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Background & Aims
Following liver damage, ductular reaction often coincides with liver fibrosis. Proliferation of hepatic progenitor cells is observed in ductular reaction, whereas activated hepatic stellate cells (HSCs) are the main drivers of liver fibrosis. These observations may suggest a functional interaction between these 2 cell types. Here, we report on an in vitro co-culture system to examine these interactions and validate their co-expression in human liver explants.
Methods
In a 3D organoid co-culture system, we combined freshly isolated quiescent mouse HSCs and fluorescently labeled progenitor cells (undifferentiated intrahepatic cholangiocyte organoids), permitting real-time observation of cell morphology and behavior. After 7 days, cells were sorted based on the fluorescent label and analyzed for changes in gene expression.
Results
In the 3D co-culture system, the proliferation of progenitor cells is enhanced, and HSCs are activated, recapitulating the cellular events observed in the patient liver. Both effects in 3D co-culture require close contact between the 2 different cell types. HSC activation during 3D co-culture differs from quiescent (3D mono-cultured) HSCs and activated HSCs on plastic (2D mono-culture). Upregulation of a cluster of genes containing Aldh1a2, Cthrc1, and several genes related to frizzled binding/Wnt signaling were exclusively observed in 3D co-cultured HSCs. The localized co-expression of specific genes was confirmed by spatial transcriptomics in human liver explants.
Conclusion
An in vitro 3D co-culture system provides evidence for direct interactions between HSCs and progenitor cells, which are sufficient to drive responses that are similar to those seen during ductular reaction and fibrosis. This model paves the way for further research into the cellular basis of liver pathology.
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Molinaro, Antonio; Engesæter, Lise Katrine; Jorns, Carl; Nordin, Arno; Rasmussen, Allan & Line, Pål Dag
[Show all 11 contributors for this article]
(2025).
Outcome of Liver Retransplantation in Patients With Primary Sclerosing Cholangitis.
Liver international (Print).
ISSN 1478-3223.
45(1).
doi:
10.1111/liv.16214.
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Background and Aims
Primary sclerosing cholangitis (PSC) is among the most common indications for liver transplantation in the Nordic countries and with an increasing trend in Europe and North America. Due to post-transplant complications and high prevalence of disease recurrence this group is at risk of requiring retransplantation (re-LTX). Results from re-LTX for PSC are not extensively studied and there is a lack of knowledge regarding prognosis after re-LTX in this population.
Methods
Graft and patient survival after re-LTX for patients with PSC and a comparable comparison group from the Nordic liver transplant registry were analysed. One-hundred and eighty-five patients with PSC and 208 patients in the comparison group were included.
Results
The graft and patient survival were better for patients with PSC compared to the comparison group (p < 0.001). Re-LTX for recurrence of PSC (rPSC) compared to other aetiologies had similar and better outcomes for graft and patient survival (p = 0.093 and p = 0.023, respectively). Moreover, re-LTX for rPSC compared to the comparison group had a lower 30-day and 5-year mortality (p < 0.001 and p = 0.041, respectively).
Conclusion
Outcomes after retransplantation for PSC were similar or better compared to the comparison group. Retransplantation represents a treatment option with the potential for excellent outcomes in patients with PSC and should be considered in transplanted PSC patients with graft failure.
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Frank, Anna Katharina; Chung, Brian K.; Novales, Miguel Larraz Lopez De; Engesæter, Lise Katrine; Hoyle, Henry William & Øgaard, Jonas Daniel Sjøberg
[Show all 15 contributors for this article]
(2024).
Single-Cell Transcriptomic Profiling of Cholangiocyte Organoids Derived from Bile Ducts of Primary Sclerosing Cholangitis Patients.
Digestive Diseases and Sciences.
ISSN 0163-2116.
69,
p. 3810–3823.
doi:
10.1007/s10620-024-08570-y.
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Background and Aims Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disorder without effective medical treatment which is characterized by inflammation and fibrotic structures around the bile ducts. Biliary epithelial cells (cholangiocytes) are the target and potential disease drivers in PSC, yet little is known if cholangiocytes from PSC patients differ from non-PSC controls. To characterize cholangiocytes at early rather than end-stage disease, cholangiocyte organoids (COs) were derived from diseased bile ducts of PSC patients and compared to organoids generated from disease controls. Methods Cholangiocytes were obtained during endoscopic retrograde cholangiopancreatography (ERCP) brushing of diseased bile duct areas and expanded as organoids using previously established culture methods. Stable CO lines were analyzed for cell type identity, basic cholangiocyte function, and transcriptomic signature. Results We demonstrate that cholangiocytes, derived from the damaged area within the bile ducts of PSC patients, can be expanded in culture without displaying functional or genetic disease-related features. We further show that COs from patients who later were diagnosed with dysplasia exhibit higher expression of the cancer-associated genes PGC, FXYD2, MIR4435-2HG, and HES1. Conclusions Our results demonstrate that PSC organoids are largely similar to control organoids after culture and highlight the significance of COs as a tool for regenerative medicine approaches as well as their potential for discovering new potential biomarkers for diagnosing cholangiocarcinoma.
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Gregersen, Ida; Kong, Xiang Yi; Kooijman, Sander; Foyn, Håvard; Grannes, Helene & Olsen, Maria Belland
[Show all 25 contributors for this article]
(2024).
T cells with increased responsiveness cause obesity in mice without diet intervention.
iScience.
27(4).
doi:
10.1016/j.isci.2024.109471.
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Obesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell responsiveness, we show that development of obesity can be driven by immune cells. This was confirmed with bone marrow transplantation and adoptive T cell transfer to several recipient mouse models. Single-cell RNA sequencing and CyTOF analysis showed that the mice display altered composition of circulating T cells and increased T cell activation in visceral adipose tissue, suggesting activated T cells as critical players in the increased fat mass. In this study, we provide evidence that obesity can be driven by immune cell activity and in particular by T cells, which could have broad implications for prevention and treatment of this condition.
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Braadland, Peder Rustøen; Bergquist, Annika; Kummen, Martin; Bossen, Lars; Engesæter, Lise Katrine & Reims, Henrik Mikael
[Show all 21 contributors for this article]
(2023).
Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation.
Journal of Hepatology.
ISSN 0168-8278.
79(4),
p. 955–966.
doi:
10.1016/j.jhep.2023.05.038.
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Background and aims We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5’-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). Methods We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. Results In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. Conclusions Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. Impact and implications We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.
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Oldereid, Tine Simensen; Jiang, Xiaojun; Øgaard, Jonas Daniel Sjøberg; Schrumpf, Elisabeth; Bjørnholt, Jørgen & Rasmussen, Henrik
[Show all 7 contributors for this article]
(2023).
Microbial exposure during early life regulates development of bile duct inflammation.
Scandinavian Journal of Gastroenterology.
ISSN 0036-5521.
59(2),
p. 192–201.
doi:
10.1080/00365521.2023.2278423.
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Objectives The early life microbiome has been linked to inflammatory diseases in adulthood and a role for the microbiome in bile duct inflammation is supported by both human and murine studies. We utilized the NOD.c3c4 mouse model that develops a spontaneous immune-driven biliary disease with a known contribution of the microbiome to evaluate the temporal effects of the early life microbiome. Materials and methods Germ-free (GF) NOD.c3c4 mice were conventionalized into a specific pathogen free environment at birth (conventionally raised, CONV-R) or at weaning (germ-free raised, GF-R) and compared with age and gender-matched GF and conventional (CONV) NOD.c3c4 mice. At 9 weeks of age, liver pathology was assessed by conventional histology and flow cytometry immunophenotyping. Results Neonatal exposure to microbes (CONV-R) increased biliary inflammation to similar levels as regular conventional NOD.c3c4 mice, while delayed exposure to microbes (GF-R) restrained the biliary inflammation. Neutrophil infiltration was increased in all conventionalized mice compared to GF. An immunophenotype in the liver similar to CONV was restored in both CONV-R and GF-R compared to GF mice displaying a proportional increase of B cells and reduction of T cells in the liver. Conclusions Microbial exposure during early life has a temporal impact on biliary tract inflammation in the NOD.c3c4 mouse model suggesting that age-sensitive interaction with commensal microbes have long-lasting effects on biliary immunity that can be of importance for human cholangiopathies.
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Oldereid, Tine Simensen; Jiang, Xiaojun; Nordhus, Kathrine Sivertsen; Ponzetta, Andrea; Bjørnholt, Jørgen & Björkström, Niklas K.
[Show all 8 contributors for this article]
(2023).
Role of bacteria and microbial metabolites in immune modulation during early life.
Scandinavian Journal of Immunology.
ISSN 0300-9475.
doi:
10.1111/sji.13336.
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Abstract Host–microbiome interplay from birth is essential for immune imprinting and tuning. Live gut microbes and microbial‐derived metabolites regulate the development and modulation of the immune system, but whether microbial metabolites solely are sufficient to induce immune maturation remains unclear. Sterile faecal filtrates (FFT) were generated from murine gut contents. Newborn germ‐free (GF) mice were treated twice daily with FFT (GF‐FFT) or saline (GF‐NaCl) from post‐natal day 5 until 4 weeks of age. A third group of GF neonates were conventionalized by the transfer of caecal microbiota with live gut microbes. Host immune compartments were comprehensively immunophenotyped and systemically analysed in all available immune‐related organs using flow cytometry. Oral FFT was associated with reduced survival among neonates (n = 7/19; 36.8% mortality), while saline treatment was well tolerated (n = 1/17, 5.9% mortality). Four‐week‐old FFT‐treated pups were comparable in body weight to GF‐NaCl, and the major B‐cell, conventional T‐cell and unconventional T‐cell subsets were unchanged from saline‐treated mice. Live bacteria administered during early life induced clear changes in proportions of B cells, T cells and T‐cell subsets in all mucosal tissues and secondary lymphoid organs compared to GF‐FFT, including restoration of intestinal natural killer T (NKT) cells with characteristics similar to conventional pups. Our findings show that oral administration of a FFT made of microbial metabolites, antigens and bacteriophages alone is insufficient to induce normal immune development elicited by the presence of live bacteria. Reduced survival during neonatal FFT treatment suggests a potential bioactive attribute of sterile faecal filtrates.
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Harrison, Sean Philip; Siller, Richard; Tanaka, Yoshiaki; Dugarte, Maria Eugenia Chollet; Morena-Barrio, María Eugenia de la & Xiang, Yangfei
[Show all 36 contributors for this article]
(2023).
Scalable production of tissue-like vascularized liver organoids from human PSCs.
Experimental and Molecular Medicine.
ISSN 1226-3613.
55,
p. 2005–2024.
doi:
10.1038/s12276-023-01074-1.
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Abstract The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology.
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Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette
[Show all 40 contributors for this article]
(2022).
Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants.
npj Vaccines.
7(1).
doi:
10.1038/s41541-022-00586-7.
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Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.
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Tønnessen, Theis Christian; Melleby, Arne Olav; Hauge-Iversen, Ida Marie; Espe, Emil Knut Stenersen; Ahmed, Muhammad Shakil & Ueland, Thor
[Show all 12 contributors for this article]
(2022).
Impact of delayed type hypersensitivity arthritis on development of heart failure by aortic constriction in mice.
PLOS ONE.
17(1).
doi:
10.1371/journal.pone.0262821.
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Aims
Patients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta.
Methods
Aorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls.
Results
Significant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced.
Conclusion
DTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.
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Chung, Brian K.; Øgaard, Jonas; Reims, Henrik Mikael; Karlsen, Tom Hemming & Melum, Espen
(2022).
Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis.
Hepatology communications..
6(9),
p. 2538–2550.
doi:
10.1002/hep4.2001.
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Liver fibrosis and cirrhosis have limited therapeutic options and represent a serious unmet patient need. Recent use of single-cell RNA sequencing (scRNAseq) has identified enriched cell types infiltrating cirrhotic livers but without defining the microanatomical location of these lineages thoroughly. To assess whether fibrotic liver regions specifically harbor enriched cell types, we explored whether whole-tissue spatial transcriptomics combined with scRNAseq and gene deconvolution analysis could be used to localize cell types in cirrhotic explants of patients with end-stage liver disease (total n = 8; primary sclerosing cholangitis, n = 4; primary biliary cholangitis, n = 2, alcohol-related liver disease, n = 2). Spatial transcriptomics clearly identified tissue areas of distinct gene expression that strongly correlated with the total area (Spearman r = 0.97, p = 0.0004) and precise location (parenchyma, 87.9% mean congruency; range, 73.1%–97.1%; fibrosis, 68.5% mean congruency; range, 41.0%–91.7%) of liver regions classified as parenchymal or fibrotic by conventional histology. Deconvolution and enumeration of parenchymal and fibrotic gene content as measured by spatial transcriptomics into distinct cell states revealed significantly higher frequencies of ACTA2+ FABP4+ and COL3A1+ mesenchymal cells, IL17RA+ S100A8+ and FCER1G+ tissue monocytes, VCAM1+ SDC3+ Kupffer cells, CCL4+ CCL5+ KLRB1+ and GZMA+ IL17RA+ T cells and HLA-DR+, CD37+ CXCR4+ and IGHM+ IGHG+ B cells in fibrotic liver regions compared with parenchymal areas of cirrhotic explants. Conclusion: Our findings indicate that spatial transcriptomes of parenchymal and fibrotic liver regions express unique gene content within cirrhotic liver and demonstrate proof of concept that spatial transcriptomes combined with additional RNA sequencing methodologies can refine the localization of gene content and cell lineages in the search for antifibrotic targets.
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Brevini, Teresa; Maes, Mailis; Webb, Gwilym J; John, Binu V; Fuchs, Claudia Daniela & Buescher, Gustav
[Show all 42 contributors for this article]
(2022).
FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.
Nature.
ISSN 0028-0836.
doi:
10.1038/s41586-022-05594-0.
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Abstract Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2) 1 , could represent a new chemoprophylactic approach for COVID-19 that complements vaccination 2,3 . However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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Valestrand, Laura Cecilie; Zheng, Fei; Hansen, Simen Hyll; Øgaard, Jonas; Hov, Johannes Espolin Roksund & Björkström, Niklas K.
[Show all 9 contributors for this article]
(2022).
Bile from Patients with Primary Sclerosing Cholangitis Contains Mucosal-Associated Invariant T-Cell Antigens.
American Journal of Pathology.
ISSN 0002-9440.
192(4),
p. 629–641.
doi:
10.1016/j.ajpath.2021.12.008.
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Primary sclerosing cholangitis (PSC) is associated with altered microbiota of the gut and bile. Mucosal-associated invariant T (MAIT) cells, enriched in human liver, uniquely recognize microbial-derived metabolites. This study aimed to determine whether bile from patients with PSC contains antigens activating MAIT cells. Bile was collected at the time of liver transplantation from patients with PSC (n = 28). The bile samples were either directly incubated with peripheral blood mononuclear cells from healthy donors or with antigen-presenting cells followed by co-culture with peripheral blood mononuclear cells. MAIT cell activation was assessed by flow cytometry. An anti-MR1 antibody was used to determine whether the activation was major histocompatibility complex class I–related protein (MR1) restricted. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing, and the abundance of the bacterial gene ribD was predicted. Eight of 28 bile samples could activate MAIT cells. This activation was partly MR1-dependent in five of eight bile samples. Microbial DNA was detected in 15 of 28 bile samples, including the five bile samples leading to MR1-dependent activation. A higher abundance of the ribD gene expression in the group of bile samples that could activate MAIT cells was predicted on the basis of the 16S sequencing. In co-culture experiments, cholangiocytes could take up and present biliary antigens to MAIT cells. These findings suggest a pathophysiological pathway in PSC connecting the immune system and the microbiome.
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Yu, Jingru; Refsum, Erle; Helsingen, Lise Mørkved; Folseraas, Trine; Ploner, Alexander & Wieszczy, Paulina
[Show all 15 contributors for this article]
(2022).
Risk of hepato-pancreato-biliary cancer is increased by primary sclerosing cholangitis in patients with inflammatory bowel disease: A population-based cohort study.
United European Gastroenterology Journal (UEG Journal).
ISSN 2050-6406.
10(2),
p. 212–224.
doi:
10.1002/ueg2.12204.
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Background There is continued uncertainty regarding the risks of hepato-pancreato-biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). Objective To give updated estimates on risk of hepato-pancreato-biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra – and extrahepatic cholangiocarcinoma. Methods In a population-based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato-pancreato-biliary cancers by PSC and other clinical characteristics. Results Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow-up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8–5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0–2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2–1.5). The relative risks were considerably higher in PSC-IBD patients, with SIR of 140 (95% CI 123–159) for biliary tract, 38.6 (95% CI 29.2–50.0) for hepatocellular, and 9.0 (95% CI 6.3–12.6) for pancreatic cancer. The SIRs were still slightly increased in non-PSC-IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC-IBD patients, and 0.4% in non-PSC-IBD patients. Conclusions The dramatically increased risks of hepato-pancreato-biliary cancers in PSC-IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non-PSC-IBD patients were not trivial compared to non-IBD related risk factors.
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Busek, Mathias; Aizenshtadt, Aleksandra; Koch, Timo; Frank, Anna; Delon, Ludivine Sylvie Claude & Martinez, Mikel Amirola
[Show all 12 contributors for this article]
(2022).
Pump-less, recirculating organ-on-a-chip (rOoC) platform.
Lab on a Chip.
ISSN 1473-0197.
p. 345–361.
doi:
10.1039/d2lc00919f.
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We developed a novel, pump-less directional flow recirculating organ-on-a-chip (rOoC) platform that creates controlled unidirectional gravity-driven flow by a combination of a 3D-tilting system and an optimized microfluidic layout. The rOoC platform was assembled utilizing a layer-to-layer fabrication technology based on thermoplastic materials. It features two organoid compartments supported by two independent perfusion channels and separated by a hydrogel barrier. We developed a computational model to predict wall shear stress values and then measured the flow rate in the microfluidic channels with micro-Particle-Image-Velocimetry (μPIV). The suitability of the rOoC for functional culture of endothelial cells was tested using HUVECs seeded in the perfusion channels. HUVECs aligned in response to the directional flow, formed a barrier and were able to sprout into the organoid compartments. Next, we demonstrated the viability of human stem-cell derived liver organoids in the organoid compartments. Finally, we show the possibility to circulate immune cells in the microfluidic channels that retain viability without being trapped or activated. The rOoC platform allows growing and connecting of two or more tissue or organ representations on-chip with the possibility of applying gradients, endothelial barriers, microvasculature and circulating cells independent of external tubing and support systems.
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Zimmer, Christine L.; Filipovic, Iva; Cornillet, Martin; O’Rourke, Colm J.; Berglin, Lena & Jansson, Hannes
[Show all 20 contributors for this article]
(2021).
Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma.
Hepatology.
ISSN 0270-9139.
doi:
10.1002/hep.32222.
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Background and Aims Cholangiocarcinoma (CCA) is a malignancy arising from biliary epithelial cells of intra- and extrahepatic bile ducts with dismal prognosis and few nonsurgical treatments available. Despite recent success in the immunotherapy-based treatment of many tumor types, this has not been successfully translated to CCA. Mucosal-associated invariant T (MAIT) cells are cytotoxic innate-like T cells highly enriched in the human liver, where they are located in close proximity to the biliary epithelium. Here, we aimed to comprehensively characterize MAIT cells in intrahepatic (iCCA) and perihilar CCA (pCCA). Approach and Results Liver tissue from patients with CCA was used to study immune cells, including MAIT cells, in tumor-affected and surrounding tissue by immunohistochemistry, RNA-sequencing, and multicolor flow cytometry. The iCCA and pCCA tumor microenvironment was characterized by the presence of both cytotoxic T cells and high numbers of regulatory T cells. In contrast, MAIT cells were heterogenously lost from tumors compared to the surrounding liver tissue. This loss possibly occurred in response to increased bacterial burden within tumors. The residual intratumoral MAIT cell population exhibited phenotypic and transcriptomic alterations, but a preserved receptor repertoire for interaction with tumor cells. Finally, the high presence of MAIT cells in livers of iCCA patients predicted long-term survival in two independent cohorts and was associated with a favorable antitumor immune signature. Conclusions MAIT cell tumor infiltration associates with favorable immunological fitness and predicts survival in CCA.
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Hausken, John; Haugaa, Håkon; Hagness, Morten; Line, Pål-Dag; Melum, Espen & Tønnessen, Tor Inge
(2021).
Thoracic Epidural Analgesia for Postoperative Pain Management in Liver Transplantation: A 10-year Study on 685 Liver Transplant Recipients.
Transplantation direct.
7(2),
p. 1–6.
doi:
10.1097/TXD.0000000000001101.
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Background.
Thoracic epidural analgesia (TEA) is not widely used for postoperative pain management in liver transplantation due to hepatic coagulopathy-related increased risk of inducing an epidural hematoma. However, an increasing number of patients are transplanted for other indications than the end-stage liver disease and without coagulopathy allowing insertion of an epidural catheter.
Methods.
This study is a retrospective observational single-center study of all adult patients undergoing first-time liver transplantation at Oslo University Hospital between January 1, 2008, and December 31, 2017. Data regarding patient characteristics were obtained from the Nordic liver transplant registry, medical records, and pain registration forms. Patients without coagulopathy (international normalized ratio <1.5 and platelets >100 × 109/L) were eligible for TEA.
Results.
Out of 685 first-time liver transplantations in a 10-year period, 327 received TEA, and 358 did not. The median Model of End-stage Liver Disease score was lower in the TEA group than in the non-TEA-group (9 versus 17, P < 0.001), and fewer patients were hospitalized preoperatively (16 versus 127, P < 0.001). The median international normalized ratio (1.1 versus 1.6, P < 0.001) and platelet count (190 versus 78, P < 0.001) were different between the TEA and non-TEA groups. There were no serious complications related to insertion or removal of the TEA catheters. Patients in the TEA group had less pain with a mean numeric rating scale at postoperative days 0–5 of 1.4 versus 1.8 (P = 0.008). Nearly 50% of the patients were prescribed opioids when discharged from hospital (non-TEA 154 versus TEA 158, P = 0.23), and there was no difference after 1 year (P = 0.718).
Conclusions.
Our report revealed very good pain control with both TEA and the non-TEA modality. TEA was without any serious complications like epidural hematoma or infection/abscess in selected liver transplant recipients without severe coagulopathy. Opioid prescription at hospital discharge and by 1-year follow-up did not differ between the groups.
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Valestrand, Laura Cecilie; Berntsen, Natalie Lie; Fei, Zheng; Schrumpf, Erik; Hansen, Simen Hyll & Karlsen, Tom Hemming
[Show all 10 contributors for this article]
(2020).
Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.
Clinical and Experimental Immunology.
ISSN 0009-9104.
doi:
10.1111/cei.13541.
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Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non‐invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end‐stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non‐invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non‐invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT‐reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology.
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Louwe, Maria Cornelia; Olsen, Maria Belland; Kaasbøll, Ole Jørgen; Yang, Kuan; Fosshaug, Linn Elisabeth Lillerud & Alfsnes, Katrine
[Show all 25 contributors for this article]
(2020).
Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction.
JACC: Basic to Translational Science.
ISSN 2452-302X.
5(12),
p. 1210–1224.
doi:
10.1016/j.jacbts.2020.09.013.
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An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3−/− mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients.
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Lissing, Mattias; Nowak, Greg; Adam, René; Karam, Vincent; Boyd, Alexander & Gouya, Laurent
[Show all 21 contributors for this article]
(2020).
Liver Transplantation for Acute Intermittent Porphyria.
Liver transplantation.
ISSN 1527-6465.
doi:
10.1002/lt.25959.
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Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18‐58), and 34 (89%) of the patients were women. A total of 9 patients died during follow‐up, and 2 patients were retransplanted. The 1‐year and 5‐year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5‐year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
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Melum, Espen; Jiang, Xiaojun; Baker, Kirsti B; Macedo, M Fatima; Fritsch, Jürgen & Dowds, C Marie
[Show all 21 contributors for this article]
(2019).
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.
Nature Immunology.
ISSN 1529-2908.
20(12),
p. 1644–1655.
doi:
10.1038/s41590-019-0504-0.
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Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann–Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.
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Thorgersen, Ebbe Billmann; Melum, Espen; Folseraas, Trine; Larsen, Stein Gunnar & Line, Pål Dag
(2018).
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei in a liver-transplanted patient: A case report.
World Journal of Surgical Oncology (WJSO).
16:180,
p. 1–5.
doi:
10.1186/s12957-018-1482-7.
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Background Diagnostic work-ups in transplanted immunosuppressed patients are a challenge as non-specific findings may be interpreted as transplant-related complications. If the disease in question is rare and slowly developing like pseudomyxoma peritonei (PMP), it is even more difficult. Cytoreductive surgery (CRS) and subsequent hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for PMP even with extensive peritoneal spread. CRS-HIPEC for PMP after liver transplantation (LTX) has not been described before. Case presentation A 48-year-old female patient with end-stage primary sclerosing cholangitis (PSC) underwent orthotopic LTX and subsequent pancreaticoduodenectomy after the finding of cholangiocarcinoma in situ in the native common bile duct. Ten years after the transplantation, she developed symptoms and signs suspected to represent graft-related complications. An extensive work-up revealed PMP. Upon reassessment, a cystic mass near the coecum could be seen on computed tomography scan 1 year after transplantation. The multidisiplinary team was hesitant to accept the patient for CRS-HIPEC because of extensive PMP and possible risk to the graft. However, she was eventually accepted and underwent the procedure. The Peritoneal Cancer Index (PCI) was 28 of 39, and surgical debulking was performed followed by HIPEC. The transplant control 2 months after surgery showed no harm to the graft. Conclusions Previous LTX should not exclude the possibility for CRS-HIPEC in PMP, even with extensive burden of disease.
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Schrumpf, Elisabeth; Kummen, Martin; Valestrand, Cecilie; Greiner, Thomas U; Holm, Kristian & Arulampalam, Velmurugesam
[Show all 13 contributors for this article]
(2017).
The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation.
Journal of Hepatology.
ISSN 0168-8278.
66(2),
p. 382–389.
doi:
10.1016/j.jhep.2016.09.020.
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Background & Aims A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intra-hepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice. Methods We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning. Results The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD.c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice. Conclusions NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. Germ free NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal microbiota contributes to disease in this murine model of biliary inflammation. Lay Summary Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. When these mice, that under normal circumstances spontaneously develops disease in their bile ducts, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice.
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Meijerink, Hinta; White, Richard; Løvlie, Astrid Louise; Blasio, Birgitte Freiesleben De; Dalgard, Olav & Amundsen, Ellen Johanna
[Show all 8 contributors for this article]
(2017).
Modelling the burden of hepatitis C infection among people who inject drugs in Norway, 1973–2030.
BMC Infectious Diseases.
17.
doi:
10.1186/s12879-017-2631-2.
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Background Lack of Hepatitis C virus (HCV) incidence data in (Norwegian) high-risk groups impedes the ability to make informed decisions on prevention measures. Thus we rely on modelling to estimate the incidence and burden of HCV infections. Methods We constructed a compartmental model for HCV infections in Norway among active and former people who inject drugs (PWIDs). We based yearly transition rates on literature. The model was fitted to absolute numbers of hepatitis C associated cirrhosis, hepatocellular carcinoma (HCC) and death from national data sources (2000–2013). We estimated the number (95%CI) of HCV infections, cirrhosis, HCC and death and disability adjusted life years (DALYs) due to HCV infections in Norway, 1973–2030. We assumed treatment rates in the projected period were similar to those in 2013. Results The estimated proportion of chronic HCV (including those with cirrhosis and HCC) among PWIDs was stable from 2000 (49%; 4441/9108) to 2013 (43%; 3667/8587). We estimated that the incidence of HCV among PWIDs was 381 new infections in 2015. The estimated number of people with cirrhosis, HCC, and liver transplant was predicted to increase until 2022 (1537 people). DALYs among active PWIDs estimated to peak in 2006 (3480 DALYs) and decrease to 1870 DALYs in 2030. Chronic HCV infection contributes most to the total burden of HCV infection, and peaks at 1917 DALYs (52%) in 2007. The burden of HCV related to PWID increased until 2006 with 81/100,000 DALYs inhabitants and decreased to 68/100,000 DALYs in 2015. Conclusion The burden of HCV associated with injecting drug use is considerable, with chronic HCV infection contributing most to the total burden. This model can be used to estimate the impact of different interventions on the HCV burden in Norway and to perform cost-benefit analyses of various public health measures.
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Landskron, Johannes; Kraggerud, Sigrid M.; Wik, Elisabeth; Dørum, Anne; Bjørnslett, Merete Pauline & Melum, Espen
[Show all 11 contributors for this article]
(2017).
C77G in PTPRC (CD45) is no risk allele for ovarian cancer, but associated with less aggressive disease.
PLOS ONE.
12:e0182030(7),
p. 1–12.
doi:
10.1371/journal.pone.0182030.
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The pan lymphocyte marker CD45 exists in various isoforms arising from alternative splicing of the exons 4, 5 and 6. While naïve T cells express CD45RA translated from an mRNA containing exon 4, exons 4–6 are spliced out to encode the shorter CD45R0 in antigen-experienced effector/memory T cells. The SNP C77G (rs17612648) is located in exon 4 and blocks the exon’s differential splicing from the pre-mRNA, enforcing expression of CD45RA. Several studies have linked C77G to autoimmune diseases but lack of validation in other cohorts has left its role elusive. An incidental finding in an ovarian cancer patient cohort from West Norway (Bergen region, n = 312), suggested that the frequency of C77G was higher among ovarian cancer patients than in healthy Norwegians (n = 1,357) (3.0% vs. 1.8% allele frequency). However, this finding could not be validated in a larger patient cohort from South-East Norway (Oslo region, n = 1,198) with 1.2% allele frequency. Hence, C77G is not associated with ovarian cancer in the Norwegian population. However, its frequency was increased in patients with FIGO stage II, endometrioid histology or an age at diagnosis of 60 years or older indicating a possible association with a less aggressive cancer type.
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Vesterhus, Mette; Holm, Anders; Hov, Johannes Espolin Roksund; Nygård, Ståle; Schrumpf, Erik & Melum, Espen
[Show all 23 contributors for this article]
(2017).
Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.
Journal of Hepatology.
ISSN 0168-8278.
66(6),
p. 1214–1222.
doi:
10.1016/j.jhep.2017.01.019.
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Background & Aims Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC). Methods Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992–2006] and n = 138 [2008–2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100). Results In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p <0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p <0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival. Conclusions Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC. Lay summary Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis.
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Liaskou, Evaggelia; Henriksen, Eva Kristine Klemsdal; Holm, Kristian; Kaveh, Fatemeh; Hamm, D & Fear, Janine
[Show all 13 contributors for this article]
(2016).
High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires.
Hepatology.
ISSN 0270-9139.
63(5),
p. 1608–1619.
doi:
10.1002/hep.28116.
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Hepatic T-cell infiltrates and a strong genetic human leukocyte antigen association represent characteristic features of various immune-mediated liver diseases. Conceptually the presence of disease-associated antigens is predicted to be reflected in T-cell receptor (TCR) repertoires. Here, we aimed to determine if disease-associated TCRs could be identified in the nonviral chronic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD). We performed high-throughput sequencing of the TCRβ chain complementarity-determining region 3 of liver-infiltrating T cells from PSC (n = 20), PBC (n = 10), and ALD (n = 10) patients, alongside genomic human leukocyte antigen typing. The frequency of TCRβ nucleotide sequences was significantly higher in PSC samples (2.53 ± 0.80, mean ± standard error of the mean) compared to PBC samples (1.13 ± 0.17, P < 0.0001) and ALD samples (0.62 ± 0.10, P < 0.0001). An average clonotype overlap of 0.85% was detected among PSC samples, significantly higher compared to the average overlap of 0.77% seen within the PBC (P = 0.024) and ALD groups (0.40%, P < 0.0001). From eight to 42 clonotypes were uniquely detected in each of the three disease groups (≥30% of the respective patient samples). Multiple, unique sequences using different variable family genes encoded the same amino acid clonotypes, providing additional support for antigen-driven selection. In PSC and PBC, disease-associated clonotypes were detected among patients with human leukocyte antigen susceptibility alleles. Conclusion: We demonstrate liver-infiltrating disease–associated clonotypes in all three diseases evaluated, and evidence for antigen-driven clonal expansions. Our findings indicate that differential TCR signatures, as determined by high-throughput sequencing, may represent an imprint of distinctive antigenic repertoires present in the different chronic liver diseases; this thereby opens up the prospect of studying disease-relevant T cells in order to better understand and treat liver disease. (Hepatology 2015)
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Olin, Per Bertil Mårten; Hausken, John; Foss, Aksel; Karlsen, Tom Hemming; Melum, Espen & Haugaa, Håkon
(2015).
Continuous molecular adsorbent recirculating system treatment in 69 patients listed for liver transplantation.
Scandinavian Journal of Gastroenterology.
ISSN 0036-5521.
50(9),
p. 1127–1134.
doi:
10.3109/00365521.2015.1027262.
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Næss, Sigrid; Lie, Benedicte Alexandra; Melum, Espen; Olsson, Marita; Hov, Johannes Espolin Roksund & Croucher, PJP
[Show all 15 contributors for this article]
(2014).
Refinement of the MHC risk map in a Scandinavian primary sclerosing cholangitis population.
PLOS ONE.
9:e0114486(12).
doi:
10.1371/journal.pone.0114486.
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Background Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel. Methodology/Principal Findings A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10−11). Conclusions/Significance Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.
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Eskesen, Arne N; Bjøro, Kristian; Aandahl, Einar Martin; Line, Pål Dag & Melum, Espen
(2014).
Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway-A population-based cohort study.
Cancer Epidemiology.
ISSN 1877-7821.
38(6),
p. 741–747.
doi:
10.1016/j.canep.2014.10.005.
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Fosby, Bjarte; Næss, Sigrid; Hov, Johannes Espolin Roksund; Traherne, James; Boberg, Kirsten Muri & Trowsdale, John
[Show all 12 contributors for this article]
(2014).
HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation.
World Journal of Gastroenterology (WJG).
ISSN 1007-9327.
20(14),
p. 3986–4000.
doi:
10.3748/wjg.v20.i14.3986.
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AIM: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX). METHODS: In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR. RESULTS: Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups. CONCLUSION: We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
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Folseraas, Trine; Melum, Espen; Franke, Andre & Karlsen, Tom Hemming
(2011).
Genetics in primary sclerosing cholangitis.
Baillière's Best Practice & Research Clinical Gastroenterology.
ISSN 1521-6918.
25(6),
p. 713–726.
doi:
10.1016/j.bpg.2011.09.010.
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Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models. (C) 2011 Elsevier Ltd. All rights reserved.
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Folseraas, Trine; Melum, Espen; Franke, Andre & Karlsen, Tom Hemming
(2011).
Best Practice & Research Clinical Gastroenterology.
Baillière's Best Practice & Research Clinical Gastroenterology.
ISSN 1521-6918.
25(6),
p. 713–726.
doi:
10.1016/j.bpg.2011.09.010.
Full text in Research Archive
Show summary
Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models. (C) 2011 Elsevier Ltd. All rights reserved.
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Huang, Yu-Hwa; Zhu, Chen; Kondo, Yasuyuki; Anderson, Ana C.; Gandhi, Amit & Russell, Andrew
[Show all 24 contributors for this article]
(2024).
Correction to: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion (Nature, (2015), 517, 7534, (386-390), 10.1038/nature13848).
Nature.
ISSN 0028-0836.
doi:
10.1038/s41586-024-07164-y.
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Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette
[Show all 40 contributors for this article]
(2023).
Author Correction: Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants (npj Vaccines, (2022), 7, 1, (174), 10.1038/s41541-022-00586-7).
npj Vaccines.
8(1).
doi:
10.1038/s41541-023-00600-6.
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Fosby, Bjarte; Karlsen, Tom Hemming & Melum, Espen
(2012).
Recurrence and rejection in liver transplantation for primary sclerosing cholangitis.
World Journal of Gastroenterology (WJG).
ISSN 1007-9327.
18(1),
p. 1–15.
doi:
10.3748/wjg.v18.i1.1.
Full text in Research Archive
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Eskesen, Arne N; Melum, Espen; Moghaddam, Amir; Bjøro, K; Verbaan, H & Ring-Larsen, H.
[Show all 7 contributors for this article]
(2011).
GENETIC VARIANTS AT THE ITPA LOCUS PROTECTS AGAINST RIBAVIRIN-INDUCED HEMOLYTIC ANEMIA - A REPLICATION STUDY IN A SCANDINAVIAN HCV G2/G3 COHORT.
Journal of Hepatology.
ISSN 0168-8278.
54,
p. S455–S455.
Full text in Research Archive
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Dalgard, Olav; Moghaddam, Amir; Verbaan, Hans; Ring-Larsen, Helmer; Bjøro, Kristian & Melum, Espen
(2010).
IL28B GENETIC VARIATION AND TREATMENT RESPONSE IN PATIENTS WITH HCV GENOTYPE 3 INFECTION.
Hepatology.
ISSN 0270-9139.
52(4),
p. 751A–751A.
Full text in Research Archive
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Published
Mar. 15, 2018 9:30 AM
- Last modified
Nov. 9, 2022 12:59 PM
