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  • 1.
    Ahluwalia, Bani
    et al.
    Department of Microbiology and Immunology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Calmino Group AB, Sahlgrenska Science Park, Gothenburg, Sweden.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Isaksson, Stefan
    Department of Microbiology and Immunology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Larsson, Fredrik
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Effects of Aloe barbadensis Mill. extract (AVH200®) on human blood T cell activity in vitro2016In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 179, p. 301-309Article in journal (Refereed)
    Abstract [en]

    ETHNOPHARMACOLOGICAL RELEVANCE: Aloe barbadensis Mill. (Aloe vera) is a widely used medicinal plant well reputed for its diverse therapeutic applications. It has been used for thousands of years in folk medicine to treat various conditions and the Aloe vera gel has been reported to possess anti-inflammatory as well as immunostimulatory and immunomodulatory properties. However, the mode of action is still unclear.

    AIM OF THE STUDY: The aim of this study was determine the effects of two well-defined A. barbadensis Mill. extracts AVH200® and AVE200 on human blood T cells in vitro.

    MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated polyclonally in the presence or absence of AVH200® and AVE200. The T cell phenotype was investigated by flow cytometry, cell proliferation was determined by CFSE dye and thymidine assay, respectively and cytokine secretion was determined by MSD® Multi-Spot Assay system and ELISA.

    RESULTS: The presence of AVH200® resulted in a reduced expression of CD25 among CD3(+) T cells and suppression of T cell proliferation in a dose dependent manner. Furthermore, AVH200® reduced the expression of CD28 on CD3(+) T cells. AVH200® also reduced the secretion of IL-2, IFN-γ and IL-17A in PBMC cultures. The AVH200® dose dependent reduction in T cell activation and proliferation recorded in the cell cultures was not due to apoptosis or cell death. Additionally, AVH200® was found to be more effective as compared to AVE200 in reducing T cell activation and proliferation.

    CONCLUSION: AVH200® has the potential to reduce the activation, proliferation and cytokine secretion of healthy human blood T cells. Our study suggests that AVH200® has a suppressive effect on human blood T cells in vitro.

  • 2.
    Badam, Tejaswi
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Bioinformatics Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Hellberg, Sandra
    Bioinformatics Department of Physics, Chemistry and Biology, Linköping University, Sweden ; Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Mehta, Ratnesh B.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Lechner-Scott, Jeannette
    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia ; Centre for Brain and Mental Health, Hunter Medical Research Institute, New Lambton Heights, Australia ; Department of Neurology, John Hunter Hospital, New Lambton Heights, Australia.
    Lea, Rodney A.
    School of Medicine and Public Health, University of Newcastle, Callaghan, Australia ; Centre for Brain and Mental Health, Hunter Medical Research Institute, New Lambton Heights, Australia ; Institute of Health and Biomedical Innovations, Genomics Research Centre, Queensland University of Technology, Kelvin Grove, Australia.
    Tost, Jorg
    Laboratory of Epigenetics and Environment, Centre National De Recherche En Génomique Humaine, CEA-Institut De Biologie Francois Jacob, Evry, France.
    Mariette, Xavier
    Université Paris-Saclay, AP-HP-Université Paris-Saclay, Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (Inserm) U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, France.
    Svensson-Arvelund, Judit
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Nestor, Colm E.
    The Centre for Individualized Medicine, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Benson, Mikael
    The Centre for Individualized Medicine, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Berg, Göran
    Department of Obstetrics and Gynaecology and Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Jenmalm, Maria C.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Gustafsson, Mika
    Bioinformatics Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine and Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases2022In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 17, no 9, p. 1040-1055Article in journal (Refereed)
    Abstract [en]

    Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.

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  • 3.
    Badam, Tejaswi V. S.
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    de Weerd, Hendrik A.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    Martínez-Enguita, David
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Alfredsson, Lars
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden ; Institute of Environmental Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Jagodic, Maja
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Lubovac-Pilav, Zelmina
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Gustafsson, Mika
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis2021In: BMC Genomics, E-ISSN 1471-2164, Vol. 22, no 1, article id 631Article in journal (Refereed)
    Abstract [en]

    Background: There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules. Result: We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10− 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS. Conclusions: We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases. 

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  • 4.
    Bennet, Sean M. P.
    et al.
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Polster, Annikka
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Törnblom, Hans
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Isaksson, Stefan
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Capronnier, Sandrine
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Tessier, Aurore
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Le Nevé, Boris
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.
    Öhman, Lena
    University of Skövde, School of Health and Education. Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Global Cytokine Profiles and Association With Clinical Characteristics in Patients With Irritable Bowel Syndrome2016In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 111, no 8, p. 1165-1176Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Evidence suggests that patients with irritable bowel syndrome (IBS) have an altered cytokine profile, although it is unclear whether cytokines are linked with symptom severity. We aimed to determine whether global serum and mucosal cytokine profiles differ between IBS patients and healthy subjects and whether cytokines are associated with IBS symptoms.

    METHODS: Serum from 144 IBS patients and 42 healthy subjects was analyzed for cytokine levels of interleukin (IL)-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF) by MSD MULTI-ARRAY. In total, 109 IBS and 36 healthy sigmoid colon biopsies were analyzed for mRNA expression of IL-8, IL-10, TNF, and FOXP3 by quantitative reverse transcription PCR. Multivariate discrimination analysis evaluated global cytokine profiles. Rectal sensitivity, oroanal transit time, and psychological and gastrointestinal symptom severity were also assessed.

    RESULTS: Global cytokine profiles of IBS patients and healthy subjects overlapped, but cytokine levels varied more in IBS patients. Serum levels of IL-6 and IL-8 tended to be increased and levels of IFN-γ tended to be decreased in IBS patients. Mucosal mRNA expression of IL-10 and FOXP3 tended to be decreased in IBS patients. Within both the full study cohort and IBS patients alone, serum level of TNF was associated with looser stool pattern, while subjects with more widespread somatic symptoms had increased serum levels of IL-6. Although neither IBS bowel habit subgroups nor patients with possible post-infectious IBS were associated with distinct cytokine profiles, a small cluster of IBS patients with comparatively elevated immune markers was identified.

    CONCLUSIONS: Global cytokine profiles did not discriminate IBS patients from healthy subjects, but cytokine profiles were more varied among IBS patients than among healthy subjects, and a small subgroup of patients with enhanced immune activity was identified. Also, association of inflammatory cytokines with some clinical symptoms suggests that immune activation may be of importance in a subset of IBS patients.

  • 5.
    Dige, Anders
    et al.
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hvas, Christian Lodberg
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Kelsen, Jens
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Wick, Mary Jo
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Agnholt, Jørgen
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn's disease2016In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, no 6, p. 692-699Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Anti-TNF-α treatment constitutes a mainstay in the treatment of Crohn's disease (CD), but its mechanisms of action are not fully understood. We aimed to investigate the effects of adalimumab, a human monoclonal TNF-α antibody, on macrophage (MQ) and dendritic cell (DC) subsets in mucosal biopsies and peripheral blood.

    MATERIAL AND METHODS: Intestinal biopsies and blood samples were obtained from 12 different CD patients both before and 4 weeks after the initiation of the induction of adalimumab treatment. Endoscopic disease activity was estimated by the Simple Endoscopic Score for Crohn's Disease. Biopsies were obtained from inflamed and non-inflamed areas. The numbers of lamina propria CD14 (+) DR(int) and CD14 (+) DR(hi) MQs, CD141(+), CD141(-) and CD103(+ )DCs subsets, and circulating monocytes and DCs were analyzed using flow cytometry.

    RESULTS: At baseline, we observed higher numbers of DR(int) MQs and lower numbers of CD103(+ )DCs in inflamed versus non-inflamed mucosa [843 vs. 391/10(5) lamina propria mononuclear cells (LPMCs) (p < 0.05) and 9 vs. 19 × 10(5) LPMCs (p = 0.01), respectively]. After four weeks of adalimumab treatment, the numbers of DR(int) MQs decreased [843 to 379/10(5) LPMCs (p = 0.03)], whereas the numbers of CD103(+ )DCs increased [9-20 × 10(5) LPMCs (p = 0.003)] compared with baseline. In peripheral blood, no alterations were observed in monocyte or DC numbers between baseline and week 4.

    CONCLUSIONS: In CD, mucosal inflammation is associated with high numbers of DR(int) MQs and low numbers of CD103(+ )DCs. This composition of intestinal myeloid subsets is reversed by anti-TNF-α treatment. These results suggest that DR(int) MQs play a pivotal role in CD inflammation.

  • 6.
    Elgbratt, Kristina
    et al.
    Univ Örebro, Sch Hlth & Med Sci, Orebro, Sweden.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Hultgren-Hornquist, Elisabeth
    Univ Örebro, Sch Hlth & Med Sci, Orebro, Sweden.
    A Quantitative Study of the Mechanisms behind Thymic Atrophy in G alpha i2-Deficient Mice during Colitis Development2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 5, p. e36726-Article 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.

  • 7.
    Friman, Vanda
    et al.
    Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Sweden.
    Quinti, Isabella
    Department of Molecular Medicine, Sapienza University of Rome, Italy.
    Davydov, Alexey N.
    Central European Institute of Technology, Brno, Czech Republic.
    Shugay, Mikhail
    Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation ; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation ; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation.
    Farroni, Chiara
    Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy ; B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Engström, Erik
    Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden.
    Pour Akaber, Shirin
    Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria.
    Barresi, Sabina
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
    Mohamed, Ahmed
    Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden ; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
    Pulvirenti, Federica
    Centre for Primary Immune Deficiency, AUO Policlinico Umberto I, Rome, Italy.
    Milito, Cinzia
    Department of Molecular Medicine, Sapienza University of Rome, Italy.
    Granata, Guido
    Clinical and Research Department for Infectious Diseases, National Institute for Infectious Diseases L. Spallanzani (IRCCS), Rome, Italy.
    Giorda, Ezio
    Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Ahlström, Sara
    Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Johanna
    Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Sweden.
    Marasco, Emiliano
    Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Marcellini, Valentina
    Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Bocci, Chiara
    B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Cascioli, Simona
    Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Scarsella, Marco
    Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Phad, Ganesh
    Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Tartaglia, Marco
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
    Bemark, Mats
    Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Immunology and Transfusion Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Chudakov, Dmitriy M.
    Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation ; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation ; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation ; Central European Institute of Technology, Brno, Czech Republic.
    Carsetti, Rita
    B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy ; Unit of Diagnostic Immunology, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Grimsholm, Ola
    Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria ; Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden ; B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
    Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 5, article id 112446Article in journal (Refereed)
    Abstract [en]

    Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity. 

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  • 8.
    Gjertsson, Inger
    et al.
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    McGrath, Sarah
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Grimstad, Kristoffer
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Jonsson, Charlotte A.
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Thorarinsdottir, Katrin
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Mårtensson, Inga-Lill
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    A close-up on the expanding landscape of CD21-/low B cells in humans2022In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 210, no 3, p. 217-229Article, review/survey (Refereed)
    Abstract [en]

    Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21-/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21-/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies and associate with key disease manifestations in some conditions. These cells can be divided into subsets based on classical B-cell and other markers, e.g. CD11c, FcRL4, and Tbet which, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted, or simply CD21-/low B cells. It is however unclear whether the expanded 'CD21-/low' cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21-/low B cells are comparable in different conditions.

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  • 9.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hornquist, Elisabeth Hultgren
    Univ Örebro, Sch Hlth & Med Sci, Dept Biomed, Örebro, Sweden.
    Toward Quantifying the Thymic Dysfunctional 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 G alpha i2-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 G alpha i2-deficient mice and in other mouse models of colitis.

  • 10.
    Jonefjäll, Börje
    et al.
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine, Kungälv Hospital, Kungälv, Sweden.
    Öhman, Lena
    University of Skövde, School of Health and Education. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Center for Functional GI and Motility Disorders, University of North Carolina, USA.
    Strid, Hans
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
    IBS-like Symptoms in Patients with Ulcerative Colitis in Deep Remission Are Associated with Increased Levels of Serum Cytokines and Poor Psychological Well-being2016In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 22, no 11, p. 2630-2640Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gastrointestinal symptoms (GI) compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in remission. The causes of these symptoms remain to be clarified. Our aim was to investigate prevalence and factors associated with IBS-like symptoms in patients with UC in deep remission.

    METHODS: We included 298 patients with UC and used Mayo score, sigmoidoscopy, and fecal calprotectin to define deep remission versus active disease. Presence of IBS-like symptoms according to the Rome III criteria, severity of GI, extraintestinal and psychological symptoms, stress levels, and quality of life were measured with validated questionnaires. Serum cytokines and high-sensitive C-reactive peptide were determined.

    RESULTS: The criteria for deep remission was fulfilled by 132 patients (44%) and 24 of these fulfilled the Rome III criteria for IBS (18%). Patients with UC in deep remission with IBS-like symptoms had comparable levels of GI symptoms, non-GI somatic symptoms, and quality of life as patients with active UC. The patients with UC in deep remission with IBS-like symptoms had similar levels of fecal calprotectin as patients in deep remission without IBS-like symptoms (18 versus 31 μg/g, P = 0.11), but higher levels of serum cytokines (interleukin [IL]-1β, IL-6, IL-13, IL-10 and IL-8, P < 0.05) and higher levels of anxiety (P < 0.001), depression (P = 0.02) and perceived stress (P = 0.03).

    CONCLUSIONS: IBS-like symptoms in patients with UC in deep remission are common, but not as prevalent as previously reported. Poor psychological well-being and increased serum cytokine levels, but not colonic low-grade inflammation, were associated with IBS-like symptoms.

  • 11.
    Keane, Simon
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Herring, Matthew
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Rolny, Peter
    Division of Gastroenterology/Hepatology, Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, The Sahlgrenska Academy at University of Gothenburg, SU/Östra, Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Inflammation suppresses DLG2 expression decreasing inflammasome formation2022In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 149, no 9, p. 2295-2311Article in journal (Refereed)
    Abstract [en]

    Purpose

    Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction.

    Methods

    The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release.

    Results

    The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling.

    Conclusion

    DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes.

    Trial registration

    NCT03072641.

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  • 12.
    Komuraiah, Myakala
    University of Skövde, School of Life Sciences.
    Proliferation Signal Inhibitor associated proteinuria in a renal transplant recipient: Dysfunction of proximal tubular epithelial cells is a result of decreased cubilinand/or megalin expression?: Proliferation Signal Inhibitor associated Proteinuria2010Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background The proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (ERL) are the potent immunosuppressive drugs using in organ transplantation and has been used successfully in renal transplant recipients (RTX) as well. PSIs are the key factors to overcome the allograft rejections after successful organ transplantation since the immune system starts to react against the graft. SRL and ERL prevents the action of immune system b inhibits the proliferation of T- and B-cells by inhibiting the intracellular signaling of interleukin-2. The presence of excess amount of serum proteins including albumin in the urine is considered as proteinuria, which reflects the loss of kidney function. The occurrence of proteinuria can be the result of abnormal glomerular filtration and/or impaired tubular endocytic function of renal proximal tubular epithelial cells (PTECs). Megalin and cubulin are two scavenger receptors present on epical surface of PTECs and involved in reabsorption of proteins after glomerular ultrafiltration process in the kidney. Proteinuria appears too high in renal transplanted patients during ongoing   treatment with PSIs.

    Aim Our study aimed to investigate and correlate the expression level of megalin and cubilin and albumin uptake in PTEC of renal transplanted patients before and after conversion to PSI.

    Methods To retrieve the maximal expression of our interest molecules in renal PTECs, we optimized antigen retrieval (AR) method and primary antibody dilution for each molecule separately. An optimization experiment was performed on 3 different normal patients renal biopsies were used. Later, human renal biopsy specimens originated from 4 different renal transplanted patients were used in this study. From all the 4 patients biopsy specimens were taken before and ongoing administration of PSIs (SRL, ERL). The expression of megalin, cubilin and albumin uptake in PTEC of renal transplant patients was determined by immunohistochemical staining.

    Results Based on the optimization experiments, we selected the AR method and primary antibody dilution for the expression of megalin, cubilin and albumin uptake. In 4 renal transplanted patients following administration of PSIs results in patients 1, 2, 3 expression of megalin, cubilin and albumin uptake during ongoing PSI treatment was not comparable or even more intense than before PSIs introduction. The expression of megalin, cubilin and albumin uptake was reduced in patient 4 during ongoing PSI treatment.

    Conclusion Our findings suggest that the renal transplant patient 4 developed proteinuria during PSI medication. The expression of megalin, cubilin and albumin uptake was markedly decreased during ongoing PSI treatment in patient 4. We concluded that there is a direct link between PSI medication and tubular dysfunction, which might cause proteinuria

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  • 13.
    Larsson, Susanna
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Holmgren, Sandra
    VERIGRAFT, Gothenburg, Sweden.
    Jenndahl, Lachmi
    VERIGRAFT, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Strehl, Raimund
    VERIGRAFT, Gothenburg, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ghosheh, Nidal
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Proteome of Personalized Tissue-Engineered Veins2024In: ACS Omega, E-ISSN 2470-1343, Vol. 9, no 13, p. 14805-14817Article in journal (Refereed)
    Abstract [en]

    Vascular diseases are the largest cause of death globally and impose a major global burden on healthcare. The gold standard for treating vascular diseases is the transplantation of autologous veins, if applicable. Alternative treatments still suffer from shortcomings, including low patency, lack of growth potential, the need for repeated intervention, and a substantial risk of developing infections. The use of a vascular ECM scaffold reconditioned with the patient's own cells has shown successful results in preclinical and clinical studies. In this study, we have compared the proteomes of personalized tissue-engineered veins of humans and pigs. By applying tandem mass tag (TMT) labeling LC/MS-MS, we have investigated the proteome of decellularized (DC) veins from humans and pigs and reconditioned (RC) DC veins produced through perfusion with the patient's whole blood in STEEN solution, applying the same technology as used in the preclinical studies. The results revealed high similarity between the proteomes of human and pig DC and RC veins, including the ECM texture after decellularization and reconditioning. In addition, functional enrichment analysis showed similarities in signaling pathways and biological processes involved in the immune system response. Furthermore, the classification of proteins involved in immune response activity that were detected in human and pig RC veins revealed proteins that evoke immunogenic responses, which may lead to graft rejection, thrombosis, and inflammation. However, the results from this study imply the initiation of wound healing rather than an immunogenic response, as both systems share the same processes, and no immunogenic response was reported in the preclinical and clinical studies. Finally, our study assessed the application of STEEN solution in tissue engineering and identified proteins that may be useful for the prediction of successful transplantations. 

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  • 14.
    Lebrero-Fernandez, Cristina
    et al.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Wenzel, Ulf Alexander
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Akeus, Paulina
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Wang, Ying
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Strid, Hans
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden / Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.
    Gustavsson, Bengt
    Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
    Börjesson, Lars G.
    Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
    Cardell, Susanna L.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    University of Skövde, School of Health and Education. 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.
    Quiding-Järbrink, Marianne
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bas-Forsberg, Anna
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer2016In: Immunity, Inflammation and Disease, ISSN 2050-4527, Vol. 4, no 2, p. 191-200Article in journal (Refereed)
    Abstract [en]

    Several Butyrophilin (BTN) and Btn-like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real-time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2(-/-)) and intestinal tumorigenesis (Apc(Min/+)). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2(-/-) mice significantly down-regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from Apc(Min/+) mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family.

  • 15.
    Lewander, Andreas
    et al.
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Gao, Jinfang
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Carstensen, John
    Department of Health and Society, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
    Arbman, Gunnar
    Department of Surgery, Country Council of Östergötland, Norrköping, Sweden.
    Zhang, Hong
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sun, Xiao-Feng
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    NF-kappa B p65 phosphorylated at serine-536 is an independent prognostic factor in Swedish colorectal cancer patients2012In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 27, no 4, p. 447-452Article in journal (Refereed)
    Abstract [en]

    The NF-kappa B transcription factor protein family has diverse cellular and biological functions, and posttranslational modification is important to regulate these functions. An important site of phosphorylation of NF-kappa B p65 subunit is at serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization, and protein stability. In this study, we investigated expression of phospho-Ser536-p65 in colorectal cancers and its relationships with clinicopathological factors. The expression of phospho-Ser536-p65 was examined by immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens, and 18 metastases in the lymph nodes. The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumor (p < 0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumors correlated with worse survival of the patients independently of gender, age, tumor location, stage, and differentiation (p = 0.04; hazard ratio, 1.89; 95% CI 1.03-3.47). The NF-kappa B p65 subunit phosphorylated at serine-536 is an independent prognostic factor in colorectal cancer patients.

  • 16.
    Magnusson, Maria K.
    et al.
    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.
    Brynjólfsson, Siggeir F.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Dige, Anders
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Uronen-Hansson, Heli
    Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Börjesson, Lars G.
    Department of Surgery, Sahlgrenska University Hospital, Gotenburg, Sweden.
    Bengtsson, Jonas L.
    Department of Surgery, Sahlgrenska University Hospital, Gotenburg, Sweden.
    Gudjonsson, Sigurdur
    Department of Urology, Skåne University Hospital, Malmö, Sweden.
    Öhman, Lena
    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.
    Agnholt, Jørgen
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Sjövall, Henrik
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Agace, William W.
    Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden / Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark.
    Wick, Mary Jo
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Macrophage and dendritic cell subsets in IBD: ALDH+ cells are reduced in colon tissue of patients with ulcerative colitis regardless of inflammation2016In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 9, no 1, p. 171-182Article in journal (Refereed)
    Abstract [en]

    Disruption of the homeostatic balance of intestinal dendritic cells (DCs) and macrophages (MQs) may contribute to inflammatory bowel disease. We characterized DC and MQ populations, including their ability to produce retinoic acid, in clinical material encompassing Crohn's ileitis, Crohn's colitis and ulcerative colitis (UC) as well as mesenteric lymph nodes (MLNs) draining these sites. Increased CD14(+)DR(int) MQs characterized inflamed intestinal mucosa while total CD141(+) or CD1c(+) DCs numbers were unchanged. However, CD103(+) DCs, including CD141(+)CD103(+) and CD1c(+)CD103(+) DCs, were reduced in inflamed intestine. In MLNs, two CD14(-) DC populations were identified: CD11c(int)HLADR(hi) and CD11c(hi)HLADR(int) cells. A marked increase of CD11c(hi)HLADR(int) DC, particularly DR(int)CD1c(+) DCs, characterized MLNs draining inflamed intestine. The fraction of DC and MQ populations expressing aldehyde dehydrogenase (ALDH) activity, reflecting retinoic acid synthesis, in UC colon, both in active disease and remission, were reduced compared to controls and inflamed Crohn's colon. In contrast, no difference in the frequency of ALDH(+) cells among blood precursors was detected between UC patients and non-inflamed controls. This suggests that ALDH activity in myeloid cells in the colon of UC patients, regardless of whether the disease is active or in remission, is influenced by the intestinal environment.

  • 17.
    Magnusson, Maria K.
    et al.
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Strid, Hans
    Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
    Isaksson, Stefan
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Swede.
    The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis2017In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 956-966Article in journal (Refereed)
    Abstract [en]

    Background: The clinical disease course of ulcerative colitis (UC) varies substantially between individuals and can currently not be reliably predicted. The gut microbiota and the host's immune defense are key players for gut homeostasis and may be linked to disease outcome. The aim of this study was to determine fecal microbiota composition and mucosal antibacterial response profile in untreated patients with newly diagnosed UC and the impact of these factors on disease course. Methods: Stool samples and intestinal biopsies were obtained from therapy-naive newly diagnosed patients with UC. Patients were defined to have mild or moderate/severe disease course assessed by disease activity during the 3 years follow-up. Fecal microbiota was analyzed by the GA-map Dysbiosis test (n = 18), and gene expression in intestinal biopsies was analyzed by RT2 Profiler polymerase chain reaction array (n = 13) and real-time polymerase chain reaction (n = 44). Results: At the time of diagnosis of UC, the fecal microbiota composition discriminated between patients with mild versus moderate/severe disease course. Also, the mucosal antibacterial gene expression response profile differed between patients with mild versus moderate/severe disease course with bactericidal/permeability-increasing protein (BPI) being most important for the discrimination. Mucosal bactericidal/permeability-increasing protein gene expression at diagnosis was higher in patients with mild versus moderate/severe disease course when confirmed in a larger patient cohort (P = 0.0004, n = 44) and was a good predictor for the number of flares during the 3 years follow-up (R-2 = 0.395, P < 0.0001). Conclusions: In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.

  • 18.
    Sundell, Timothy
    et al.
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
    Grimstad, Kristoffer
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Gjertsson, Inger
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
    Mårtensson, Inga-Lill
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden.
    Single-cell RNA sequencing analyses: interference by the genes that encode the B-cell and T-cell receptors2023In: Briefings in Functional Genomics & Proteomics, ISSN 2041-2649, E-ISSN 2041-2657, Vol. 22, no 3, p. 263-273, article id elac044Article in journal (Refereed)
    Abstract [en]

    B and T cells are integral parts of the immune system and are implicated in many diseases, e.g. autoimmunity. Towards understanding the biology of B and T cells and subsets thereof, their transcriptomes can be analyzed using single-cell RNA sequencing. In some studies, the V(D)J transcripts encoding the variable regions of the B- and T-cell antigen receptors have been removed before the analyses. However, a systematic analysis of the effects of including versus excluding these genes is currently lacking. We have investigated the effects of these transcripts on unsupervised clustering and down-stream analyses of single-cell RNA sequencing data from B and T cells. We found that exclusion of the B-/T-cell receptor genes prior to unsupervised clustering resulted in clusters that represented biologically meaningful subsets, such as subsets of memory B and memory T cells. Furthermore, pseudo-time and trajectory inference analyses of early B-lineage cells resulted in a developmental pathway from progenitor to immature B cells. In contrast, when the B-/T-cell receptor genes were not removed, with the PCs used for clustering consisting of up to 70% V-genes, this resulted in some clusters being defined exclusively by V-gene segments. These did not represent biologically meaningful subsets; for instance in the early B-lineage cells, these clusters contained cells representing all developmental stages. Thus, in studies of B and T cells, to derive biologically meaningful results, it is imperative to remove the gene sequences that encode B- and T-cell receptors.

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  • 19.
    Östensson, Malin
    et al.
    Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Montén, Caroline
    Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Bacelis, Jonas
    Institute of Biomedicine, Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Gudjonsdottir, Audur H.
    Queen Silvia Children’s Hospital, Sahlgrenska Academy at the University of Gothenburg, Department of Pediatrics, Gothenburg, Sweden.
    Adamovic, Svetlana
    Institute of Biomedicine, Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Ek, Johan
    Buskerud Central Hospital, Department of Pediatrics, Drammen, Norway.
    Ascher, Henry
    Sahlgrenska Academy at the University of Gothenburg, Department of Public Health and Community Medicine, Unit of Social Medicine, Gothenburg, Sweden.
    Pollak, Elisabet
    Institute of Biomedicine, Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Arnell, Henrik
    Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
    Browaldh, Lars
    Department of Clinical Science and Education, Karolinska Institutet Södersjukhuset, Stockholm, Sweden.
    Agardh, Daniel
    Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Wahlström, Jan
    Institute of Biomedicine, Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Staffan
    Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Torinsson-Naluai, Åsa
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Institute of Biomedicine, Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    A Possible Mechanism behind Autoimmune Disorders Discovered By Genome-Wide Linkage and Association Analysis in Celiac Disease2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 8, article id e70174Article in journal (Refereed)
    Abstract [en]

    Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component.

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