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  • 1.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Örebro University, School of Health Sciences. Department of Gastroenterology, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. School of Medical Sciences, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden.
    Sapnara, Maria
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden .
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden .
    Hultgren Hörnquist, Elisabeth
    Örebro University Hospital. Örebro University, School of Medical Sciences. School of Medical Sciences, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden .
    Elevated fecal peptidase D at onset of colitis in Galphai2-/- mice, a mouse model of IBD.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174275Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms.

    METHODS: Fecal samples were collected at onset of inflammation in Galphai2-/- mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice.

    RESULTS: As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai2-/- mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gαi2-/- mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai2-/- mice at different stages of disease.

    CONCLUSIONS: These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

  • 2.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Sapnara, Maria
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Elevated fecal peptidase D at onset of colitis in Galphai2(-/-) mice, a mouse model of IBD2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174275Article in journal (Refereed)
    Abstract [en]

    Background: The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms.

    Methods: Fecal samples were collected at onset of inflammation in Galphai2(-/-) mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice.

    Results: As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai24mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gai2(-/-) mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai24- mice at different stages of disease.

    Conclusions: These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

  • 3.
    Berglund, Martin
    et al.
    Dept Microbiol & Immunol, Inst Biomed, Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Melgar, Silvia
    Alimentary Pharmabiot Ctr, Univ Coll Cork, Cork, Ireland; Immunoinflammat CEDD GlaxoSmithKline, Stevenage Herts, England.
    Kobayashi, Koichi S.
    Harvard Univ, Boston MA, USA.
    Flavell, Richard A.
    Yale Univ, New Haven CT, USA.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Hultgren, Olof H.
    Department of Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Örebro University Hospital, Örebro, Sweden.
    IL-1 receptor-associated kinase M downregulates DSS-induced colitis2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 10, p. 1778-1786Article in journal (Refereed)
    Abstract [en]

    Background: Ulcerative colitis is associated with increased colon permeability resulting in bacterial translocation into the lamina propria. We investigate the importance of the Toll-like receptor (TLR) regulating protein IL-1 receptor-associated kinase M (IRAK-M) using the erosive dextran sulfate sodium (DSS)-induced model of colitis. Methods: IRAK-M-competent and -incompetent mice were treated with 3% DSS for 5 days followed by 2 days of regular drinking water. Clinical signs of disease were followed for 7 days. At day 7 the mice were sacrificed and plasma and tissue were collected for histopathological examination and analyses of the production of cytokines and chemokines as well as expression of T-cell transcription factors. Results: At day 7 IRAK-M-deficient mice display a reduced total body weight (77.1 +/- 2.1 versus 88.5 +/- 2.0, *P=0.002) and an increased macroscopical (2.7 +/- 0.2 versus 1.6 +/- 0.1, *P 0.002) and histopathological (6.0 +/- 0 versus 3.3 +/- 60.5, *P < 0.001) colon score compared to wildtype mice. Furthermore, IRAK-M-deficient mice have increased colon mRNA expression of proinflammatory cytokines and increased tumor necrosis factor concentrations (41.1 +/- 13.5 versus 12.8 +/- 2.0 pg/mL, *P = 0.010) in plasma. Conclusions: This is the first report examining the role of IRAK-M in colitis. We find that IRAK-M is of critical importance in downregulating induction and progression of DSS colitis, and thereby suggesting that IRAK-M might be a target for future interventional therapies. (Inflamm Bowel Dis 2010; 16: 1778-1786)

  • 4.
    Berglund, Martin
    et al.
    Inst. för Biomedicin, göteborgs Universitet.
    Thomas, J. A.
    Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA .
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Hultgren, Olof H.
    Department of Clinical Microbiology, Orebro University Hospital, Orebro, Sweden .
    Toll-like receptor cross-hyporesponsiveness is functional in interleukin-1-receptor-associated kinase-1 (IRAK-1)-deficient macrophages: differential role played by IRAK-1 in regulation of tumour necrosis factor and interleukin-10 production2008In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 67, no 5, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Signalling downstream Toll-like receptors (TLR) is regulated at several levels in order to activate the immune response and prevent excessive inflammation. Altered intracellular signalling may be one reason that repeated stimulation of various TLRs results in hyporesponsiveness and cross-tolerance. We report that TLR cross-tolerance is inducible in the absence of interleukin-1 receptor-associated kinase-1 (IRAK-1) in peritoneal macrophages. Similar to wild-type macrophages, IRAK-1-deficient macrophages respond with decreased tumour necrosis factor (TNF) production to a secondary TLR stimulation, but in opposite to IRAK-1(+/+), IRAK-1(-/-) macrophages display increased interleukin (IL)-10 production at TLR restimulation. IRAK-1-deficient peritoneal macrophages have a defective TNF and IL-10 production in response to lipoteichoic acid stimulation as well as a defective IL-10-but a normal TNF production in response to high concentration of lipopolysaccharide. Our results demonstrate that IRAK-1 is not necessary for induction of TLR cross-tolerance as judged by TNF production.

  • 5. Berglund, Martin
    et al.
    Thomas, James A.
    Fritsch Fredin, Maria
    Melgar, Silvia
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Hultgren, Olof H.
    Gender dependent importance of IRAK-1 in dextran sulfate sodium induced colitis2009In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 259, no 1, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Toll-like receptor (TLR) signaling is important for the induction of pro-inflammatory cytokines and interferon (IFN)-inducible genes in response to bacterial and viral challenge. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a signaling kinase situated downstream of the adapter protein myeloid differentiation factor 88 (MyD88) in the TLR intracellular signaling cascade and is required for normal signal transduction through this pathway. We investigated the importance of IRAK-1 in intestinal inflammation by using the dextran sulfate sodium (DSS)-colitis model. We show that IRAK-1 deficient mice are protected against systemic signs of inflammation, i.e., weight loss and spleen enlargement compared to wild-type controls irrespective of gender. However, IRAK-1(-/y) males but not IRAK-1(-/-) females display significant protection against colitis and thymic atrophy compared to wild-type mice. Our results indicate a gender specific effect of IRAK-1 in the DSS-induced colitis, an interesting finding since the Irak-1 gene is located on the X-chromosome and several inflammatory diseases have a gender dependent incidence. (C) 2009 Elsevier Inc. All rights reserved.

  • 6.
    Bohr, Johan
    et al.
    Örebro University, School of Health Sciences. Örebro University Hospital. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Wickbom, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Hegedus, Agnes
    Department of Laboratory Medicine/Pathology, Örebro University Hospital, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Diagnosis and management of microscopic colitis: Current perspectives2014In: Clinical and Experimental Gastroenterology, ISSN 1178-7023, E-ISSN 1178-7023, Vol. 7, p. 273-284Article, review/survey (Refereed)
    Abstract [en]

    Collagenous colitis and lymphocytic colitis, together constituting microscopic colitis, are common causes of chronic diarrhea. They are characterized clinically by chronic nonbloody diarrhea and a macroscopically normal colonic mucosa where characteristic histopathological findings are seen. Previously considered rare, they now have emerged as common disorders that need to be considered in the investigation of the patient with chronic diarrhea. The annual incidence of each disorder is five to ten per 100,000 inhabitants, with a peak incidence in 60- to 70-year-old individuals and a predominance of female patients in collagenous colitis. The etiology and pathophysiology are not well understood, and the current view suggests an uncontrolled mucosal immune reaction to various luminal agents in predisposed individuals. Clinical symptoms comprise chronic diarrhea, abdominal pain, fatigue, weight loss, and fecal incontinence that may impair the patient's health-related quality of life. An association is reported with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. The best-documented treatment, both short-term and long-term, is budesonide, which induces clinical remission in up to 80% of patients after 8 weeks' treatment. However, after successful budesonide therapy is ended, recurrence of clinical symptoms is common, and the best possible long-term management deserves further study. The long-term prognosis is good, and the risk of complications, including colonic cancer, is low. We present an update of the epidemiology, pathogenesis, diagnosis, and management of microscopic colitis.

  • 7. Chiu Götlind, Y. Y.
    et al.
    Raghavan, S.
    Bland, P. W.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    CD4+FoxP3+ regulatory T cellsare functionally active in the Gαi2−/− mouse, but do not prevent thedevelopment of colitis2010Conference paper (Other academic)
  • 8.
    Daferera, Niki
    et al.
    Linköping University, Linköping, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ignatova, Simone
    Linköping University, Linköping, Sweden .
    Ström, Magnus
    Linköping University, Linköping, Sweden.
    Münch, Andreas
    Linköping University, Linköping, Sweden.
    Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report2015In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 19, p. 6065-6071Article in journal (Refereed)
    Abstract [en]

    In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1β, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-γ, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis.

  • 9.
    Elgbratt, Kristina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jansson, Andreas
    Systems Biology Research Centre, University of Skövde, Skövde, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    A quantitative study of the mechanisms behind thymic atrophy in G alpha i2-deficient mice during colitis development2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, article id e36726Article in journal (Refereed)
    Abstract [en]

    Mice deficient for the G protein subunit G alpha i2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a thymic involution in these mice and an aberrant thymocyte dynamics. The G alpha i2(-/-) mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the G alpha i2(-/-) mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gai2(-/-) mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the G alpha i2(-/-) SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4(+) and CD8(+) thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC+ T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. G alpha i2(-/-) mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis.

  • 10.
    Elgbratt, Kristina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Kurlberg, G.
    Dept Surg, Sahlgrens Univ Hosp, Gothenburg, Sweden.
    Hahn-Zohric, M.
    Dept Clin Immunol & Transfus Med, Sahlgrens Univ Hosp, Gothenburg, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences. MIVAC Mucosal Immunobiol & Vaccine Ctr, Gothenburg Univ, Gothenburg, Sweden.
    Rapid migration of thymic emigrants to the colonic mucosa in ulcerative colitis patients2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 162, no 2, p. 325-336Article in journal (Refereed)
    Abstract [en]

    P>Inflammatory bowel disease (IBD) is associated with imbalances of the local intestinal immune responses, with dysregulated CD4+ T cells contributing to the chronic inflammation. Having demonstrated altered T cell maturation in the thymus in two different mouse models of colitis, we set out to investigate whether abnormalities in T cell maturation is present in patients with ulcerative colitis (UC) or Crohn's disease (CD). Specimens were obtained from peripheral blood (CD; n = 14, UC; n = 22), colon and small intestinal specimens (CD; n = 6, UC; n = 13). As controls, peripheral blood specimens were obtained from healthy volunteers, patients with adenocarcinomas (n = 18) and colonic specimens from patients with adenocarcinomas (n = 14). Recent thymic emigrants were estimated by analysis of the normalized ratio of T cell receptor excision circles (TRECs) by real-time polymerase chain reaction (PCR). The frequency of naive- and proliferating T lymphocytes and markers of extrathymic T cell maturation in the mucosa was analyzed by flow cytometry and real time-PCR. TREC levels in peripheral blood T lymphocytes were similar between IBD patients and controls. In contrast, UC patients demonstrated significantly increased levels of TRECs both in intraepithelial and lamina propria lymphocytes from the colonic mucosa compared to patients with adenocarcinomas and CD. However, markers for extrathymic T cell maturation in the mucosa were not different between controls and IBD patients. The increased TREC levels in mucosal but not peripheral blood lymphocytes in UC patients in the absence of increased extrathymic maturation in situ in the mucosa together demonstrate that recent thymic emigrants are recruited rapidly to the inflamed mucosa of these patients.

  • 11.
    Fant, F.
    et al.
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Tina, Elisabet
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Research Centre.
    Sandblom, D.
    Department of Urology and the Health Academy, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology and the Health Academy, Örebro University Hospital, Örebro, Sweden.
    Magnuson, A.
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Axelsson, Kjell
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Gupta, Anil
    Department of Anesthesiology and Intensive Care, University Hospital, Örebro, Sweden.
    Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response after radical retropubic prostatectomy2013In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 110, no 5, p. 747-757Article in journal (Refereed)
    Abstract [en]

    Background: Epidural anaesthesia and analgesia has been shown to suppress the neurohormonal stress response, but its role in the inflammatory response is unclear. The primary aim was to assess whether the choice of analgesic technique influences these processes in patients undergoing radical retropubic prostatectomy.

    Methods: Twenty-six patients were randomized to Group P (systemic opioid-based analgesia) or Group E (thoracic epidural-based analgesia) perioperatively. Induction and maintenance of anaesthesia followed a standardized protocol. The following measurements were made perioperatively: plasma cortisol, glucose, insulin, C-reactive proteins, leucocyte count, plasma cytokines [interleukin (IL)-6, tumour necrosis factor (TNF)-alpha], and pokeweed mitogen-stimulated cytokines [interferon (IFN)-gamma, IL-2, IL-12p70, IL-10, IL-4, and IL-17]. Other parameters recorded were pain, morphine consumption, and perioperative complications.

    Results: Plasma concentration of cortisol and glucose were significantly higher in Group P compared with Group E at the end of surgery, the mean difference was 232 nmol litre(-1) [95% confidence interval (CI) 84-381] (P=0.004) and 1.6 mmol litre(-1) (95% CI 0.6-2.5) (P=0.003), respectively. No significant differences were seen in IL-6 and TNF-alpha at 24 h (P=0.953 and 0.368, respectively) and at 72 h (P=0.931 and 0.691, respectively). IL-17 was higher in Group P compared with Group E, both at 24 h (P=0.001) and 72 h (P=0.018) after operation. Pain intensity was significantly greater in Group P compared with Group E (P<0.05) up to 24 h.

    Conclusions: In this small prospective randomized study, thoracic epidural analgesia reduced the early postoperative stress response but not the acute inflammatory response after radical retrobupic prostatectomy, suggesting that other pathways are involved during the acute phase reaction.

  • 12.
    Fant, Federica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, E.
    Clinical Reaserch Centre, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospita.
    Sandblom, Dag
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Axelsson, Kjell
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response following radical retropubic prostatectomyManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Epidural anesthesia and analgesia has been shown to suppress the neurohormonalstress response in certain types of surgery, but its role in the inflammatory responseto surgery is unclear. The primary aim of this study was to assess whether the choice ofanalgesic technique influences these processes in patients undergoing radical retropubicprostatectomy (RRP).

    Method: 26 patients undergoing RRP were randomized to Group P (systemic opioid-basedanalgesia) or Group E (thoracic epidural-based analgesia) perioperatively. Induction andmaintenance of anesthesia in both groups followed a standardized protocol. The followingmeasurements were made perioperatively : plasma cortisol, glucose, insulin, plasma cytokines(IL-6, TNF-a) and pokeweed mitogen-stimulated cytokines (IFN-g, IL-2, IL-12p70, IL-10,IL-4, and IL-17), C-reactive proteins and leucocyte count. Other parameters recordedincluded pain, morphine consumption and perioperative complications during 72 hours.

    Results: Plasma concentration of cortisol and glucose were significantly higher in Group Pcompared to Group E at the end of surgery with a mean difference between groups of 232nmol/L (95% CI 84-381) (P=0.004) and 1.6 mmol/L (95% CI 0.6-2.5) (P=0.003) respectively.No significant differences were seen in any plasma cytokine except IL-17, which was higherin Group P compared with Group E, both at 24 h (P< 0.001) and 72 h (P=0.018)postoperatively. Significantly higher pain intensity was seen up to 24 hours postoperatively inGroup P compared to Group E (p < 0.05).

    Conclusion: Thoracic epidural analgesia reduces the early postoperative stress response butnot the acute inflammatory response to radical retrobupic prostatectomy suggesting that otherpathways are involved during the acute phase reaction.

  • 13.
    Fant, Federica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, E.
    Sandblom, Dag
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Early perioperative immunological effects of anesthesia and analgesia in patients undergoing prostate cancer surgeryManuscript (preprint) (Other academic)
    Abstract [en]

    Background:Clinical studies in humans as well as experimental evidence from animal studiessuggests that the immune system plays an important role in perioperative metastases following cancer surgery. However, the precise role of the different components of the immune system in this process appears conflicting. Our primary aim was to assess T cell activity and natural killer (NK) cell toxicity in patients undergoing prostate cancer surgery and randomized to epidural or intravenous analgesia.

    Methods:26 patients were randomized to receive general anaesthesia and patient controlled analgesia (PCA) with morphine postoperatively (Group P) or combined, general and epidural anaestesia with patient-controlled thoracic epidural analgesia postoperatively (Group E). Blood sample were obtained perioperatively at different time points for analyses of: subpopulations of leukocytes, cell- ediated immune response after mitogen stimulation, NK cell cytotoxicity, vascular endothelial growth factor (VEGF), IFN-g/IL-10 ratio, C-reactive protein (CRP) and white blood cell (WBC) count. In addition, pain and morphine consumtion were also determined.

    Results: T lymphocytes decreased more in Group P compared to Group E at 24 hours postoperatively while T-helper lymphocytes decreased more in Group E compared to Group P at the same time point without reaching statistically significant difference.No differences were seen in NK cells or cytotoxic T lymphocytes between the groups. The CD4+/CD8+ ratio remained constant between the groups over time. Natural Killer Cell cytotoxicity did not show statistically significant differences between the groups at the different postoperative time points. No other differences ere found between the groups except in pain intensity which was lower in Group E, and morphine consumption which was greater in Group P. Conclusions:Our findings suggest that regional anaesthesia and analgesia appears to play a minor role in immunomodulation following surgery for prostate cancer. If regional anesthesia does prevent tumour growth or metastases perioperatively, the mechanism for this needs to be further elucidated.

  • 14.
    Fritsch Fredin, Maria
    et al.
    Astra-Zeneca, Mölndal.
    Hultin, Leif
    Astra-Zeneca, Mölndal.
    Hyberg, Gina
    Astra-Zeneca, Mölndal.
    Rehnström, Erika
    Astra-Zeneca, Mölndal.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Melgar, Silvia
    Astra-Zeneca, Mölndal.
    Jansson, Liselotte
    Astra-Zeneca, Mölndal.
    Predicting and monitoring colitis development in mice by micro-computed tomography2008In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 4, p. 491-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Computed tomography (CT) has been developed as a tool for monitoring human inflammatory bowel disease (IBD). The aim of this study was to evaluate colon wall thickness as a noninvasive marker in the dextran sodium sulfate (DSS) mouse model of colitis using micro-CT. METHODS: Mice were examined by micro-CT 1, 2, or 4 times between day 0 (d0) and d26 after induction of colitis to document the kinetics of changes in colon wall thickness and its relation to colitis development. RESULTS: DSS-treated mice displayed a significantly thicker colon wall at all timepoints (days 5, 8, 12, 19, and 26) investigated compared to healthy controls. Colon wall thickness showed a good correlation to the macroscopic grading of colitis (r = 0.81). The increase in colon wall thickness occurred mainly during the acute phase of colitis (between days 5 and 12) and did not progress much further in the chronic phase of colitis (d26). Colon wall thickness at d26 was thereby predicted by measurements at d12. All mice did not respond equally to DSS and this difference was manifest during the first 2 weeks of colitis, providing an important tool in stratifying responders from nonresponders. CONCLUSIONS: While the potential impact of handling and anesthesia should be considered on repeated micro-CT, irradiation exposure during repeated micro-CT did not affect the development of colitis. Thus, the results suggest that micro-CT can be used for monitoring and prediction of the inflammatory response in mouse colitis in future therapeutic studies.

  • 15.
    Fritsch Fredin, Maria
    et al.
    Astra-Zeneca, Mölndal.
    Vidal, Alexander
    Astra-Zeneca, Mölndal.
    Utkovic, Helena
    Astra-Zeneca, Mölndal.
    Götlind, Yu-Yuan
    Inst. för Biomedicin, Göteborgs Universitet.
    Willén, Roger
    Uppsala Universitet.
    Jansson, Liselotte
    Astra-Zeneca, Mölndal.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Melgar, Silvia
    Astra-Zeneca, Mölndal.
    The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis2008In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 58, no 3-4, p. 222-231Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Galphai2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Galphai2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1beta, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.

  • 16. Gotlind, Yu-Yuan C.
    et al.
    Raghavan, Sukanya
    Bland, Paul W.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    CD4(+)FoxP3(+) Regulatory T Cells from G alpha i2(-/-) Mice Are Functionally Active In Vitro, but Do Not Prevent Colitis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e25073-Article in journal (Refereed)
    Abstract [en]

    Background: Mice deficient in the inhibitory G protein subunit G alpha i2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4(+) FoxP3(+) regulatory T cells (Treg) underpins the pathogenesis of colitis in the G alpha i2(-/-) (G alpha i2-deficient) colitis model. Methodology/Principal Findings: Using flow cytometry, we found that thymus and colonic lamina propria, but not spleen and mesenteric lymph nodes, of colitic G alpha i2(-/-) mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in G alpha i2(-/-) compared to G alpha i2(-/-) or G alpha i2(+/+) wild type (WT) mice. The frequency of CD4(+)FoxP3(+) T cells expressing CD103 was significantly increased in G alpha i2(-/-) compared to WT mice. Treg in colons from WT mice clustered in the T cell areas of colonic lymphoid patches (CLP), with relatively few Treg in the lamina propria, as demonstrated by immunohistochemistry. In G alpha i2(-/-) mice, CLP were not observed but lamina propria Treg were increased in number and frequency within the CD4(+) infiltrate, compared to WT mice. Using an in vitro co-culture system and flow cytometric analysis of cell division we could demonstrate that the in vitro suppressive function of WT and G alpha i2(-/-) CD4(+)FoxP3(+) regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4(+)25(-) T cells) from G alpha i2(-/-) mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor G alpha i2(-/-) Treg was able to suppress colitis induced by adoptive transfer of G alpha i2(-/-) effector T cells (KO-Teff) to RAG2(-/-) recipients. The enhanced inflammatory activity of G alpha i2(-/-) effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-gamma. Conclusions: There is an increased frequency of G alpha i2(-/-) Treg in the colon, and they demonstrate no endogenous functional defect. However, G alpha i2(-/-) T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease.

  • 17.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ghiboub, M.
    Frenche Comte Univ, Besancon, France.
    Hultgren, Olof
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    The role of IL-37 on cytokine responses downstream of TLR4 and TLR5 signalling in intestinal epithelial cells2014In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 143, p. 94-95Article in journal (Other academic)
  • 18.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Institute of Infection, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University Hospital. Division of Gastroenterology, Department of Medicine, Örebro University, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX(3)CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX(3)CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

  • 19.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Increased expression of T cell recruiting chemokines in the colonic mucosa of microscopic colitis patients2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 135-135Article in journal (Other academic)
  • 20.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren, Olof
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    IL-1/TLR signaling inhibitors in microscopic and ulcerative colitis: Immunopathogenic markers of active disease and remission2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 167-167Article in journal (Other academic)
  • 21.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Rademacher, Lech
    Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden; Department of Medicine, Avesta Hospital, Avesta, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences. Örebro University Hospital. Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Clinical and immunologic effects of faecal microbiota transplantation in a patient with collagenous colitis2017In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 23, no 7, p. 1319-1324Article in journal (Refereed)
    Abstract [en]

    One to six percent of patients with microscopic colitis are refractory to medical treatment. The effect of faecal microbiota transplantation (FMT) in active collagenous colitis (CC) has, to the best of our knowledge, never been reported before. Here, we report the effect of repeated FMT in a patient with CC. The patient presented with severe symptoms including profuse diarrhea and profound weight loss. Although she responded to budesonide in the beginning, she became gradually refractory to medical treatment, and was therefore treated with FMT. The patient remained in remission for 11 mo after the third faecal transplantation. The immunomodulatory effect of the therapy was evaluated using flow cytometry, which showed alterations in the profile of intraepithelial and lamina propria lymphocyte subsets after the second transplantation. Our observations indicate that FMT can have an effect in CC, which support the hypothesis that luminal factors, influencing the intestinal microbiota, are involved in the pathogenesis of CC.

  • 22.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine, Div. of Gastroenterol., Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Department of Medicine, Div of Gastroenterol, Örebro Univ Hosp, Örebro, Sweden; Fac of Med and Hlth, Örebro Univ, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Department of Microbiology and Immunology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis2017In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 932-945Article in journal (Refereed)
    Abstract [en]

    Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.

    Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.

    Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.

    Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.

  • 23. Göranzon, C.
    et al.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok Kumar
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Eriksson, J.
    Bohr, J.
    Nyhlin, Nils
    Immunohistokemisk karakterisering av lymfocyter vid microscopisk kolit2011In: Gastrokuriren, ISSN 1651-0453, Vol. 16, no 29, p. PO16-PO16Article in journal (Other academic)
  • 24. Göranzon, C.
    et al.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok Kumar
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Eriksson, S.
    Bohr, Johan
    Nyhlin, Nils
    Immunohistochemical characterization of lymphocytes in microscopic colitis2010Conference paper (Other academic)
  • 25.
    Göranzon, C.
    et al.
    Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren-Hörnqvist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Eriksson, S.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Immunohistochemical characterization of lymphocytes in microscopic colitis2013In: Journal of Crohn's and Colitis, ISSN 1197-4982, Vol. 7, no 10, p. e434-e442Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry.

    Methods Paraffin-embedded biopsies from 23 untreated patients with MC (CC = 13, LC = 10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP.

    Results In CC and LC, an increase of predominantly CD8+ lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4+ lymphocytes was found in the lamina propria. CD45RO+ and Foxp3+ cells were more abundant in all areas in both patient groups compared to controls, as were CD20+ areas, although more scarce. Ki67+ areas were only more abundant in the epithelium, whereas CD30+ areas were more abundant in the lamina propria of both patient groups compared to controls.

    Conclusions This study confirms an increased amount of CD8+ lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4+ lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).

  • 26.
    Götlind, Y. Y.
    et al.
    Department of Microbiology and Immunology, Institute of Biomedicine and MIVAC, Sahlgrenska Academy, Göteborg, Sweden.
    Fritsch Fredin, M.
    Department of Bioscience, AstraZeneca, Mölndal, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Strid, H.
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Willén, R.
    Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Bland, P. W.
    Department of Microbiology and Immunology, Institute of Biomedicine and MIVAC, Sahlgrenska Academy, Göteborg, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Clinical Medicine.
    Interplay between Th1 and Th17 effector T cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the Gai2-deficient mouse2013In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 25, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.

  • 27.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Ghiboub, Mohammed
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam University, Amsterdam, The Netherlands..
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Microbiology and Immunology, Örebro University Hospital, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells2017In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 62, no 5, p. 1204-1215Article in journal (Refereed)
    Abstract [en]

    Background and Aim: Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. Previously, we showed enhanced chemokine productions in microscopic colitis patients, indicating dysregulated immune cell chemotaxis in the immunopathogenesis. We also showed decreased mRNA of IL-37, mainly regarded as an anti-inflammatory cytokine, in the colonic mucosa of these patients, potentially an important factor for the chronicity of the colitis. Our aim in this study was to understand the possible role of IL-37 in chemokine production using a cell line model.

    Methods: A colon epithelial cell line, T84, was stimulated with the TLR5 ligand flagellin. IL-37 protein production was reduced 20% using the CRISPR/Cas9 system, and the changes in chemokine mRNA and protein expressions were compared to cells transfected with empty plasmid.

    Results: The 20% reduction in IL-37 protein levels spontaneously increased CCL5, CXCL8, CXCL10, and CXCL11 mRNA and protein expressions. CCL2 mRNA and protein levels were enhanced upon TLR5 stimulation. CCL3, CCL20, and CX3CL1 mRNA expressions were increased either spontaneously or following TLR5 stimulation, whereas CCL4 and CCL22 mRNA expressions were significantly decreased.

    Conclusions: Even a minor decrease in the ability of colon epithelial cells to produce IL-37 results in altered chemokine expression, mainly an increase in the production of several chemokines. Our results indicate that a decreased IL-37 expression by colon epithelial cells may be an important factor for increasing the recruitment of immune cells and subsequently developing microscopic colitis.

  • 28.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Ghiboub, Mohammed
    Amsterdam university.
    Hultgren, Olof
    Örebro University, School of Medical Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cellsManuscript (preprint) (Other academic)
  • 29.
    Günaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Microbiology and Immunology, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis2014In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, no 34, p. 12249-12259Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients.

    METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction.

    RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001).

    CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

  • 30.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 31.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Medicine, Örebro University, Sweden.
    The mucosal immune system in microscopic colitis2012In: Microscopic colitis / [ed] S. Miehlke, A. Münich, Basel: S. Karger, 2012, p. 33-39Conference paper (Other academic)
  • 32.
    Hultgren Hörnquist, Elisabet
    et al.
    Örebro University, School of Health and Medical Sciences.
    Nilsson, Kerstin
    Örebro University, School of Health and Medical Sciences.
    Andersson, T.
    Örebro University, School of Health and Medical Sciences.
    Tidefelt, Ulf
    Örebro University, School of Health and Medical Sciences.
    Lidskog, Marie
    Örebro University, School of Health and Medical Sciences.
    Building a PBL-based integrated curriculum for a new medical school in Sweden2011Conference paper (Other academic)
  • 33.
    Jansson, A.
    et al.
    School of Life Sciences, Systems Biology Research Centre, University of Skövde, Skövde, Sweden.
    Pernestig, A.-K.
    School of Life Sciences, Systems Biology Research Centre, University of Skövde, Skövde, Sweden.
    Nilsson, P.
    School of Life Sciences, Systems Biology Research Centre, University of Skövde, Skövde, Sweden.
    Jirstrand, M.
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Biomedicine.
    Toward quantifying the thymic dysfunction state in mouse models of inflammatory bowel disease2013In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, no 4, p. 881-888Article, review/survey (Refereed)
    Abstract [en]

    Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in Gαi2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the Gαi2-deficient mice and in other mouse models of colitis.

  • 34. Kumawat, A. K.
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, N.
    Tysk, Curt
    Bohr, Johan
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Ökat uttryck av Th1/CTL-associerade gener samt högre frekvens CD8+ och CD4+8+, Ki67+ prolifererande, CD45RO+ aktiverade/minnes-T-celler i tarmslemhinnan hos patienter med kollagen kolit2011In: Gastrokuriren, ISSN 1651-0453, Vol. 16Article in journal (Other academic)
  • 35.
    Kumawat, Ashok
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elgbratt, Kristina
    Örebro University, School of Health and Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Increased frequencies of Ki67+ proliferating and CD45RO+ memory CD8+ and CD4+8+ T lymphocytes in the intestinal mucosa of collagenous colitis patients2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 4, p. 374-374Article in journal (Refereed)
  • 36. Kumawat, Ashok
    et al.
    Götlind, Yu-Yuan
    Fritsch Fredin, Maria
    Willén, Roger
    Chazot, Paul
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Modulation of histamine 4 receptor mRNA and protein expression in Gai2-deficient mice during colitis progression2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 4, p. 373-373Article in journal (Refereed)
  • 37.
    Kumawat, Ashok K.
    et al.
    Örebro University, School of Health and Medical Sciences.
    Götlind, Y. Y.
    School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Fredin, M. F.
    School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Willén, R.
    School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Expression patterns of histamine receptors in the g alpha i2-deficient mouse model of colitis2010In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 59, p. S358-S359Article in journal (Other academic)
    Abstract [en]

    Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo andin vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.

  • 38.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elgbratt, Kristina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Region Örebro County, Örebro, sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Reduced T cell receptor excision circle levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosa2013In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 408638Article in journal (Refereed)
    Abstract [en]

    Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic biopsies from CC (n = 8), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 3) (LC-HR, n = 6), non-inflamed diarrhoea patients (n = 17), and controls (n = 10) by real-time PCR. We observed lower median TREC levels in both CC and LC patients as well as in LC-HR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did, however, reach statistical significance. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined and reached statistical significance in LC patients compared to controls. In conclusion, reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67(+) T cells, suggests local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.

  • 39.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elgbratt, Kristina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Reduced T cell receptor excision circle (TREC) levels in the colonic mucosa of microscopic colitis patients indicate local proliferation rather than homing of peripheral lymphocytes to the inflamed mucosaManuscript (preprint) (Other academic)
    Abstract [en]

    Aims: Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic mucosa of CC and LC patients.

    Methods: Mucosal biopsies from CC (n=8), LC (n=5), and CC or LC patients in histopathological remission, (CC-HR, n=3), (LC-HR, n=6), non-inflamed diarrhoea patients (n=17) and controls (n=10) were analysed for TRECs expression by real time PCR.

    Results: The median TREC levels were lower in both CC and LC patients as well as in LCHR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did however reach statistical significance. No differences were observed in median TREC levels in either CC-HR or LC-HR patients compared to active CC and LC patients. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined; and reached statistical significance in LC patients compared to controls. LC patients had ignificantly increased CD3 mRNA levels also compared to CC, CC-HR, LC-HR and non-inflamed iarrhoea patients.

    Conclusions: Reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67+ T cells, suggest local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.

  • 40. Kumawat, Ashok Kumar
    et al.
    Götlind, Y. Y.
    Fritsch Fredin, M.
    Willén, R.
    Strid, H.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Expression patterns of histamine receptors in the Gai2-deficient mouse model of colitis2010In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 59, no Suppl 4, p. S358-S359Article in journal (Refereed)
  • 41.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Wickbom, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital. Department of Microbiology and Immunology, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    An In Vitro Model to Evaluate the Impact of the Soluble Factors from the Colonic Mucosa of Collagenous Colitis Patients on T Cells: Enhanced Production of IL-17A and IL-10 from Peripheral CD4(+) T Cells2014In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 879843Article in journal (Refereed)
    Abstract [en]

    Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4(+) T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-gamma, IL-17A, IL-6, and IL-1 beta and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4(+) T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro-and anti-inflammatory cytokines.

  • 42. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, Nils
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Bohr, J.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Collagenous colitis patients demonstrate a Th1/CTL-associated gene expression profile with increased frequencies of Ki67+ proliferating and CD45RO+ activated/ memory CD8+ and CD4+8+ mucosal T cells2011Conference paper (Other academic)
  • 43. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, Nils
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Bohr, J.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Collagenous colitis patients demonstrate a Th1/CTL-associated gene expression profile with increased frequencies of Ki67+ proliferating and CD45RO+ activated/memory CD8+ and CD4+8+ mucosal T cells2011In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 60, no Suppl. 3, p. A318-Article in journal (Refereed)
  • 44. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bohr, J.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Patienter med mikroskopisk kolit har blandad Th1/Th17 samt CTL-associerad cytokinprofil2012Conference paper (Other academic)
  • 45.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Elgbratt, Kristina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept. of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept. of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Microscopic colitis patients have increased frequencies of Ki67+proliferating and CD45RO+ active/memory CD8+ and CD4+8mucosal T cells2013In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 7, no 9, p. 694-705Article in journal (Refereed)
    Abstract [en]

    Background: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory bowel disorders of unknown etiology. This study investigated phenotypic characteristics of the mucosal lymphocytes in CC and LC.

    Methods: Lamina propria and intraepithelial lymphocytes (LPLs, IELs) isolated from mucosal biopsies from CC (n = 7), LC (n = 6), as well as LC or CC patients in histopathological remission, (LC-HR) (n = 6) and CC-HR (n = 4) and non-inflamed controls (n = 10) were phenotypically characterized by four-color flow cytometry.

    Results: The proportions of CD8+ IELs were increased in CC and LC (p < 0.01) compared to controls. Increased proportions of CD45RO+CD8+ IELs and LPLs were observed in LC and even more in CC patients (p < 0.01). Both CC (p < 0.05) and LC patients had elevated proportions of CD4+8+ IELs and LPLs compared to controls. The proportions of CD45RO+ cells were increased in CD4+8+ IELs and LPLs (p < 0.05) in CC and LC patients compared to controls. Both CC (p < 0.05) and LC patients had higher proportions of Ki67+CD8+ IELs and LPLs compared to controls.

    In contrast, decreased proportions of CD4+ LPLs were observed in CC and LC as well as CD4+ IELs in LC compared to controls. Increased proportions of Ki67+CD4+ IELs and LPLs (p < 0.05) were observed in CC and LC patients. CC-HR but not LC-HR patients demonstrated normalized proportions of both IELs and LPLs compared to CC and LC patients respectively.

    Conclusion: LC and CC patients have differences in mucosal lymphocyte subsets, with increased proportions of Ki67+ and CD45RO+ CD8+ and CD4+8+ mucosal T cells.

  • 46.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital.
    Bohr, Johan
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Region Örebro County, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 55, no 3-4, p. 355-364Article in journal (Refereed)
    Abstract [en]

    Background:

    Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients.

    Methods:

    Mucosal biopsies from CC (n = 10), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 4), (LC-HR, n = 6), ulcerative colitis (UC, n = 3) and controls (n = 10) were analysed by real-time PCR and Luminex for expression/production of IL-1 beta, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-gamma, TNF-alpha, T-bet and RORC2.

    Results:

    Mucosal mRNA but not protein levels of IFN-gamma and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1 beta mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-gamma, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients.

    Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-alpha protein was increased in CC, LC as well as in UC patients.

    Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production.

    Conclusion:

    LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

  • 47.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren, Olof
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    An in vitro model for analysis of the impact of the colonic milieu in collagenous colitis patients on peripheral T lymphocyte activation and differentiationManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Soluble factors released by intestinal mucosal cells contribute to immune homeostasis in the gut. This is the first study to investigate the role of soluble factors from the intestinal mucosa of collagenous colitis (CC) patients in the regulation of effector T cells using a novel system that mimics the in vivo exposure of newly recruited peripheral blood T cells to soluble factors derived from the colonic milieu of normal individuals and inflamed CC patient mucosa.

    Methods: Denuded biopsies (DNB) and isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients and non-inflamed controls were cultured to collect conditioned medium (CM). Enriched peripheral blood CD4+ T cells from healthy donors were polyclonally activated in the absence or presence of CM from CC patients and controls. Proliferation, as well as secretion of IL-1β IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α was analysed the latter with Luminex® analysis.

    Results: Peripheral CD4+ T cells exposed to CM from the colonic mucosa demonstrated reduced proliferation. This inhibition was less pronounced with DNB-CM derived from CC patients compared to non-inflamed control mucosa. In contrast, LPMC-CM from non-inflamed controls inhibited T-cell proliferation less than LPMC-CM from CC patients. Both DNB-CM and LPMC-CM from CC patients induced more or less increased production of the proinflammatory cytokines IFN-γ, IL-17A, IL-6 and TNF-α as well as the anti-inflammatory cytokines IL-4 and IL-10 from peripheral CD4+ T cells compared to non-inflamed controls. In contrast, IL-1β production by peripheral T cells showed mixed results – it was either increased or reduced in the presence of both DNB and LPMC-CM from CC patients compared to noninflamed controls with different blood donors and different concentrations.

    Conclusion: Our preliminary data indicates reduced inhibition of proliferation of peripheral CD4+ T cells in the presence of mucosa-derived soluble factors from CC patients compared to controls. In addition, increased production of both inflammatory and anti-inflammatory cytokines by peripheral CD4+ T cells was recorded in the presence of soluble factors from the colonic mucosa of CC patients compared to controls. This model can be valuable in evaluating the effect(s) of existing and new drugs on T cell differentiation in the intestinal mucosa.

  • 48.
    Kumawat, Ashok
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tysk, Curt
    Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    An in vitro model for analysis of the impact of the colonic milieu in collagenous colitis patients on peripheral T lymphocyte activation and differentiation2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 168-168Article in journal (Other academic)
  • 49.
    Lindberg, Erika
    et al.
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Andersson, Bert
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Magnusson, Yvonne
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Impaired activation of IFN-gamma+CD4+ T cells in peripheral blood of patients with dilated cardiomyopathy2010In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 263, no 2, p. 224-229Article in journal (Refereed)
    Abstract [en]

    Viral persistence and autoantibodies are pathogenic components in patients with idiopathic dilated cardiomyopathy (DCM). The aim was to evaluate T-cell function in DCM using different flow cytometry based detection techniques. Following stimulation, the frequency of IFN-gamma-producing CD4+ T cells was significantly lower in patients compared with controls. In contrast, the frequency of IL-4 producing CD4+ T cells was no different. In supernatants of cultured PBMC, IFN-gamma and IL-10 were significantly lower in patients. In addition, lymphocyte proliferation was significantly lower in patients compared with controls, whereas major lymphocyte subsets were not different. IFN-gamma and IL-10 are key cytokines in the ability to mount protective immune responses and to maintain self-tolerance. A reduced activation of T-helper 1 (IFN-gamma producing) cells and a decreased capacity to produce IL-10, found in the present study, could explain parts of the autoimmune features seen in patients with DCM.

  • 50. Rangel, I.
    et al.
    Ganda-Mall, J.-P.
    Elgbratt, K.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Development of colitis in Gai2-deficient mice is associated with profound changes in the microbiota2010Conference paper (Other academic)
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