| 1. |
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| 2. |
- Amcoff, Karin, et al.
(author)
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Prognostic significance of faecal eosinophil granule proteins in inflammatory bowel disease
- 2019
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In: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 54:10, s. 1237-1244
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Journal article (peer-reviewed)abstract
- Background: Non-invasive markers for predicting relapse would be a useful tool for the management of patients with inflammatory bowel disease. Eosinophil granulocytes and their granule proteins eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) have previously been shown to reflect disease activity in Crohn's disease and ulcerative colitis.Aim: To examine the capacity of faecal ECP and EDN to predict relapse in ulcerative colitis and Crohn's disease, and to compare these proteins with faecal calprotectin.Methods: Patients with Crohn's disease (n=49) and ulcerative colitis (n=55) were followed prospectively until relapse or end of the two-year study period. Faecal samples were obtained every third month. The predictive value of ECP and EDN was assessed in Cox regression models.Results: In ulcerative colitis, a doubled EDN or ECP concentration was associated with a 31% and 27% increased risk of relapse, respectively. EDN levels were increased both at relapse and three months prior. By contrast, in Crohn's disease, the concentration of EDN was higher among patients in remission than in those who relapsed. Correlations between faecal calprotectin, ECP and EDN were observed in both diseases.Conclusions: We demonstrate that the risk of relapse in ulcerative colitis can be predicted by consecutively measuring faecal EDN every third month, and suggest EDN as a complementary faecal marker to calprotectin to predict future relapse in ulcerative colitis. Our finding of higher EDN in Crohn's disease-patients staying in remission than in those who relapsed indicates different functions of the protein in ulcerative colitis and Crohn's disease.
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| 3. |
- Eberhardson, Michael, et al.
(author)
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Towards improved control of inflammatory bowel disease
- 2019
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In: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 89:3
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Research review (peer-reviewed)abstract
- Inflammatory bowel disease (IBD) is characterized by activation of both the innate and adaptive immune system in genetically susceptible individuals, resulting in chronic intestinal inflammation. The triggers that initiate and perpetuate this continuous inflammation are the subject of much speculation and research, although the central role of the intestinal microbiota is recognized, and is even a target for treatment in some circumstances. The mainstay of modern IBD treatment is suppression of the immune response towards as yet unspecified antigens, and conventional therapy includes corticosteroids, 5-aminosalicylic acid (5-ASA), thiopurines and methotrexate. Reducing activity of specific mediators has proven efficacious, including adhesion molecules, such as the gut-homing integrin alpha(4)beta(7) expressed on the surface of circulating immune cells, and cytokines, such as tumour necrosis factor alpha (TNF-alpha). This has been achieved using biologic agents including monoclonal antibodies. Recent discoveries in immunology and neuroscience have revealed that signals in the peripheral nervous system regulate inflammation, including levels of TNF-alpha. The understanding of the mechanisms of the neuro-immune communication involved in inflammation control in the gut is evolving, but is as yet incomplete. Clinical studies using implanted vagus nerve stimulators for treatment of IBD show encouraging results. Accordingly, the neural reflex control of inflammation is emerging as a potential therapeutic target in treatment of IBD. Here, we review current therapeutic options and neural reflex control of gut immunity in the context of intestinal inflammation.
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| 4. |
- Halfvarson, Jonas, 1970-, et al.
(author)
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Genetic and shared environmental risk factors do not lead to eosinophil activation in healthy twins of IBD patients
- 2020
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In: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:10, s. 1163-1170
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Journal article (peer-reviewed)abstract
- Objective: To examine the role of eosinophils in the pre-diagnostic phase of inflammatory bowel disease (IBD), we studied the influence of genetic and shared environmental risk factors in a twin cohort of IBD.Material and methods: We analysed eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in faecal samples from twin pairs with Crohn's disease (n = 37) or ulcerative colitis (n = 21) and from external healthy controls (n = 44). Eosinophils stained with eosinophil peroxidase (EPO) were quantified in rectal biopsies. Ratios with 95% confidence intervals were calculated.Results: Twins with Crohn' disease displayed higher levels of EDN (Ratio = 2.98, 1.65-5.37) and ECP (Ratio 1.83, 1.24-2.70) than their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.52, 0.79-2.94 and ECP, Ratio = 0.93, 0.56-1.54). Higher levels of EDN (Ratio = 2.43, 1.13-5.24) and ECP (Ratio = 1.53, 0.92-2.53) were observed among twins with ulcerative colitis vs their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.08, 0.51-2.25 and ECP, Ratio = 1.29, 0.74-2.26). Using intra-class correlation coefficient (ICC), we found no agreement in levels of EDN or ECP in discordant pairs, except for ECP in monozygotic Crohn's disease pairs (ICC = 0.63). In contrast, agreement was observed in monozygotic pairs concordant for Crohn's disease (EDN, ICC = 0.67 and ECP, ICC = 0.66). The number of eosinophils in rectum was increased in twins with ulcerative colitis vs their healthy sibling (Ratio = 2.22, 1.50-3.27).Conclusions: Activation of eosinophils in IBD seems to be a consequence of inflammation rather than an effect of genetic and shared environmental risk factors alone.
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| 5. |
- Hashemi, Helya, et al.
(author)
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Localized IgG4-related disease manifested on the tongue : a case report
- 2021
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In: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 126:1
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Journal article (peer-reviewed)abstract
- Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs. IgG4-RD may show a variety of initial symptoms. In the oral mucosa, lesions present as inflammatory fibrosis with a large number of IgG4-positive plasma cells. Evaluating treatment is a well-known problem in IgG4-RD due to the absence of an established assessment system. There are difficulties in defining the severity of the disease, which is why treatment is primarily based on its clinical manifestations. We present a case report of localized IgG4-RD with ulcerative and proliferative manifestations on the tongue, which clinically mimicked oral squamous cell carcinoma. A tumor-like lesion on the tongue can indicate something else other than the malignant or reactive changes commonly found in the oral mucosa. Multiple differential diagnoses of these atypical oral lesions, including localized IgG4-RD, should be considered.
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| 6. |
- Kisiel, Marta A., 1984-, et al.
(author)
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Inflammatory bowel disease and asthma. Results from the RHINE study
- 2023
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In: Respiratory Medicine. - : Elsevier. - 0954-6111 .- 1532-3064. ; 216
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Journal article (peer-reviewed)abstract
- Background: Asthma and inflammatory bowel disease (IBD) are common inflammatory diseases. The aim of this study was to investigate the associations of IBD with asthma and respiratory symptoms. Methods: This study is based on 13,499 participants from seven northern European countries that filled in a postal questionnaire on asthma, respiratory symptoms, IBD including ulcerative colitis and Crohn's disease and various lifestyle variables. Results: There were 195 participants with IBD. The prevalence of asthma (14.5 vs 8.1%, p = 0.001), different respiratory symptoms (range 11.9-36.8% vs range 6.0-18.6%, p < 0.005), non-infectious rhinitis (52.1 vs. 41.6%, p = 0.004) and chronic rhinosinusitis (11.6 vs 6.0%, p = 0.001) were higher in subjects with IBD than in those without IBD. In multivariable regression analysis, the association between IBD and asthma was statistically significant (OR 1.95 (95% CI 1.28-2.96)) after adjusting for confounders such as sex, BMI, smoking history, educational level and physical activity. There was a significant association between asthma and ulcerative colitis (adjusted OR 2.02 (95% CI 1.27-2.19)), and asthma but not Crohn's disease (adjusted OR 1.66 (95% CI 0.69-3.95)). A significant gender interaction was found with a significant association between IBD and asthma in women but not in men ((OR 2.72 (95% CI 1.67-4.46) vs OR 0.87 (95% CI 0.35-2.19), p = 0.038). Conclusions: Patients with IBD, particularly those with ulcerative colitis and female, have a higher prevalence of asthma and respiratory symptoms. Our findings indicate that it is important to consider respiratory symptoms and disorders when examining patients with manifest or suspected IBD.
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| 7. |
- Lampinen, Maria, et al.
(author)
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Downregulated eosinophil activity in ulcerative colitis with concomitant primary sclerosing cholangitis
- 2018
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In: Journal of Leukocyte Biology. - : John Wiley & Sons. - 0741-5400 .- 1938-3673. ; 104:1, s. 173-183
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Journal article (peer-reviewed)abstract
- Primary sclerosing cholangitis (PSC) is a chronic bile duct inflammation strongly connected to ulcerative colitis (UC). PSC is associated with an increased risk of colon cancer, but the link between the intestinal and the bile duct inflammation is still unknown. Also, the involvement of intestinal immune cells in the pathogenesis of PSC remains to be determined. The eosinophil granulocyte is one of the immune cells implicated in the inflammatory process of ulcerative colitis. This study was performed to determine how the accumulation and activation of intestinal eosinophils may differ between UC with and without concomitant PSC, and how this may be influenced by the cytokine/chemokine profile of the intestinal compartment. Eosinophils from peripheral blood and multiple parts of the colon were analyzed by flow cytometry. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay and a quantitative immunoassay. We found that colonic eosinophils were more abundant in both UC and PSC-UC compared with controls, but that their expression of activation markers was significantly increased in UC only. The colonic level of pro-inflammatory cytokines was increased in active UC but not in PSC-UC. In conclusion, we show for the first time that eosinophil activation phenotype discriminates between UC and PSC-UC, and that this may depend on the local cytokine profile of the colonic mucosa. Lower expression of activation markers on eosinophils in UC with concomitant PSC may depend on the local protein profile of the colonic mucosa.
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| 8. |
- Lampinen, Maria, et al.
(author)
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High Serum sCD40 and a Distinct Colonic T Cell Profile in Ulcerative Colitis Associated With Primary Sclerosing Cholangitis
- 2019
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In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 13:3, s. 341-350
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Journal article (peer-reviewed)abstract
- Background and Aims: There is a strong association between primary sclerosing cholangitis [PSC] and ulcerative colitis [UC], but the immunological link between the two diseases is obscure. We compared serum cytokine profiles of patients with PSC-UC and UC, and investigated a number of selected cytokines in colonic biopsy samples. We also assessed the presence and activation of T cells in peripheral blood and colonic mucosa.Methods: Serum samples from 22 patients with PSC-UC, 28 patients with UC, and 19 controls were analysed by a proximity extension assay including 92 inflammatory cytokines. Biopsies from caecum, sigmoid colon, and rectum were collected from the same patients. Quantitative analysis for IFN-, IL-2, IL-4, IL-5, IL-13, IL-17A/ E/F, IL-21, IL-22, IL-23, and IL-27 was carried out on tissue homogenates. T cell phenotype was evaluated by flow cytometry.Results: By multivariate analysis we identified a cluster of serum cytokines with higher levels in PSC-UC, and sCD40 in particular was strongly associated with this patient group. In contrast, colonic cytokines were only modestly increased in PSC-UC, whereas several Th1-, Th2-, and Th17-associated cytokines were increased in UC. Patients with PSC-UC had increased colonic levels of CXCR3-positive CD8(+) T cells but fewer CD25-positive CD4(+) T cells. An increased CRTH2/CXCR3-quote indicated a predominance of Th-2 type CD4(+) T cells in UC patients.Conclusions: Our study reveals different cytokine profiles and T cell profiles in PSC-UC and UC, with higher systemic levels of cytokines in PSC-UC, and a more pronounced colonic inflammation in UC. Serum sCD40 could potentially be investigated as a marker for PSC in UC.
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| 9. |
- Ling Lundström, Maria, et al.
(author)
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Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease
- 2023
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In: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 14:8
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Journal article (peer-reviewed)abstract
- Introduction: Fecal calprotectin (FC) is anoninvasive tool for examining response to biologics in inflammatory boweldisease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown.Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated.Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids.Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.
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| 10. |
- Mary, Kämpe, et al.
(author)
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Patients with allergic rhinitis and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen challenge
- 2011
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In: Clinical and Molecular Allergy. - : Springer Science and Business Media LLC. - 1476-7961. ; 9:1, s. 3-
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Journal article (peer-reviewed)abstract
- Background:Patients with allergic rhinitis and allergic asthma demonstrate comparable local and systemic eosinophil inflammation, and yet they present with different clinical pictures. Less is even known about the contribution of neutrophil inflammation in allergic diseases. The aim of the study was to examine the propensity and selectivity of granule release from primed systemic eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen exposure. We hypothesize that the dissimilar clinical manifestations are due to diverse eosinophil and neutrophil degranulation. Methods: Nine birch pollen allergic patients with rhinitis, eight with asthma and four controls were studied during pollen season and after nasal and bronchial allergen challenge. Eosinophils and neutrophils were incubated in vitro with assay buffer and opsonized Sephadex particles for spontaneous and C3b-induced granule protein release. The released amount of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) was measured by specific radioimmunoassay.Results:C3b-induced degranulation resulted in increased release of ECP and MPO from primed blood eosinophils and neutrophils in both allergic rhinitis and allergic asthma during pollen season and after both nasal and bronchial challenge (p-values 0.008 to 0.043). After bronchial challenge, the ECP release was significantly higher in the rhinitic group compared to the asthmatic group [19.8 vs. 13.2 %, (p=0.010)]. The propensity for EPO release was weak in all challenge models but followed the same pattern in both allergic groups.Conclusion: Systemically allergen primed eosinophils and neutrophils have similar patterns of degranulation after allergen exposure in allergic rhinitis and allergic asthma. The released amount of ECP, EPO and MPO was similar in all allergen challenge models in both allergic groups. Our results indicate that other mechanisms than the magnitude of eosinophil and neutrophil inflammation or the degranulation pattern of the inflammatory cells determines whether or not an allergic patient develops asthma.
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| 11. |
- Moraes Holst, Luiza, et al.
(author)
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Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis
- 2022
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In: Clinical and Experimental Gastroenterology. - : DOVE MEDICAL PRESS LTD. - 1178-7023. ; 15, s. 129-144
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Journal article (peer-reviewed)abstract
- Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
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| 12. |
- Stenberg, Marie, et al.
(author)
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Collaboration between first year undergraduate nursing students : A focused ethnographic study
- 2022
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In: Nurse Education in Practice. - : Elsevier. - 1471-5953 .- 1873-5223. ; 64
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Journal article (peer-reviewed)abstract
- AIM: The aim was to explore collaboration between first year undergraduate nursing students in a three-year bachelor program during clinical skills lab practices.BACKGROUND: The ability to collaborate is important in the nursing profession to ensure patient safety. Thus, efforts supporting nursing students with learning activities emphasizing this ability is crucial in nurse education as a preparation for the requirements of the nursing profession. Collaborative learning models are described as ways that support the students' interaction during education. However, collaboration between students has shown to have challenges such as negative competition and confrontations. This stresses the need to explore the collaboration between students to find ways to support the interaction.DESIGN: The study was conducted with a focused ethnographic approach.METHOD: Data were generated by participant observations during one semester, involving 70 h observation of 87 first year nursing students for 6 months and 24 training sessions in clinical skills lab practices. Two focus group discussions were used to elaborate students' views of collaboration and to provide an opportunity for follow up questions and interpretations from the observations. Field notes and focus group discussions were interpreted as one unit of analysis conducted with thematic network analysis. A global theme were synthesized from organizational and additional basic themes presenting the overall metaphor of the students' collaboration.RESULT: The global theme, Between adaptation and non-conformity, revealed a field of tension in the nursing students' collaboration. One the one hand, the global theme involved the students' ability to adopt to new knowledge and to being a nursing student in a clinical skills lab and to others' perspective. On the other hand, non-conformity creates a collaboration with less reflection between the students and non-synchronized and time-consuming laboratory work.CONCLUSION: Collaborative activities in nurse education fosters and challenges nursing students' collaboration required for clinical practices and later in the nursing profession. By the presented scaffolding efforts, nurse educators can arrange a learning environment that can support the collaboration between students and facilitate the transition into the profession.
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| 13. |
- Stenberg, Marie, et al.
(author)
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Formative peer assessment in higher healthcare education programmes : a scoping review
- 2021
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:2
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Research review (peer-reviewed)abstract
- Objectives Formative peer assessment focuses onlearning and development of the student learning process.This implies that students are taking responsibility forassessing the work of their peers by giving and receivingfeedback to each other. The aim was to compile researchabout formative peer assessment presented in higherhealthcare education, focusing on the rationale, theinterventions, the experiences of students and teachersand the outcomes of formative assessment interventions.Design A scoping review.Data sources Searches were conducted until May 2019in PubMed, Cumulative Index to Nursing and Allied HealthLiterature, Education Research Complete and EducationResearch Centre. Grey literature was searched in LibrarySearch, Google Scholar and Science Direct.Eligibility criteria Studies addressing formative peerassessment in higher education, focusing on medicine,nursing, midwifery, dentistry, physical or occupationaltherapy and radiology published in peer-reviewedarticlesor in grey literature.Data extractions and synthesis Out of 1452 studies,37 met the inclusion criteria and were critically appraisedusing relevant Critical Appraisal Skills Programme, JoannaBriggs Institute and Mixed Methods Appraisal Tool tools.The pertinent data were analysed using thematic analysis.Result The critical appraisal resulted in 18 includedstudies with high and moderate quality. The rationale forusing formative peer assessment relates to giving andreceiving constructive feedback as a means to promotelearning. The experience and outcome of formativepeer assessment interventions from the perspectiveof students and teachers are presented within threethemes: (1) organisation and structure of the formativepeer assessment activities, (2) personal attributes andconsequences for oneself and relationships and (3)experience and outcome of feedback and learning.Conclusion Healthcare education must considerpreparing and introducing students to collaborativelearning, and thus develop well-designedlearningactivities aligned with the learning outcomes. Since peercollaboration seems to affect students’ and teachers’experiences of formative peer assessment, empiricalinvestigations exploring collaboration between studentsare of utmost importance.
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| 14. |
- Stenberg, Marie, et al.
(author)
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Supporting each other towards independence : A narrativeanalysis of first‐year nursing students' collaborative process
- 2024
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In: Nursing Inquiry. - : John Wiley & Sons. - 1320-7881 .- 1440-1800.
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Journal article (peer-reviewed)abstract
- Collaboration for nursing is a core competence and therefore educational interventions are essentials for collaborative skills. To identify such interventions, we carried out a study to understand nursing students' collaborative process. A narrative inquiry method was used to explore the collaborative process of first-year undergraduate nursing students. The analysis was conducted on field notes from 70 h of observation of 87 nursing students' collaboration during skills lab activities. It also included transcriptions of four focus group discussions with 11 students. The results are presented as a sequential process of (1) navigating in unfamiliar territory, (2) navigating together to cope, and (3) navigating together towards independency and the future nursing profession. We identified a transition from teacher-led assistance and guidance to student interdependency and reciprocal learning, ending with student-led assistance supporting independency. In line with Vygotsky's theory of zone of proximal development, different scaffolding interventions are needed depending on where the students are in the collaborative process.
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| 15. |
- Vessby, Johan, 1972-, et al.
(author)
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A two-step proteomic approach identifies candidate biomarker in ulcerative colitis with concomitant primary sclerosing cholangitis.
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Other publication (other academic/artistic)abstract
- Introduction: Ulcerative colitis (UC) with concomitant primary sclerosing cholangitis (PSC-UC or PSC-IBD) is today considered a unique IBD entity, including a more malignant disease course compared with classical UC. Biomarkers for identifying UC patients at risk of developing PSC is lacking, which may delay the onset of endoscopy surveillance. Mass spectrometric development has enabled the use of formalin-fixed paraffin embedded tissue (FFPE) for high resolution proteome analysis. In this study, we search for PSC-IBD proteomic fingerprints in FFPE by utilizing mass spectrometry.Methods: Protein was extracted out of FFPE colon archival samples from PSC-IBD (n=9), UC (n=7), and healthy controls (n=7). IBD-patients were all in clinical remission, without biologics or steroids, and all UC patients had a history of pancolitis. Samples were processed by the Multienzyme Digestion FASP and were analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Proteins were quantified using the Total Protein Approach. Data was analysed using linear regression and in a multiple manner using random forest algorithms. Candidate findings were validated in a second cohort (n: PSC-IBD=16 UC=21) using the same proteomic technique. To make an over-all proteome comparison, we performed principal component analysis, as well as a meta-analysis for the most prominent findings.Results: In the exploratory proteomic step, 7279 unique proteins were detected. After statistical analysis including multiple testing, the top-5 proteins (CD47, LSM7, NDUFAF4, AGPAT1 and THEM192) were selected as candidate proteins. When validating these findings in a confirmatory cohort, AGPAT1 was verified (p=0.009). According to meta-analysis, AGPAT1 was also found to be the most distinctive protein between PSC-IBD and UC. The overall proteomic profiles in step 1 and step 2 (7706 proteins) confirmed small biologic variations between the IBD-groups.Conclusions: In this two-step proteomic study on remissive IBD, we were able to verify AGPAT1 as a colonic PSC-IBD biomarker. We found high overall proteome resemblance, in contrast to the phenotypical differences existing between PSC-IBD and UC. Our findings have possible implication in future PSC-IBD diagnostics, and adds further knowledge to the evasive PSC-IBD phenotype.
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| 16. |
- Vessby, Johan, 1972-, et al.
(author)
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AGPAT1 as a Novel Colonic Biomarker for Discriminating Between Ulcerative Colitis With and Without Primary Sclerosing Cholangitis
- 2022
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In: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 13:5
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC-UC) is considered a unique inflammatory bowel disease (IBD) entity. PSC diagnosis in an IBD individual entails a significantly higher risk of gastrointestinal cancer; however, biomarkers for identifying patients with UC at risk for PSC are lacking. We, therefore, performed a thorough PSC-UC biomarker study, starting from archived colonic tissue.METHODS: Proteins were extracted out of formalin-fixed paraffin-embedded proximal colon samples from PSC-UC (n = 9), UC (n = 7), and healthy controls (n = 7). Patients with IBD were in clinical and histological remission, and all patients with UC had a history of pancolitis. Samples were processed by the multienzyme digestion FASP and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Candidate proteins were replicated in an independent cohort (n: PSC-UC = 16 and UC = 21) and further validated by immunohistochemistry.RESULTS: In the discovery step, 7,279 unique proteins were detected. The top 5 most differentiating proteins (PSC-UC vs UC) based on linear regression analysis were selected for replication. Of these, 1-acetylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) was verified as higher in PSC-UC than UC (P = 0.009) in the replication cohort. A difference on the group level was also confirmed by immunohistochemistry, showing more intense AGPAT1 staining in patients with PSC-UC compared with UC.DISCUSSION: We present AGPAT1 as a potential colonic biomarker for differentiating PSC-UC from UC. Our findings have possible implication for future PSC-IBD diagnostics and surveillance.
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| 17. |
- Vessby, Johan, 1972-
(author)
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Studies of ulcerative colitis with concomitant primary sclerosing cholangitis : Beyond the clinical phenotype
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Inflammatory bowel disease (IBD) is a group of chronically relapsing immune-related disorders, engaging the gastrointestinal tract. Symptoms vary depending on inflammatory phenotype, but may include diarrhoea, bowel pain and weight loss. The two most common entities are Crohn's disease and ulcerative colitis (UC). A minority of IBD patients, particularly UC, is concomitantly affected by primary sclerosing cholangitis (PSC) – an inflammatory bile duct disease with dismal prognosis. IBD with associated PSC has distinct clinical features, and is regarded a unique IBD phenotype (PSC-IBD or PSC-UC). These features include higher rates of pancolitis, a milder clinical course, and an unexplained increased risk of colorectal neoplasia.This thesis aimed to compare immunological conditions in PSC-UC and UC, but also to search for molecular differences, potentially facilitating PSC-UC diagnosis.In paper I and II, we compared eosinophil and lymphocyte activation and regulation. PSC-UC had down-regulated mucosal eosinophil activity, during both flare and remission. Compared with UC, PSC-UC had a dampened, and less Th2 dominated mucosal immune response. This was evident by a low quote of CRTH2/CXCR3 CD4+ cells and a cytokine milieu with no upregulated Th2 cytokines. In contrast, PSC-UC had highly up-regulated cytokines in peripheral blood. Among these, sCD40 stood out as being most important for inter-group separation according to multivariate analysis.In paper III, we gave a detailed description of colonic tissue factor (TF) expression. We found discrepancies in TF depending on UC subtype and inflammatory status, where inflammation- associated TF up-regulation was detected in UC only. Also, we identified stromal TF deposition as a sensitive indicator of acute colitis.In paper IV, PSC-UC and UC intestinal proteomes were compared using LC-MS/MS. After detecting more than 7200 unique proteins in the discovery step, the top-five most distinctive findings were chosen for verification. Of these, AGPAT1 was verified, being significantly higher in PSC-UC. Despite phenotypical differences, the overall colonic proteome comparison showed high degree of concordance.In summary, this thesis demonstrates distinct immunological and molecular properties in PSC-UC, implying phenotypical features beyond clinical observations. Moreover, serum sCD40 and colonic AGPAT1 are suggested possible PSC-UC biomarkers.
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| 18. |
- Vessby, Johan, 1972-, et al.
(author)
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Tissue factor in ulcerative colitis, with and without concomitant primary sclerosing cholangitis
- 2019
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In: Upsala Journal of Medical Sciences. - : Taylor & Francis Group. - 0300-9734 .- 2000-1967. ; 124:4, s. 238-245
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Journal article (peer-reviewed)abstract
- Background: Ulcerative colitis (UC) in patients with the severe disease primary sclerosing cholangitis (PSC) constitutes a distinct clinical phenotype (PSC-UC) with a high incidence of colorectal cancer. Today, PSC-UC diagnosis is built on clinical observations only. Tissue factor (TF) has a potential use in UC diagnostics, and also in colorectal cancer prognostication. Here we evaluate TF expression in an inflammatory bowel disease (IBD) cohort, with special focus on differences between UC and PSC-UC patients.Materials and methods: Colonic biopsies from UC (n = 23), PSC (n = 24), and healthy controls (n = 11) were stained for TF by immunohistochemistry. Mononuclear cell contribution to TF expression was verified using flow cytometry.Results: TF was distributed at three distinct colonic locations: in subepithelial pericryptal sheath cells, in mononuclear cells, and in the intestinal stroma. In contrast to UC-where inflammation was accompanied with TF up-regulation-PSC-UC activity remained low during inflammation. Stromal TF positivity was found exclusively in ongoing inflammation.Conclusion: Our study provides additional support for a divergent pathogenesis in PSC-UC, with an inflammatory environment that differs from classical UC. Stromal TF emerges as a new marker of colonic inflammation.
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| 19. |
- Wagner, Michael, 1957-, et al.
(author)
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Budesonide Treatment of Patients With Collagenous Colitis Restores Normal Eosinophil and T-cell Activity in the Colon
- 2010
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In: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 16:7, s. 1118-1126
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Journal article (peer-reviewed)abstract
- Objective: The aim of this study was to assess the activity of eosinophils, neutrophils and CD4+ as well as CD8+ T-cells in eleven patients with active collagenous colitis (CC) before and after eight weeks of budesonide treatment (9 mg once daily) compared to ten healthy individuals. Methods: Clinical symptoms were recorded and intestinal biopsy samples were taken and analysed by flow cytometry. Eosinophils with a high surface expression of CD44 and low CD9 expression were classified as activated. Neutrophil activity was assessed by their expression of CD66b and CD69 was used as an activation marker for T cells. Results: All patients responded to the treatment. The eosinophils in active CC showed increased activity compared to controls. The activity was back to control levels after treatment. Neutrophils were not activated in CC patients before or after treatment. CD8+ T cells from untreated CC patients had a lower activity than controls, and a tendency of lower activity was observed on CD4+ T cells. After treatment, the activity was increased on both types of T cells and was not different from controls. Conclusions: In the present study we demonstrated that the inflammation in CC is characterized by activated eosinophils but there is no neutrophil activity. CD4+ and CD8+ T cells are increased in numbers in active CC but, surprisingly, they had a lower grade of activity than in control subjects. The major finding in this study is that budesonide treatment restores the normal activation of eosinophils and T-cells, accompanied by clinical remission.
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| 20. |
- Wagner, Michael, 1957-
(author)
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Clinical and Experimental Studies on Inflammatory Bowel Disease with special emphasis on Collagenous Colitis
- 2010
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Doctoral thesis (other academic/artistic)abstract
- This thesis describes studies in patients with inflammatory bowel disease (IBD) and collagenous colitis (CC). We investigated mucosal eosinophil and neutrophil granulocytes and T-cells involved in the inflammatory processes and aimed at determining whether these processes are reflected in the faecal (F) contents of specific proteins secreted by cells in the intestinal mucosa. Thus, we measured eosinophil cationic protein (ECP) and eosinophil protein X (EPX) and the neutrophil derived myeloperoxidase (MPO) and calprotectin (C); and in addition, chromogranin A (CgA), Chromogranin B (CgB) and secretoneurin (SN), derived from EEC cells and cells in the enteric nervous system. We found that a normalised FC level can serve as a surrogate marker for successful treatment in patients with IBD, but persistently high FC levels need further evaluation (study I). Furthermore, FC and F-MPO appear to relate better than F-EPX to treatment outcome in IBD. We evaluated F-ECP, F-EPX, F-MPO and FC as markers of disease activity and treatment outcome in patients with CC (study III) and concluded that F-ECP was the best discriminator of detecting active CC. Normalised F-ECP and F-EPX could serve as markers of successful treatment. We showed that the inflammation in CC is characterised by activated eosinophils, but that there is no neutrophil activity (study II). T-cells have a lower grade of activity in active CC than in control subjects. During budesonide treatment the normal activation of eosinophils and T-cells is restored, with concomitant clinical remission. The findings in studies II and III indicate that the eosinophils have an essential role in the pathophysiology of CC. Markedly higher values of F-CgA, F-CgB and F-SN were found in patients with CC than in those with IBD and controls (study IV) indicating a crucial role for the intestinal neuro-endocrine system in the pathogenesis of collagenous colitis.
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| 21. |
- Wagner, Michael, 1957-, et al.
(author)
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Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis : A pilot study
- 2011
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:7-8, s. 849-854
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Journal article (peer-reviewed)abstract
- Background and aims. Fecal calprotectin (FC) is used as a marker for intestinal inflammation in inflammatory bowel disease (IBD) but there is no reliable marker for collagenous colitis (CC). We have previously demonstrated that the mucosal inflammation in CC is characterized by eosinophil activation, which is restored during budesonide treatment, but there is no enhanced neutrophil activity. The aim of this study was to evaluate the use of fecal eosinophil cationic protein (F-ECP) and eosinophil protein X (F-EPX) compared with the neutrophil-derived myeloperoxidase (F-MPO) and FC in patients treated for active CC. Methods. Patients with active CC (n = 12) were studied before and after 3, 7, 28 and 56 days of budesonide treatment. Clinical symptoms and stool frequency were recorded, fecal samples were collected, and F-ECP, F-EPX, F-MPO and FC were measured at each occasion. Results. All but one patient achieved remission. On inclusion 92%, 67%, 67% and 75% of the patients had elevated F-ECP, F-EPX, F-MPO and FC levels, respectively. All markers decreased during the treatment, particularly F-ECP and F-EPX, which decreased after only 3 days. At the end of the study 100%, 92%, 83% and 75% of the patients had normal F-ECP, F-EPX, F-MPO and FC values, respectively. Conclusion. F-ECP demonstrated the best discriminating capacity in detecting active CC. A normalized F-ECP and F-EPX may further be studied as a marker for successful treatment. During budesonide treatment there is a rapid fall in F-ECP and F-EPX, accompanied by clinical improvement, indicating an essential role for the eosinophil participating in the pathophysiology of CC.
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| 22. |
- Wagner, Michael, 1957-, et al.
(author)
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Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease
- 2008
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In: World Journal of Gastroenterology. - : WJG Press. - 1007-9327 .- 2219-2840. ; 14:36, s. 5584-5589
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Journal article (peer-reviewed)abstract
- Aims: To evaluate fecal calprotectin (FC) as a surrogate marker for treatment outcome of a relapse of inflammatory bowel disease (IBD) and, secondly, to compare FC to fecal myeloperoxidase (MPO) and fecal eosinophil protein X (EPX). Methods: Thirty-eight patients with IBD, whereof twenty-seven with ulcerative colitis (UC) and 11 with Crohn´s disease (CD) were studied before treatment (inclusion), and after four and eight weeks of treatment. Treatment outcome, based on clinical activity and endoscopy in UC patients, and clinical activity in CD patients, were evaluated together with fecal samples analysed for FC with ELISA and MPO and EPX with RIA. Results: At inclusion 37/38 (97%) patients had elevated FC levels (>94.7 µg/g). At the end of the study 31/38 (82%) patients fulfilled predefined criteria of a complete response [UC 21/27 (78%); CD 10/11 (91%)]. Overall, a normalised FC level at the end of the study predicted a complete response in 100% whereas elevated FC level predicted noncomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90%, respectively. However, elevated MPO or EPX levels predicted noncomplete response in 23% and 22%, respectively. Conclusion: A normalised FC level poses the potential to be used as a surrogate marker for successful treatment outcome in IBD patients, but cases with persistent elevated FC levels needs further evaluation. FC and MPO appears to discriminate better than EPX to treatment outcome in IBD.
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| 23. |
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| 24. |
- Zhulina, Yaroslava, 1973-, et al.
(author)
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Subclinical Inflammation with Increased Neutrophil Activity in Healthy Twin Siblings Reflect Environmental Influence in the Pathogenesis of Inflammatory Bowel Disease
- 2013
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In: Inflammatory Bowel Diseases. - Philadelphia, USA : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 19:8, s. 1725-1731
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Journal article (peer-reviewed)abstract
- Background: The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context.Methods: Nuclear factor kappa B (NF-B) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-B and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay.Results: In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-B was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately.Conclusions:We observed increased NF-B, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives.
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