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  • 1.
    Abuabaid, Hanan
    et al.
    Örebro University, School of Science and Technology.
    Karlsson, Mattias
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Probiotic Lactobacillus rhamnosus alters inflammatory responses of bladder epithelial and macrophage-like cells in co-cultureManuscript (preprint) (Other academic)
  • 2.
    Andersson, Josefin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Utvärdering av Malaria Antigen ELISA kit för diagnostik av malaria vid Christian Medical College and Hospital i Vellore, Indien.: en jämförande studie mellan Quantitative buffy coat och enzyme-linked immunosorbent assays (ELISA) metodik.2006Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Malaria är ett globalt hälsoproblem som orsakar många dödsfall runt om i världen varje år och nästan hälften av jordens befolkning ligger i riskzonen att drabbas av sjukdomen. I Indien drabbas mellan 2-3 miljoner människor varje år och det inträffar omkring 900 dödsfall. Malaria orsakas av Plasmodium sp. som är en protozoe, och det finns fyra olika arter som är patogena för människor, P. vivax, P. ovale, P. falciparium samt P. malariae.

    Vanliga metoder för att diagnostisera malaria är genom tunna och tjocka blodutstryk som färgas till exempel med Giemsa, Fields eller Leishmans färgningsteknik och studeras mikroskopiskt, Quantitative Buffy Coat (QBC), PCR tester, acridinorange färgning samt olika immunologiska tester för detektion av antikroppar eller antigen som till exempel enzyme-linked immunosorbent assays (ELISA) test och dipstick test.

    Syftet med denna studie är att utvärdera om en användning av SD Bio Line Malaria Antigen ELISA kit ger en mer känslig, tillförlitlig, praktisk samt mindre kostsam diagnostikmetod för malaria hos patienter med misstänkt malariainfektion än den nuvarande guldstandardmetoden, QBC tillsammans med blodutstryk, vid Christian Medical College and Hospital i Vellore.

    Patientproverna har i både ELISA testet samt QBC testet tillsammans med utstryk erhållit samma resultat vilket tyder på att SD Bio Line Malaria Antigen ELISA kitet skulle kunna vara en lika bra diagnostikmetod som QBC testet för diagnos av malaria. ELISA kitet har dock fler nackdelar, i jämförelse med QBC testet, så därför är slutsatsen att SD Bio Line Malaria Antigen ELISA kitet inte är en mer lämplig diagnostisk metod för malaria än den som används vid CMCH. Men då ELISA testet ändå ger en säker diagnos, enligt resultatet i studien, kan den vara ett lämpligt test inom något annat användningsområde.

  • 3.
    Bengtsson, Torbjörn
    et al.
    Örebro University, School of Medical Sciences.
    Lönn, Johanna
    Department of Oral Biology, Institute of Odontology, Malmö University, Malmö, Sweden; PEAS Research Institute, Linköping, Sweden.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    The lantibiotic gallidermin acts bactericidal against Staphylococcus epidermidis and Staphylococcus aureus and antagonizes the bacteria-induced proinflammatory responses in dermal fibroblasts2018In: MicrobiologyOpen, ISSN 2045-8827, E-ISSN 2045-8827, Vol. 7, no 6, article id e606Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance needs to be tackled from new angles, and antimicrobial peptides could be future candidates for combating bacterial infections. This study aims to investigate in vitro the bactericidal effects of the lantibiotic gallidermin on Staphylococcus epidermidis and Staphylococcus aureus, possible cytotoxic effects and its impact on host-microbe interactions. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of gallidermin were determined, and cytotoxicity and proinflammatory effects of gallidermin on fibroblasts, red blood cells (RBCs) and in whole blood were investigated. Both MIC and MBC for all four tested strains of S. epidermidis was 6.25 μg/ml. Both MIC and MBC for methicillin-sensitive S. aureus was 12.5 μg/ml and for methicillin-resistant S. aureus (MRSA) 1.56 μg/ml. Gallidermin displayed no cytotoxic effects on fibroblasts, only a high dose of gallidermin induced low levels of CXCL8 and interleukin-6. Gallidermin hemolyzed less than 1% of human RBCs, and did not induce reactive oxygen species production or cell aggregation in whole blood. In cell culture, gallidermin inhibited the cytotoxic effects of the bacteria and totally suppressed the bacteria-induced release of CXCL8 and interleukin-6 from fibroblasts. We demonstrate that gallidermin, expressing low cell cytotoxicity, is a promising candidate for treating bacterial infections caused by S. epidermidis and S. aureus, especially MRSA.

  • 4.
    Björkstén, Bengt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Diverse microbial exposure: Consequences for vaccine development2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 29, p. 4336-4340Article, review/survey (Refereed)
    Abstract [en]

    Numerous epidemiological studies suggest that there is an inverse relationship between "immunologically mediated diseases of affluence", such as allergy, diabetes and inflammatory bowel disease on one hand and few infections encountered in early childhood, on the other hand. Careful analysis of the epidemiological, clinical and animal studies taken together, however, suggests that the protection is mediated by broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life, rather than by infections. Microbial exposure has little relationship with "hygiene" in the usual meaning of the word and the term "hygiene hypothesis" is therefore misleading. A better term would be "microbial deprivation hypothesis". The suggestion that childhood infections would protect against allergic disease led to unfortunate speculations that vaccinations would increase the risk for allergies and diabetes. Numerous epidemiological studies have therefore been conducted, searching for a possible relationship between various childhood vaccinations on one hand and allergy on the other hand. It is reasonable from these studies to conclude that vaccinations against infectious agents neither significantly increase, nor reduce the likelihood of immunologically mediated diseases. It is established that the postnatal maturation of immune regulation is largely driven by exposure to microbes. Germ free animals manifest excessive immune responses when immunised and they do not develop normal immune regulatory function. The gut is by far the largest source of microbial exposure, as the human gut microbiome contains up to 1014 bacteria, i.e. ten times the number of cells in the human body. Several studies in recent years have shown differences in the composition of the gut microbiota between allergic and non-allergic individuals and between infants living in countries with a low and a high prevalence of immune mediated diseases. The administration of probiotic bacteria to pregnant mothers and postnatal to their infants has immune modulatory effects. So far, however, probiotic bacteria do not seem to significantly enhance immune responses to vaccines. The potential to improve vaccine responses by modifying the gut microbiota in infants and the possibility to employ probiotic bacteria as adjuvants and/or delivery vehicles, is currently explored in several laboratories. Although to date few clinical results have been reported, experimental studies have shown some encouraging results.

  • 5.
    Degen, Winfried G. J.
    et al.
    Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands.
    Pieffers, Martijn
    Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands.
    Welin-Henriksson, Elisabet
    Department of Medicine, Rheumatology Research Unit, Center for Molecular Medicine, Karolinska Institutet & Karolinska Hospital, Stockholm, Sweden.
    van den Hoogen, Frank H. J.
    Department of Rheumatology, University Hospital Nijmegen, Nijmegen, The Netherlands.
    van Venrooij, Walther J.
    Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands.
    Raats, Jos M. H.
    Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands.
    Characterization of recombinant human autoantibody fragments directed toward the autoantigenic U1-70K protein2000In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 30, no 10, p. 3029-3038Article in journal (Refereed)
    Abstract [en]

    The U1-70K protein is specifically bound to stemloop I of the U1 small nuclear RNA contained in the U1 small nuclear ribonucleoprotein complex (U1 snRNP), which is involved in the splicing of pre-mRNA. All components of the U1 snRNP complex, including the U1-70K protein, are important autoantigens in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Here we describe for the first time the selection and characterization of recombinant human anti-U1-70K single chain autoantibody fragments (anti-hU1-70K scFv) from autoimmune patient-derived phage display antibody libraries. All scFv specifically recognize parts of the hU1-70K protein and its apoptotic 40-kDa cleavage product. In Western blotting assays a number of scFv preferentially recognize the 40-kDa apoptotic cleavage fragment of the U1-70K protein, suggesting a possible involvement of this apoptotic cleavage product in the autoimmune response of patients. The germline gene usage of these recombinant autoantibodies was also determined. Using several U1-70K deletion and point mutants of both human (h) and Drosophila melanogaster (Dm) origin, it was established that the U1-70K epitope that is recognized by the anti-hU1-70K scFv is located within the RNA binding domain.

  • 6.
    Eklund, Daniel
    et al.
    Division of Microbiology and Molecular Medicine, Linköping University, Linköping, Sweden.
    Welin, Amanda
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Henrik
    Division of Microbiology and Molecular Medicine, Linköping University, Linköping, Sweden.
    Verma, Deepti
    Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Stendahl, Olle
    Division of Microbiology and Molecular Medicine, Linköping University, Linköping, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden.
    Lerm, Maria
    Division of Microbiology and Molecular Medicine, Linköping University, Linköping, Sweden.
    Human Gene Variants Linked to Enhanced NLRP3 Activity Limit Intramacrophage Growth of Mycobacterium tuberculosis2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 5, p. 749-753Article in journal (Refereed)
    Abstract [en]

    Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1 beta is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequent infection of the cells with virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.

  • 7.
    Gorreja, Frida
    et al.
    Örebro University, School of Medical Sciences.
    Rush, Stephen
    Örebro University, School of Medical Sciences.
    Kasper, Dennis
    Department of Microbiology and Molecular Genetics, Boston, USA; Harvard Medical School, Boston, USA.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Meng, Di
    Harvard Medical School, Boston, USA; Mucosal Immunology Laboratory, Massachusetts General Hospital for Children, Boston, USA.
    Walker, W. Allan
    Harvard Medical School, Boston, USA; Mucosal Immunology Laboratory, Massachusetts General Hospital for Children, Boston, USA.
    Beneficial bacteria that affect Toll-like receptors in the gut immune system: the case of PSA on Bacteroides fragilis and transcription profile of developmentally-regulated genes2018Conference paper (Other academic)
  • 8.
    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.

  • 9.
    Hagemann, Urs B.
    et al.
    Affitech Research AS, Oslo, Norway; Algeta/Bayer AS, Oslo, Norway.
    Gunnarsson, Lavinia
    Örebro University, School of Science and Technology. Affitech Research AS, Oslo, Norway.
    Geraudie, Solene
    Affitech Research AS, Oslo, Norway; Radiumhospitalet, Oslo, Norway.
    Scheffler, Ulrike
    Affitech Research AS, Oslo, Norway; ProBioGen AG, Berlin, Germany.
    Griep, Remko A.
    Affitech Research AS, Oslo, Norway; AbCheck, Plzen, Czech Republic.
    Reiersen, Herald
    Affitech Research AS, Oslo, Norway; Jiffy International AS, Aas, Norway .
    Duncan, Alexander R.
    Affitech Research AS, Oslo, Norway; Actigen Ltd, Cambridge, United Kingdom.
    Kiprijanov, Sergej M.
    Affitech Research AS, Oslo, Norway; BerGenBio AS, Bergen, Norway.
    Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e103776Article in journal (Refereed)
    Abstract [en]

    Background: CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis.

    Methodology: Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies.

    Significance: For the first time, successful generation of anti-G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.

  • 10.
    Hedlund, Linda
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University Hospital.
    Söderquist, Bo
    Örebro University Hospital.
    Presence of arginine catabolic mobile element among community-acquired meticillin-resistant staphylococcus aureus is linked to a specific genetic background2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 3, p. 221-225Article in journal (Refereed)
    Abstract [en]

    The prevalence of arginine catabolic mobile element (ACME) among diverse and heterogeneous community-associated methicillin-resistant Staphylococcus aureus community-associated Methicillin-resistant S. aureus (CA-MRSA) (n = 114) in a low-endemic area, i.e. Sweden, was investigated. Among the CA-MRSA, represented by 47 different spa types, ACME was only found in 10 isolates with a common genetic background [t008, SCCmec type IV, Panton-Valentine leukocidin (PVL) positive, and indistinguishable or closely related pulsed-field gel electrophoresis (PFGE)-patterns] corresponding to USA300. This strain does not seem to be established in our area as most of the patients contracted the CA-MRSA abroad. Presence of ACME does not seem to be associated with colonization, long-term carriership, or intra-familiar transmission in a higher extent than CA-MRSA in general.

  • 11.
    Henriksson, Elisabet Welin
    et al.
    Department of Cell and Molecular Biology, Laboratory of Medical Cell Genetics, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
    Pettersson, Ingvar
    Autoepitope-mapping of the U1-70K protein with human-Drosophila chimeric proteins1997In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 10, no 6, p. 559-568Article in journal (Refereed)
    Abstract [en]

    The 70K protein is the major autoantigen for anti-RNP autoantibodies directed against the U1 small nuclear ribonucleoprotein complex particle. The U1-70K protein has been epitope-mapped by various groups, and a major antigenic region of about 70 amino acids has been found which overlaps with the RNA binding motif. Attempts to map the major antigenic region further with smaller cloned fragments or with peptides have been hampered by total loss of, or strongly reduced, antigenicity. Thus the major antigenic region is composed of conformational epitopes and a detailed analysis of particular epitopes has not been possible. In the present work, we examine the antigenicity of chimeric proteins assembled from the highly conserved Drosophila melanogaster 70K proteins grafted with human 70K segments. With this approach, the effects on antigenicity of exchanging particular segments can be assayed with the overall structure of the major antigenic domain kept relatively constant. Our results, supported by depletion experiments, show that residues 99-128 from the human protein are essential for recognition by both human and canine anti-RNP autoantibodies. These residues have to be presented in a manner that allows correct conformational interaction between the different protein domains.

  • 12.
    Henriksson, Elisabet Welin
    et al.
    Department of Cell and Molecular Biology, Laboratory of Medical Cell Genetics, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
    Pettersson, Ingvar
    Human anti-RNP sera contain both human-specific and cross-reactive anti-70K autoantibodies1996In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 9, no 4, p. 551-559Article in journal (Refereed)
    Abstract [en]

    The U1 snRNP (small nuclear ribonucleoprotein complex) associated 70K protein is the main autoantigen for the anti-RNP autoantibodies which are directed against the U1 snRNP particle. The major antigenic region of the 70K protein has by various laboratories been mapped to an RNA binding domain required for the 70K-U1 snRNA interaction. We have used recombinant proteins comprising this region from the human and the Drosophila melanogaster 70K proteins to examine the species specificity of the human anti-70K autoantibodies found in 42 patient sera. Most, but not all, anti-70K positive sera in this cross-sectional sample contained both human 70K specific anti-bodies and Drosophila 70K reactive antibodies. Results of a longitudinal follow-up of 14 patients indicated that the cross-reactive anti-70K antibodies developed secondarily to the establishment of a species-specific anti-70K reaction. In a fraction of the patient sera this broadening of the response never occurred. Taken together, the data in this study support the hypothesis that the endogenous human 70K protein is the immunogen driving the production of anti-70K autoantibodies.

  • 13.
    Hussain, Rashida
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Oliynyk, Igor
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Roomans, Godfried M.
    Örebro University, School of Medicine, Örebro University, Sweden.
    Björkqvist, Maria
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Modulation of ENaC, CFTR, and iNOS expression in bronchial epithelial cells after stimulation with Staphylococcus epidermidis (94B080) and Staphylococcus aureus (90B083)2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 9, p. 814-826Article in journal (Refereed)
    Abstract [en]

    Bacteria affect the respiratory epithelium, which is covered by airway surface liquid (ASL) and mucus. Ion concentrations in the ASL are determined by the cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial Na+ channel (ENaC). Neonatal sepsis is a major risk factor for subsequent pulmonary disease in preterm newborns. Predominating are coagulase-negative staphylococci (e.g., Staphylococccus epidermidis and Staphylococccus aureus). The aim of this study was to investigate modulation of CFTR, ENaC, mucins, proinflammatory cytokines, and inducible nitric oxide synthase (iNOS) in respiratory epithelial cells after S. epidermidis 94B080 and S. aureus 90B083 exposure. Bronchial epithelial cells were incubated with S. epidermidis 94B080 and S. aureus 90B083 (neonatal blood isolates) for 1-36h. Expression of CFTR, ENaC, iNOS, and mucins was analyzed by real-time PCR and Western blotting. Release of cytokines was analyzed by ELISA, and production of NO by the Griess assay. Expression of CFTR significantly decreased after 36h incubation with S. epidermidis and more prominently with S. aureus, whereas S. epidermidis caused a significant increase in the expression of - and -ENaC. Expression of iNOS increased, but NO was not detected. Both staphylococci caused a decrease in the intracellular Ca2+ concentration. S. aureus induced increased secretion of IL-6, IL-8, and transforming nuclear factor (TNF)- in a time-dependent manner as compared with S. epidermidis. In conclusion, expression of ENaC, CFTR, and iNOS is modulated by exposure to S. aureus 90B083 and S. epidermidis 94B080. S. aureus is more potent in causing release of IL-6, IL-8, and TNF- by bronchial epithelial cells as compared with S. epidermidis. The mRNA expression for the mucus proteins MUC2, MUC5AC, and MUC5B could not be measured, neither in the presence nor in the absence of bacteria.

  • 14.
    Jernelöv, S.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lekander, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden; OsherCenter for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, C.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Axelsson, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Development of atopic disease and disturbed sleep in childhood and adolescence: a longitudinal population-based study2013In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 43, no 5, p. 552-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Both atopic diseases and sleep disturbances have increased during recent decades, especially in children. Sleep is important for many aspects of immune regulation relevant in allergic diseases, and sleep disturbances are common in patients with such diseases. A connection between sleep disturbances and fatigue, and atopic disease is well established. However, the time course and putative causal relationships between these factors are obscure.

    OBJECTIVE: We aimed at investigating the developmental relationships between subjectively reported sleep disturbances and symptoms of atopic disease, from childhood to adolescence.

    METHODS: This longitudinal study used parent-report questionnaire data on symptoms of atopic disease, and sleep disturbances, from the Twin Study of Child and Adolescent Development (TCHAD). Overall, 1480 twin pairs born in Sweden were approached first when children were 8-9 years old, and again later at 13-14 years old. Response rates were 75% and 72%. Data from the TCHAD questionnaires were linked to the Swedish Medical Birth Register based on personal identification numbers.

    RESULTS: Being overtired at age 8 increased the risk [OR; 95% CI (2.59; 1.31-5.11)] to develop rhinitis symptoms at age 13, even when controlling for gender, previous rhinitis, Socio-economic status, birth weight and other sleep disturbances at age 8. Likewise, symptoms of asthma at age 8 was an independent risk factor for being overtired at age 13 [OR; 95% CI (2.64; 1.44-4.84)], controlling for similar confounders.

    CONCLUSION & CLINICAL RELEVANCE: The findings from this study are consonant with the proposition that atopic disease and disturbed sleep are more than passively interrelated. Future research needs to delineate whether causal relationships between these problems are at hand and, if so, at what periods in development this applies. These results point to a need for clinicians to investigate sleep difficulties and treat impaired sleep in paediatric patients with atopic disease.

  • 15.
    Kalbina, Irina
    et al.
    Örebro University, School of Science and Technology. Orebro Life Science Center.
    Lagerqvist, Nina
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Moiane, Bélisario
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Eduardo Mondlane University, Maputo, Mozambique.
    Ahlm, Clas
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Örebro Life Science Center, Department of Science and Technology, Örebro University, Örebro, Sweden; Department of Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Falk, Kerstin I.
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Arabidopsis thaliana plants expressing Rift Valley fever virus antigens: Mice exhibit systemic immune responses as the result of oraladministration of the transgenic plants2016In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 127, p. 61-67Article in journal (Refereed)
    Abstract [en]

    The zoonotic Rift Valley fever virus affects livestock and humans in Africa and on the Arabian Peninsula.The economic impact of this pathogen due to livestock losses, as well as its relevance to public health,underscores the importance of developing effective and easily distributed vaccines. Vaccines that can bedelivered orally are of particular interest.

    Here, we report the expression in transformed plants (Arabidopsis thaliana) of Rift Valley fever virusantigens. The antigens used in this study were the N protein and a deletion mutant of the Gn glycoprotein.Transformed lines were analysed for specific mRNA and protein content by RT-PCR and Westernblotting, respectively. Furthermore, the plant-expressed antigens were evaluated for their immunogenicityin mice fed the transgenic plants. After oral intake of fresh transgenic plant material, a proportionof the mice elicited specific IgG antibody responses, as compared to the control animals that were fedwild-type plants and of which none sero-converted.

    Thus, we show that transgenic plants can be readily used to express and produce Rift Valley Fever virusproteins, and that the plants are immunogenic when given orally to mice. These are promising findingsand provide a basis for further studies on edible plant vaccines against the Rift Valley fever virus.

  • 16.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fernandes, Oswaldo
    Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Oestrogen receptor ss in NSCLC: prevalence, proliferative influence, prognostic impact and smoking2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 6, p. 451-458Article in journal (Refereed)
    Abstract [en]

    In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.

  • 17.
    Karlsson, Mattias
    et al.
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-κB activity in Escherichia coli-stimulated urinary bladder cells2012In: FEMS Immunology and Medical Microbiology, ISSN 0928-8244, E-ISSN 1574-695X, Vol. 66, no 2, p. 147-156Article in journal (Refereed)
    Abstract [en]

    Lactobacillus rhamnosus GR-1 is a probiotic bacterium used to maintain urogenital health. The putative mechanism for its probiotic effect is by modulating the host immunity. Urinary tract infections (UTI) are often caused by uropathogenic Escherichia coli that frequently evade or suppress immune responses in the bladder and can target pathways, including nuclear factor-kappaB (NF-κB). We evaluated the role of L. rhamnosus GR-1 on NF-κB activation in E. coli-stimulated bladder cells. Viable L. rhamnosus GR-1 was found to potentiate NF-κB activity in E. coli-stimulated T24 bladder cells, whereas heat-killed lactobacilli demonstrated a marginal increase in NF-κB activity. Surface components released by trypsin- or LiCl treatment, or the resultant heat-killed shaved lactobacilli, had no effect on NF-κB activity. Isolation of released products from L. rhamnosus GR-1 demonstrated that the induction of NF-κB activity was owing to released product(s) with a relatively large native size. Several putative immunomodulatory proteins were identified, namely GroEL, elongation factor Tu and NLP/P60. GroEL and elongation factor Tu have previously been shown to elicit immune responses from human cells. Isolating and using immune-augmenting substances produced by lactobacilli is a novel strategy for the prevention or treatment of UTI caused by immune-evading E. coli.

  • 18.
    Khalaf, Hazem
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Clinical Medicine,, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden. Division of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Altered T-cell responses by the periodontal pathogen Porphyromonas gingivalis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, article id e45192Article in journal (Refereed)
    Abstract [en]

    Several studies support an association between the chronic inflammatory diseases periodontitis and atherosclerosis with a crucial role for the periodontal pathogen Porphyromonas gingivalis. However, the interplay between this pathogen and the adaptive immune system, including T-cells, is sparsely investigated. Here we used Jurkat T-cells to determine the effects of P. gingivalis on T-cell-mediated adaptive immune responses. We show that viable P. gingivalis targets IL-2 expression at the protein level. Initial cellular events, including ROS production and [Ca2+]i, were elevated in response to P. gingivalis, but AP-1 and NF-κB activity dropped below basal levels and T-cells were unable to sustain stable IL-2 accumulation. IL-2 was partially restored by Leupeptin, but not by Cathepsin B Inhibitor, indicating an involvement of Rgp proteinases in the suppression of IL-2 accumulation. This was further confirmed by purified Rgp that caused a dose-dependent decrease in IL-2 levels. These results provide new insights of how this periodontal pathogen evades the host adaptive immune system by inhibiting IL-2 accumulation and thus attenuating T-cell proliferation and cellular communication.

  • 19.
    Khalaf, Hazem
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Suppression of inflammatory gene expression in T cells by Porphyromonas gingivalis is mediated by targeting MAPK signaling2013In: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 10, no 5, p. 413-422Article in journal (Refereed)
    Abstract [en]

    There is increasing awareness of the effects of Porphyromonas gingivalis on host immune responses. Degradation of cytokines and chemokines by cysteine proteinases has previously been reported. However, the precise mechanisms by which P. gingivalis is able to alter intracellular signaling, and thus proliferation and inflammation, have not been described. We have previously reported suppression of activator protein-1 (AP-1) and degradation of IL-2 by proteinases from P. gingivalis. In the present study, we have analyzed the effects of P. gingivalis on Jurkat T-cell signal transduction and subsequent IL-2 and CXCL8 expression. We found that CXCL8, but not IL-2, gene expression levels were significantly suppressed by viable P. gingivalis. Analysis of intracellular signaling revealed an inhibitory effect of P. gingivalis on c-Jun and c-Fos, but not NF kappa B (p50 and p65), NFAT or STAT5 expression. This inhibitory effect was not due to suppression of mitogen-activated protein kinase (MAPK) (p38, erk and JNK) gene expression, but was rather due to prevention of protein kinase C (PKC) and p38 phosphorylation, as demonstrated by western blot analysis. Furthermore, SOCS1 and SOCS3 expression levels decreased following treatment of Jurkat T cells with viable P. gingivalis. The results indicate that P. gingivalis is able to suppress inflammatory gene expression by targeting the activity of MAPK pathways in T cells, which was confirmed by using specific inhibitors of NF-kappa B, PKC, ERK, p38 and JNK.

  • 20.
    Klarström-Engström, Kristin
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical trial unit.
    Zhang, Boxi
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Human renal fibroblasts are strong immunomobilizers during a urinary tract infection mediated by uropathogenic Escherichia coli2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, no 1, article id 2296Article in journal (Refereed)
    Abstract [en]

    To prevent the onset of urosepsis and reduce mortality, a better understanding of how uropathogenic Escherichia coli (UPEC) manages to infiltrate the bloodstream through the kidneys is needed. The present study elucidates if human renal interstitial fibroblasts are part of the immune response limiting a UPEC infection, or if UPEC has the ability to modulate the fibroblasts for their own gain. Microarray results showed that upregulated genes were associated with an activated immune response. We also found that chemokines released from renal fibroblasts upon a UPEC infection could be mediated by LPS and triacylated lipoproteins activating the TLR2/1, TLR4, MAPK, NF-κB and PKC signaling pathways. Furthermore, UPEC was also shown to be able to adhere and invade renal fibroblasts, mediated by the P-fimbriae. Furthermore, it was found that renal fibroblasts were more immunoreactive than renal epithelial cells upon a UPEC infection. However, both renal fibroblasts and epithelial cells were equally efficient at inducing neutrophil migration. In conclusion, we have found that human renal fibroblasts can sense UPEC and mobilize a host response with neutrophil migration. This suggests that renal fibroblasts are not only structural cells that produce and regulate the extracellular matrix, but also highly immunoreactive cells.

  • 21.
    Kruse, Robert
    et al.
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Essén-Gustavsson, Birgitta
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Fossum, Caroline
    2Department of Molecular Biosciences, Section of Veterinary Immunology and Virology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Jensen-Waern, Marianne
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Blood concentrations of the cytokines IL-1beta, IL-6, IL-10, TNF-alpha and IFN-gamma during experimentally induced swine dysentery2008In: Acta Veterinaria Scandinavica, ISSN 1751-0147, E-ISSN 1751-0147, Vol. 50, article id 32Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Knowledge of the cytokine response at infection with Brachyspira hyodysenteriae can help understanding disease mechanism involved during swine dysentery. Since this knowledge is still limited the aim of the present study was to induce dysentery experimentally in pigs and to monitor the development of important immunoregulatory cytokines in blood collected at various stages of the disease.

    METHODS: Ten conventional pigs (~23 kg) were orally inoculated with Brachyspira hyodysenteriae B204T. Eight animals developed muco-haemorrhagic diarrhoea with impaired general body condition. Blood was sampled before inoculation and repeatedly during acute dysentery and recovery periods and cytokine levels of IL-1beta, IL-6, Il-10, TNF-alpha and IFN-gamma were measured by ELISA.

    RESULTS: IL-1beta was increased at the beginning of the dysentery period and coincided with the appearance of Serum amyloid A and clinical signs of disease. TNF-alpha increased in all animals after inoculation, with a peak during dysentery, and IL-6 was found in 3 animals during dysentery and in the 2 animals that did not develop clinical signs of disease. IL-10 was found in all sick animals during the recovery period. IFN-gamma was not detected on any occasion.

    CONCLUSION: B. hyodysenteriae inoculation induced production of systemic levels of IL-1beta during the dysentery period and increased levels of IL-10 coincided with recovery from dysentery.

  • 22.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Medical Sciences. Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, UK.
    Yu, Chen
    Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx NY, USA.
    Mann, Elizabeth A.
    Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, UK.
    Schridde, Anika
    Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, UK.
    Finnemann, Silvia C.
    Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx NY, USA.
    Mowat, Allan McI
    Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, UK.
    Expression and characterization of αvβ5 integrin on intestinal macrophages2018In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 7, p. 1181-1187Article in journal (Refereed)
    Abstract [en]

    Macrophages play a crucial role in maintaining homeostasis in the intestine, but the underlying mechanisms have not yet been elucidated fully. Here we show for the first time that mature intestinal macrophages in mouse colon and small intestine express high levels of αvβ5 integrin, which acts as a receptor for the uptake of apoptotic cells and can activate molecules involved in several aspects of tissue homeostasis such as angiogenesis and remodelling of the extracellular matrix. αvβ5 is not expressed by other immune cells in the intestine, is already present on intestinal macrophages soon after birth, and its expression is not dependent on the microbiota. In adults, αvβ5 induces the differentiation of monocytes in response to the local environment and it confers intestinal macrophages with the ability to promote engulfment of apoptotic cells via engagement of the bridging molecule milk fat globule EGF-like molecule 8. In the absence of αvβ5, there are fewer monocytes in the mucosa and mature intestinal macrophages have decreased expression of metalloproteases and interleukin 10. Mice lacking αvβ5 on haematopoietic cells show increased susceptibility to chemical colitis and we conclude that αvβ5 contributes to the tissue repair by regulating the homeostatic properties of intestinal macrophages.

  • 23.
    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)
  • 24.
    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.

  • 25.
    Lonnberg, Tapio
    et al.
    Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppanen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    T-cell activation induces selective changes of cellular lipidome2013In: Frontiers in Bioscience (Elite Edition), ISSN 1945-0494, E-ISSN 1945-0508, Vol. 5, p. 558-573Article in journal (Refereed)
    Abstract [en]

    Activation of naïve T helper cells by presentation of cognate antigen initiates a complex intracellular signaling process leading to development of functionally active effector cell population. The switch from quiescent naïve state to activated state involves a profound change of cellular metabolism, required for completion of multiple rounds of proliferation. Using ultra performance liquid chromatography mass spectrometry, we analyzed how this change is reflected on the cellular lipid composition in human umbilical cord blood T-cells. We found that considerable concentration changes take place during the first 72 hours after T-cell receptor activation, correlating with first rounds of activation-induced cell division. Most importantly, composition of phosphatidylcholines and phosphatidylethanolamines exhibited consistent trend towards shorter and more saturated molecular species. Together with related transcriptomics data, the results clearly suggested induction of de novofatty acid synthesis and accumulation of endogenously synthesized fatty acids into the cellular membranes, leading to partial remodeling of the cellular lipidome in the newly developed effector cell population.

  • 26.
    Lönn, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hallström, J.
    Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    P. gingivalis-induced aggregation and ros production in whole blood is dependent on gingipains2012In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 93, p. S35-S35Article in journal (Other academic)
    Abstract [en]

    A large body of data accumulated over the past several years suggests that the periodontal pathogen Porphyromonas gingivalis is associated with cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. We have previously demonstrated that P. gingivalis induces aggregation and ROS production in whole blood, and that the anti-inflammatory mediator lipoxin A4 (LXA4) inhibits these responses by modulating plateletneutrophil interaction through a down-regulation of the bacterium-induced surface expression of CD11b/CD18 on neutrophils, likely by inhibiting Rac2 and Cdc42 signaling pathways. Furthermore, P. gingivalis, unlike other periodontopathic bacteria, has been shown to trigger platelet aggregation, mainly through the interaction between bacterial gingipains and protease-activating receptors (PARs) on the platelets. Since platelet aggregation precedes thromboembolic events, this is an important pathogenic feature of the bacterium. The aim of this study was to investigate the effect of gingipains on P. gingivalis-induced cell activation in whole blood. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry. This study shows that leupeptin, a protease inhibitor of gingipains, inhibits P. gingivalis-induced aggregation and ROS production in whole blood. Supernatants of bacteria suspensions induced no ROS-production, but an aggregatory response that was also inhibited by leupeptin. In conclusion, P. gingivalis-induced aggregation and ROS production in whole blood is mainly dependent on gingipains. However, since bacterial supernatants (containing soluble gingipains) stimulate only aggregation, this suggests that a gingipain/PAR-mediated mechanism in combination with phagocytosis of whole bacterium is a prerequisite for inducing a respiratory burst and an inflammatory response. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.

  • 27.
    Martinez-Murillo, Paola
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Pramanik, Lotta
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Sundling, Christopher
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Immunology Division, Garvan Institute of Medical Research, Darlinghurst NSW, Australia.
    Hultenby, Kjell
    Division of Clinical Research Centre, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Wretenberg, Per
    Department of Orthopedic Surgery, Karolinska University Hosptial, Stockholm, Sweden.
    Spångberg, Mats
    Medicine, Astrid Fagraeus Laboratory, Karolinska Institutet, Stockholm, Sweden.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    CD138 and CD31 Double-Positive Cells Comprise the Functional Antibody-Secreting Plasma Cell Compartment in Primate Bone Marrow2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 242Article in journal (Refereed)
    Abstract [en]

    Plasma cells (PCs) are defined as terminally differentiated B cells that secrete large amounts of immunoglobulin (Ig). PCs that reside in the bone marrow (BM) are responsible for maintaining long-term antibody (Ab) responses after infection and vaccination, while PCs present in the blood are generally short-lived. In rhesus macaques, a species frequently used for the evaluation of human vaccines, B cells resemble those found in humans. However, a detailed characterization of BM-resident rhesus PC phenotype and function is lacking. Here, we examined Ig secretion of distinct rhesus CD138+ populations by B cell ELISpot analysis to couple phenotype with function. We demonstrate that the CD20low/-CD138+CD31+ BM population was highly enriched for antibody-secreting cells with IgG being the predominant isotype (60%), followed by IgA (33%) and IgM (7%). Transmission electron microscopy analysis confirmed PC enrichment in the CD20low/-CD138+CD31+ population with cells containing nuclei with "spokes of a wheel" chromatin structure and prominent rough endoplasmic reticulum. This panel also stained human BM PCs and allowed a clear distinction between BM PCs and short-lived peripheral PCs, providing an improved strategy to isolate PCs from rhesus BM for further analysis.

  • 28.
    Oliynyk, Igor
    et al.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden; Dept Med Cell Biol, Uppsala Univ, Uppsala, Sweden.
    Varelogianni, Georgia
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden; Dept Med Cell Biol, Uppsala Univ, Uppsala, Sweden.
    Roomans, Godfried M.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Johannesson, Marie
    Örebro University Hospital, Örebro , Sweden; Department of Paediatrics and Child Health, University of Otago, Wellington Campus, Wellington, New Zealand.
    Effect of duramycin on chloride transport and intracellular calcium concentration in cystic fibrosis and non-cystic fibrosis epithelia2010In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 12, p. 982-990Article in journal (Refereed)
    Abstract [en]

    The lantibiotic duramycin (Moli1901, Lancovutide) has been suggested as a drug of choice in the treatment for cystic fibrosis (CF). It has been proposed that duramycin may stimulate chloride secretion through Ca2+-activated Cl channels (CaCC). We investigated whether duramycin exhibited any effect on Cl efflux and intracellular Ca2+ concentration ([Ca2+]i) in CF and non-CF epithelial cells. Duramycin did stimulate Cl efflux from CF bronchial epithelial cells (CFBE) in a narrow concentration range (around 1 μM). However, 100 and 250 μM of duramycin inhibited Cl efflux from CFBE cells. An inhibitor of the CF transmembrane conductance regulator (CFTRinh-172) and a blocker of the capacitative Ca2+ entry, gadolinium chloride, inhibited the duramycin-induced Cl efflux. No effect on Cl efflux was observed in non-CF human bronchial epithelial cells (16HBE), human airway submucosal gland cell line, human pancreatic epithelial cells, CF airway submucosal gland epithelial cells, and CF pancreatic cells. The [Ca2+]i was increased by 3 μM duramycin in 16HBE cells, but decreased after 1, and 3 μM of duramycin in CFBE cells. The results suggest that the mechanism responsible for the stimulation of Cl efflux by duramycin is mainly related to unspecific changes of the cell membrane or its components rather than to effects on CaCC.

  • 29.
    Oresic, Matej
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Simell, Satu
    Department of Pediatrics, University of Turku, Turku, Finland.
    Sysi-Aho, Marko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Näntö-Salonen, Kirsti
    Department of Pediatrics, University of Turku, Turku, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Parikka, Vilhelmiina
    Department of Pediatrics, University of Turku, Turku, Finland.
    Katajamaa, Mikko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hekkala, Anne
    Department of Pediatrics, University of Oulu, Oulu, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Keskinen, Päivi
    Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Reinikainen, Arja
    Turku Centre for Biotechnology, Turku, Finland.
    Lähde, Jyrki
    Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Suortti, Tapani
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hakalax, Jari
    Department of Pediatrics, University of Turku, Turku, Finland.
    Simell, Tuula
    Department of Pediatrics, University of Turku, Turku, Finland.
    Hyöty, Heikki
    Department of Virology, University of Tampere, Tampere, Finland; Centre for Laboratory Medicine, University Hospital of Tampere, Tampere, Finland.
    Veijola, Riitta
    Department of Pediatrics, University of Oulu, Oulu, Finland.
    Ilonen, Jorma
    Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, Turku, Finland.
    Knip, Mikael
    Department of Pediatrics, Tampere University Hospital, Tampere, Finland; Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Simell, Olli
    Department of Pediatrics, University of Turku, Turku, Finland.
    Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes2008In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 205, no 13, p. 2975-2984Article in journal (Refereed)
    Abstract [en]

    The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

  • 30.
    Ozoline, Olga N.
    et al.
    Institute of Cell Biophysics, RAS, Pushchino Research Center, RSF No 18-14-00348,RAS, Pushchino, Moscow Region, Russia.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Secretion and signalling of bacterial RNAs2019In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 366, no 1, article id fny281Article in journal (Refereed)
  • 31.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635Article in journal (Refereed)
    Abstract [en]

    The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.

  • 32.
    Rangel, Ignacio
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ganda-Mall, John-Peter
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sjöberg, F.
    University of Gothenburg, Gothenburg, Sweden.
    Willen, R.
    Univ Uppsala Hosp, Uppsala, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Alterations in gut microbiota composition in tissues and feces of G alpha i2(-/-) mice with colitis in parallel with enhanced cytokine secretion2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 168-169Article in journal (Other academic)
  • 33.
    Rasmussen, Gunlög
    et al.
    Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Asfaw Idosa, Berhane
    Örebro University, School of Medical Sciences.
    Monecke, S.
    InfectoGnostics Research Campus Jena, Jena, Germany.
    Bäckman, Anders
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical Research Laboratory.
    Strålin, Kristoffer
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden .
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.
    Caspase-1 Inflammasome Activity in Patients with Staphylococcus aureus Bacteremia2019In: Microbiology and immunology, ISSN 0385-5600, E-ISSN 1348-0421Article in journal (Refereed)
    Abstract [en]

    The inflammasome is a multiprotein complex that mediates caspase-1 activation with subsequent maturation of the pro-inflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome is known to be activated by Staphylococcus aureus, one of the leading causes of bacteremia worldwide. Inflammasome activation and regulation in response to bacterial infection have been found to be of importance for a balanced host immune response. However, inflammasome signaling in vivo in humans initiated by S. aureus is currently sparsely studied. The present study therefore aimed to investigate NLRP3 inflammasome activity in 20 S. aureus bacteremia patients, by repeated measurement during the first week of bacteremia, compared with controls. Caspase-1 activity was measured in monocytes and neutrophils by flow cytometry detecting FLICA (Fluorescent Labelled Inhibitor of Caspase-1), while IL-1β and IL-18 was measured by Luminex and ELISA, respectively. As a measure of inflammasome priming, mRNA expression of NLRP3, CASP1 (pro-caspase-1) and IL1B (pro-IL-1β) was analyzed by qPCR. We found induced caspase-1 activity in innate immune cells with subsequent release of IL-18 in patients during the acute phase of bacteremia, indicating activation of the inflammasome. There was substantial inter-individual variation in caspase-1 activity between S. aureus bacteremia patients. We also found an altered inflammasome priming with low mRNA levels of NLRP3 accompanied by elevated mRNA levels of IL1B. This increased knowledge of the individual host immune response in S. aureus bacteremia could provide support in the effort to optimize management and treatment of each individual patient.

  • 34.
    Rathsman, Sandra
    et al.
    Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Eriksson, Sune
    Department of Laboratory Medicine/Pathology, Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro, Sweden.
    Åberg, Anna-Karin
    Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro, Sweden.
    Elution of antitransglutaminase antibodies from duodenal biopsies: a novel approach in the diagnosis of celiac disease2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 8, p. 666-674Article in journal (Refereed)
    Abstract [en]

    Celiac disease (CeD) is a disease more prevalent and multisymptomatic than was earlier recognized. Whereas prompt initiation of gluten-free diet (GFD) is beneficial in relieving the symptoms, an accurate CeD diagnosis is necessary also to avoid years of restricted diet on uncertain grounds. We propose a new diagnostic method, based on elution of deposited antibodies against transglutaminase (anti-tTG) from duodenal biopsies in patients with symptoms and screening serology analyses suggestive of CeD. The eluates were analyzed in a Phadia 250 fluoroimmunoassay, demonstrating elevated concentrations of anti-tTG in CeD patients, corresponding to serology and histopathology findings. In one case histology was inconclusive, displaying only unspecific inflammation, but eluted anti-tTG was positive. This patient has clinically improved following GFD. We conclude that our novel method represents a new tool in the diagnostic work up in CeD. The detection of deposited anti-tTG at the site of inflammation appears to provide a high sensitivity and specificity using a technique that is quick, simple and reliable. Further studies are needed for optimization and elucidation of suitable applications for this elution method.

  • 35.
    Röckert Tjernberg, Anna
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics, Kalmar County Hospital, Kalmar, Sweden.
    Bonnedahl, Jonas
    Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden; Zoonotic Ecology and Epidemiology, Faculty of Health and Life Sciences, Linnaeus University, Kalmar, Sweden.
    Ludvigsson, Jonas F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Does celiac disease influence survival in sepsis?: A nationwide longitudinal study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0154663Article in journal (Refereed)
    Abstract [en]

    Background: Individuals with celiac disease (CD) are at increased risk of sepsis. The aim of this study was to examine whether CD influences survival in sepsis of bacterial origin.

    Methods: Nationwide longitudinal registry-based study. Through data on small intestinal biopsies from Sweden's 28 pathology departments, we identified 29,096 individuals with CD (villous atrophy, Marsh stage III). Each individual with CD was matched with five population-based controls. Among these, 5,470 had a record of sepsis according to the Swedish Patient Register (1,432 celiac individuals and 4,038 controls). Finally we retrieved data on mortality in sepsis patients through the Swedish Cause of Death Registry.

    Results: CD was associated with a 19% increase in overall mortality after sepsis (95% confidence interval (CI) = 1.09-1.29), with the highest relative risk occurring in children (adjusted hazard ratio (aHR) = 1.62; 95%CI = 0.67-3.91). However, aHR for death from sepsis was lower (aHR = 1.10) and failed to reach statistical significance (95%CI = 0.72-1.69). CD did not influence survival within 28 days after sepsis (aHR = 0.98; 95%CI = 0.80-1.19).

    Conclusions: Although individuals with CD seem to be at an increased risk of overall death after sepsis, that excess risk does not differ from the general excess mortality previously seen in celiac patients in Sweden. CD as such does not seem to influence short-term or sepsis-specific survival in individuals with sepsis and therefore is not an independent risk factor for poor prognosis in sepsis.

  • 36.
    Saber, Amanj
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Otolaryngology.
    Nakka, Sravya Sowdamini
    Department of Microbiology and Immunology, Institution of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hussain, Rashida
    Department of Otolaryngology, Örebro University Hospital, Örebro, Sweden.
    Hugosson, Svante
    Department of Otolaryngology, Örebro University Hospital, Örebro, Sweden; Department of Medical Education, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Staphylococcus aureus in chronic rhinosinusitis: the effect on the epithelial chloride channel (cystic fibrosis transmembrane conductance regulator, CFTR) and the epithelial sodium channel (ENaC) physiology2019In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 139, no 7, p. 652-658Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and the paranasal sinuses, often associated with an infection by Staphylococcus aureus (S. aureus). Disturbance in the function of ion channels is regarded as an etiological factor for pathogenesis of CRS.

    AIMS: The study aims to measure the mRNA expression of the ENaC and CFTR ion channels in nasal epithelial cells (NECs) and to investigate the effect of both the budesonide and S. aureus on these ion channels.

    MATERIALS AND METHOD: NECs biopsies obtained from healthy volunteers and patients with CRS. NECs were infected with S. aureus strains and/or budesonide to study the mRNA expression levels of the ENaC and CFTR ion channels.

    RESULTS: The mRNA expression level of CFTR was increased while that of ENaC was decreased. S. aureus infection and budesonide treatment induced a significant modulation of ENaC and CFTR ion channels expression.

    CONCLUSION: The CFTR and ENaC ion channel physiology are of importance in the pathogenesis of CRS. Exposure to S. aureus infection and treatment with budesonide modulated the mRNA expression of CFTR and ENaC ion channels.

    SIGNIFICANCE: Better understanding of the pathophysiology of CRS.

  • 37.
    Sahdo, Berolla
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Evans, Alina L.
    Department of Forestry and Wildlife Management, Hedmark University College, Evenstad, Norway; Section of Arctic Veterinary Medicine, Norwegian School of Veterinary Science, Tromsø, Norway.
    Arnemo, Jon M.
    Department of Forestry and Wildlife Management, Hedmark University College, Evenstad, Norway; Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Fröbert, Ole
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Cardiology, Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Blanc, Stephane
    Institut Pluridisciplinaire Hubert CURIEN (IPHC), Université de Strasbourg, Strasbourg, France; CNRS, Strasbourg, France.
    Body temperature during hibernation is highly correlated with a decrease in circulating innate immune cells in the brown bear (Ursus arctos): a common feature among hibernators?2013In: International Journal of Medical Sciences, ISSN 1449-1907, E-ISSN 1449-1907, Vol. 10, no 5, p. 508-514Article in journal (Refereed)
    Abstract [en]

    Background: Hibernation involves periods of severely depressed metabolism (torpor) and decreases in body temperature (Tb). Small arctic mammals (<5kg), in which Tb generally drop drastically, display leukopenia during hibernation. This raised the question of whether the decreased leukocyte counts in mammalian hibernators is due to torpor per se or is secondary to low Tb. The present study examined immune cell counts in brown bears (Ursus arctos), where torpor is only associated with shallow decreases in Tb. The results were compared across hibernator species for which immune and Tb data were available.

    Methods and Results: The white blood cell counts were determined by flow cytometry in 13 bears captured in the field both during summer and winter over 2 years time. Tb dropped from 39.6+/-0.8 to 33.5+/-1.1 degrees C during hibernation. Blood neutrophils and monocytes were lower during hibernation than during the active period (47%, p=0.001; 43%, p=0.039, respectively), whereas no change in lymphocyte counts was detected (p=0.599). Further, combining our data and those from 10 studies on 9 hibernating species suggested that the decline in Tb explained the decrease in innate immune cells (R-2=0.83, p<0.0001).

    Conclusions: Bears have fewer innate immune cells in circulation during hibernation, which may represent a suppressed innate immune system. Across species comparison suggests that, both in small and large hibernators, Tb is the main driver of immune function regulation during winter dormancy. The lack of a difference in lymphocyte counts in this context requires further investigations.

  • 38.
    Sahdo, Berolla
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Idosa, Berhane Asfaw
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Eriksson, Per
    Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, SE-701 85 Örebro, Sweden.
    Kelly, Anne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro universitetssjukhus, Örebro, Sweden.
    Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasomeManuscript (preprint) (Other academic)
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

    Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched noncarrier controls.

    Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K/C10X polymorphisms compared to controls, whereas no difference was found for IL- 18 and the other cytokines measured. These data suggest that these combined polymorphisms creates inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

  • 39.
    Skoglund, Caroline
    et al.
    Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Wettero, Jonas
    Rheumatology/Autoimmunity and Immune Regulation Unit (AIR), Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    C1q regulates collagen-dependent production of reactive oxygen species, aggregation and levels of soluble P-selectin in whole blood2012In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 142, no 1-2, p. 28-33Article in journal (Refereed)
    Abstract [en]

    Blood platelets express several receptors involved in immunity (e.g. complement-, toll-like- and Fc gamma-receptors) and release inflammatory mediators. Furthermore, formation of platelet-leukocyte aggregates has an important role during inflammatory conditions such as coronary artery disease. Thus, apart from their well-known role in haemostasis, platelets are today also recognized as cells with immunomodulatory properties. We have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have proceeded by investigating effects of C1q on collagen-induced aggregation, production of reactive oxygen species (ROS), formation of platelet-leukocyte aggregates and levels of soluble P-selectin in whole blood. Impedance measurements showed that C1q inhibited collagen-induced aggregation whereas it potentiated the collagen-provoked production of ROS in a luminol-dependent chemiluminescence assay. The effects of C1q on aggregation and ROS-production were dependent upon platelets, as they were no longer observed in presence of the platelet (GpIIb/IIIa) inhibitor Reopro. Furthermore, the levels of soluble P-selectin were found to be lowered upon treatment with C1q prior to addition of collagen. There was also a trend towards a decreased formation of large platelet-leukocyte aggregates in collagen-stimulated whole blood following C1q treatment. In conclusion, our data indicate that C1q could have a role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury. This has implications for inflammatory disorders such as coronary artery disease.

  • 40.
    Skovbjerg, Susann
    et al.
    Inst Biomed, Dept Infect Med Clin Bacteriol,Univ Gothenburg, Gothenburg, Sweden.
    Martner, Anna
    Inst Biomed, Dept Infect Med Clin Bacteriol, Univ Gothenburg, Gothenburg, Sweden.
    Hynsjö, Lars
    Inst Biomed, Dept Clin Chem & Transfus Med, Univ Gothenburg, Gothenburg, Sweden.
    Hessle, Christina
    Inst Biomed, Dept Infect Med Clin Bacteriol, Univ Gothenburg, Gothenburg, Sweden.
    Olsen, Ingar
    Inst Oral Biol, Fac Dent, Univ Oslo, Oslo, Norway.
    Dewhirst, Floyd E.
    Sch Dent Med, Harvard Univ, Boston MA, USA.
    Tham, Wilhelm
    Örebro University, School of Hospitality, Culinary Arts & Meal Science.
    Wold, Agnes E.
    Inst Biomed, Dept Infect Med Clin Bacteriol, Univ Gothenburg, Gothenburg, Sweden.
    Gram-Positive and Gram-Negative Bacteria Induce Different Patterns of Cytokine Production in Human Mononuclear Cells Irrespective of Taxonomic Relatedness2010In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 30, no 1, p. 23-32Article in journal (Refereed)
    Abstract [en]

    Upon bacterial stimulation, tissue macrophages produce a variety of cytokines that orchestrate the immune response that clears the infection. We have shown that Gram-positives induce higher levels of interleukin-12 (IL-12), interferon-γ (IFN-γ), and tumor necrosis factor (TNF) from human peripheral blood mononuclear cells (PBMCs) than do Gram-negatives, which instead induce more of IL-6, IL-8, and IL-10. Here, we study whether these patterns follows or crosses taxonomic borders. PBMCs from blood donors were incubated with UV-inactivated bacteria representing 37 species from five phyla. IL-12, TNF, IL-1β, IL-6, IL-8, and IL-10 were measured in the supernatants after 24 h and IFN-γ after 5 days. Irrespective of phylogenetic position, Gram-positive bacteria induced much more IL-12 (nine times more on average) and IFN-γ (seven times), more TNF (three times), and slightly more IL-1β (1.5 times) than did Gram-negatives, which instead induced more IL-6 (1.5 times), IL-8 (1.9 times), and IL-10 (3.3 times) than did Gram-positives. A notable exception was the Gram-positive Listeria monocytogenes, which induced very little IL-12, IFN-γ, and TNF. The results confirm the fundamental difference in innate immune responses to Gram-positive and Gram-negative bacteria, which crosses taxonomic borders and probably reflects differences in cell wall structure.

  • 41.
    Sundqvist, Martin
    et al.
    Örebro University Hospital. Dept Lab Med Clin Microbiol, Örebro University Hospital, Örebro, Sweden.
    Olafsson, Jonas
    Dept Clin Microbiol, Kalmar Cty Hosp, Kalmar, Sweden.
    Matuschek, Erika
    EUCAST Dev Lab, Cent Hosp Växjö, Växjö, Sweden.
    EUCAST breakpoints can be used to interpret direct susceptibility testing of Enterobacteriaceae from urine samples2015In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 123, no 2, p. 152-155Article in journal (Refereed)
    Abstract [en]

    Increasing resistance calls for rapid antibiotic susceptibility testing (AST). This study validated the use of EUCAST breakpoints for AST using disk diffusion directly from urine samples. Two hundred and thirty-three urine samples with growth of varying amounts of Enterobacteriaceae were included and susceptibility testing (disk diffusion) was performed on Mueller-Hinton agar with overnight incubation directly from urine samples in parallel with disk diffusion according to EUCAST methodology. Confluent growth was obtained in 188 of 233 urine samples and used as criteria for zone measurements. Only 15 discrepancies (3 very major errors, 5 major errors and 7 minor errors) were observed in a total of 855 tests showing the safety of this approach. Direct susceptibility testing from urine samples can be interpreted using EUCAST clinical breakpoints and can thus safely be used to achieve more rapid AST result.

  • 42.
    Säve, Susanne
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Health and Medical Sciences.
    Extracellular ATP and P2Y receptor activation induce a proinflammatory host response in the human urinary tract2010In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, no 8, p. 3609-3615Article in journal (Refereed)
    Abstract [en]

    Extracellular ATP can be released by many cell types under conditions of cellular stress and signals through activation of purinergic receptors. Bladder uroepithelial cells grown in vitro have previously been shown to release ATP in response to stretch. In the present study, we investigated ATP release from uroepithelial cells infected with bacteria and the effect of ATP on the host cell proinflammatory interleukin 8 (IL-8) response. The human kidney epithelial cell line A498 and the human uroepithelial cell line UROtsa were grown in culture and stimulated by the uropathogenic Escherichia coli (UPEC) IA2 strain or the stable ATP analogue ATP-gamma-S. ATP and IL-8 levels were measured in cell culture medium with a luciferin-luciferase assay and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that UPEC infection of uroepithelial cells for 1 h significantly increased (P < 0.01) the extracellular ATP levels. ATP-gamma-S (10 and 100 microM) stimulated release of IL-8 from UROtsa and A498 cells after 6 and 24 h. Experiments with different purinoceptor agonists suggested that P2Y receptors, and not P2X receptors, were responsible for the ATP-gamma-S-induced IL-8 release. The potency profile further suggested involvement of P2Y(1), P2Y(2), and/or P2Y(11) receptors, and reverse transcription-PCR (RT-PCR) studies confirmed that the cells expressed these receptors. The amount of IL-8 released increased 12-fold in UPEC-infected cells, and apyrase, an enzyme that degrades ATP, reduced this increase by approximately 50%. The present study suggests that enhanced ATP release and P2Y receptor activation during urinary tract infection may represent a novel, non-TLR4-mediated mechanism for production of proinflammatory IL-8 in human urinary tract epithelial cells.

  • 43.
    Södergren, Anna L.
    et al.
    Clinical Chemistry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry2017In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1594, p. 191-203Article in journal (Refereed)
    Abstract [en]

    Flow cytometry is a method that allows high throughput analysis of individual cells in suspension. By inclusion of fluorescently labelled antibodies, it is possible to analyze the abundance of one or more surface antigens, such as LAMP-1, without prior lysis of cells. Here we describe the special considerations required for the investigation of lysosomal exocytosis from platelets analyzed with flow cytometry.

  • 44.
    Welin Henriksson, Elisabet
    et al.
    Laboratory of Medical Cell Genetics, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
    Hansson, Helene
    bDept. of Small Anim. Clin. Sciences, Swed. Univ. of Agricultural Sciences, Uppsala, Sweden.
    Karlsson-Parra, Alex
    Dept. Clin. Immunol. Transfus. Med., University Hospital, Uppsala, Sweden.
    Pettersson, Ingvar
    Laboratory of Medical Cell Genetics, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
    Autoantibody profiles in canine ANA-positive sera investigated by immunoblot and ELISA1998In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 61, no 2-4, p. 157-170Article in journal (Refereed)
    Abstract [en]

    Canine systemic lupus erythematosus (SLE) has a similar disease expression as human SLE, but the serological characterisation of the canine disease is as yet incomplete. In the present study, we examined the specificity of antinuclear antibodies (ANA) in indirect immunofluorescence (IIF) positive canine sera. Sixty-four canine IIF ANA positive sera were characterised using HeLa cell nuclear extract immunoblots and recombinant U1-70K ELISA. We compared these results with a previously shown concordance between indirect immunofluorescence and immunodiffusion in canine SLE serological diagnosis. One canine serum reacting with Sm proteins was observed, and five canine sera presented anti-RNP autoantibodies against the antigens 70K, A, C, and/or B/B'. The autoantigen most frequently recognised was a 43 kDa nuclear protein, previously described as hnRNP G. This prominent canine autoantigen was missing in the commercially available extract designed for immunodiffusion testing of human sera. Other prominent canine autoantigens were found not to be identical with the principal human ones, thus making present human test systems deficient for the use in canine systemic connective disease diagnosis. The development of antigenic extract designed for canine autoimmune autoantigens is necessary in order to make immunodiffusion a useful method in canine diagnosis. The anti-RNP positive canine sera were examined in more detail and we found that the human major antigenic region of the most prominent RNP antigen, the U1-70K protein, also is targeted by canine autoantibodies. Thus, the response against the RNP antigen seems to be conserved between man and dog.

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