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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.
    Ahlberg, Emelie
    et al.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Martí, Magalí
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Govindaraj, Dhanapal
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Severin, Elisabet
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Allergy Center, Linköping University Hospital, Linköping, Sweden.
    Duchén, Karel
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Allergy Center, Linköping University Hospital, Linköping, Sweden.
    Jenmalm, Maria C.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Tingö, Lina
    Örebro University, School of Medical Sciences. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Immune-related microRNAs in breast milk and their relation to regulatory T cells in breastfed children2023In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 34, no 4, article id e13952Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The immunomodulatory capacity of breast milk may partially be mediated by microRNAs (miRNA), small RNA molecules that regulate gene expression on a post-transcriptional level and are hypothesized to be involved in modulation of immunological pathways. Here, we evaluate the expression of immune-related miRNAs in breast milk after pre- and postnatal supplementation with Limosilactobacillus reuteri and omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), and the association to infant regulatory T cell (Treg) frequencies.

    METHODS: One-hundred and twenty women included in a double-blind, randomized, placebo-controlled allergy intervention trial received L. reuteri and/or ω-3 PUFAs daily from gestational week 20. Using Taqman qPCR, 24 miRNAs were analyzed from breast milk obtained at birth (colostrum) and after 3 months (mature milk) of lactation. The proportion of activated and resting Treg cells were analyzed in infant blood using flow cytometry at 6, 12, and 24 months.

    RESULTS: Relative expression changed significantly over the lactation period for most of the miRNAs; however, the expression was not significantly influenced by any of the supplements. Colostrum miR-181a-3p correlated with resting Treg cell frequencies at 6 months. Colostrum miR-148a-3p and let-7d-3p correlated with the frequencies of activated Treg cells at 24 months, as did mature milk miR-181a-3p and miR-181c-3p.

    CONCLUSION: Maternal supplementation with L. reuteri and ω-3 PUFAs did not significantly affect the relative miRNA expression in breast milk. Interestingly, some of the miRNAs correlate with Treg subpopulations in the breastfed children, supporting the hypothesis that breast milk miRNAs could be important in infant immune regulation. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT01542970.

  • 3.
    Andersson, Henrik
    et al.
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Andersson, Blanka
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Eklund, Daniel
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Ngoh, Eyler
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Alexander
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Svensson, Kristoffer
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lerm, Maria
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Blomgran, Robert
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Stendahl, Olle
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, article id e101514Article in journal (Refereed)
    Abstract [en]

    Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.

  • 4.
    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.

    Download full text (pdf)
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  • 5.
    Andersson, Sören
    et al.
    Örebro University, School of Medical Sciences. Folkhälsomyndigheten, Public Health Agency of Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    CHIMERIC MOMP ANTIGEN2015Patent (Other (popular science, discussion, etc.))
    Download full text (pdf)
    Patent
  • 6.
    Andersson, Sören
    et al.
    Örebro University, School of Medical Sciences. Folkhälsomyndigheten, Public Health Agency of Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Chimeric MOMP antigen2014Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention regards polypeptides capable of eliciting an immunological response that is protective against Chlamydia trachomatis. The polypeptide comprises a first amino acid sequence which has at least 90% homology with the amino acid sequence according to SEQ ID NO: 1 and a second amino acid sequence which has at least 90% homology with the amino acid sequence according to SEQ ID NO: 2. Furthermore, production of these polypeptides and pharmaceutical compositions comprising them are also provided.

    Download full text (pdf)
    Patent
  • 7.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Gunaltay, Sezin
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Tran, Pham Tue Hung
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Höglund, Urban
    Adlego Biomedical AB, Uppsala, Sweden.
    Johansson, Christer
    Academy of Quality Pharm Science and BiQ Pharma AB, Södertälje, Sweden.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sällberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    DNA launched suicidal flaviviruses as therapeutic vaccine candidates2018Conference paper (Refereed)
    Abstract [en]

    Chronic liver disease, resulting from Hepatitis B virus (HBV), Hepatitis D virus (HDV), or Hepatitis C virus (HCV) infections, contributes to a major health burden worldwide. The relativelyhigh cost of the HCV treatment brings concerns about the accessibility, especially in the developing countries. Hence, there exists a need for cost effect interventions with high efficiency. We aim to develop therapeutic vaccine candidates against HBV, HCV and HDV using DNA based subgenomic flavivirus replicons as a delivery system. Tick-borne encephalitis virus (TBEV), Langat virus (LGTV), West-Nile virus (WNV), or Kunjinvirus (KUNV) replicon with firefly luciferase geneas a reporter were expressed and characterized in cell culture studies. WNV and KUNV replicons showed significantly higher replication compared to their respective negative controls with unfunctional viral RNA dependent RNA polymerase. KUNV and WNV replicons were chosen for cloning the HCV or HB/DV vaccine candidate gene by replacing luciferasegene. Owing to the self-replicating trait of the flavivirus subgenomic replicons, Western blotting demonstrated that the antigen expression by KUNV and WNV replicons was several folds higher than the positive control. These results suggest that DNA based KUNV and WNV replicons may function as carriers for the hepatitis vaccine candidate genes, and these replicons are currently used for in vivostudies in animal models.

  • 8.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tran, Pham Tue Hung
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Pasetto, Anna
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Höglund, Urban
    Adlego Biomedical AB, Uppsala, Sweden.
    Johansson, Christer
    Academy of Quality Pharm Science and BiQ Pharma AB, Södertälje, Sweden.
    Sällberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Immunogenicity of DNA launched suicidal flavivirus replicons for protective vaccination against hepatitis viruses2019Conference paper (Refereed)
    Abstract [en]

    Chronic liver disease, resulting from Hepatitis B virus (HBV), Hepatitis D virus (HDV), or Hepatitis C virus (HCV) infections, contributes to a major health burden worldwide. Chronic infections with the hepatitis C virus (HCV) can be effectively cured by antivirals. However, as cured patients can be re-infected they lack protective immune responses. In addition, the relativelyhigh cost of the HCV treatment brings concerns about the accessibility, especially in the developing countries. Hence, there exists a need for cost effect vaccines with high efficiency to control and possibly eradicate Hepatitis viruses globally. The vaccine should induce either, or both, neutralizing antibodies and protective T cell responses. We therefore have developed DNA based flavivirus replicons as a potent delivery system that effectively prime HCV-specific T cell responses. We generated suicidal subgenomic DNA replicons of Tick-borne encephalitis virus (TBEV), Langat virus (LGTV), West-Nile virus (WNV), and Kunjinvirus (KUNV) expressing either a fusion protein between the HCV NS3/4A and a stork hepatitis B virus core or a vaccine candidate gene of HB/DV. Transfection experiments showed that the antigen expression by KUNV and WNV replicons was several folds higher than the antigen expression by standard DNA plasmid with CMV promoter. The immunogenicity of three suicidal flaviviral DNA replicons expressing HCV NS3/4A was tested in mice and compared to HCV NS3/4A expression by the standard DNA plasmid. The KUNV-HCV replicon was the best replicon-based immunogen with respect to priming of HCV NS3/4A-specific T cells as determined by ELISpot, dextramer staining, and polyfunctionality. Importantly, a mutant KUNV-HCV immunogen lacking replication failed to induce immune responses. Thus, the newly developed KUNV-based suicidal DNA launched replicon vaccine for HCV is a highly attractive candidate as a prophylactic vaccine against chronic hepatitis C. In addition, we are currently testing the immunogenicity of KUNV-HB/DV replicon in mice.

  • 9.
    Axelsson, Susanne
    et al.
    Department of Pathology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Lange, Anna
    Örebro University, School of Medical Sciences. Department of Infectious Diseases.
    Alshamari, Aseel
    Department of Clinical Immunology and Transfusion Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Department of Clinical Immunology and Transfusion Medicine.
    A combination of the activation marker CD86 and the immune checkpoint marker B and T lymphocyte attenuator (BTLA) indicates a putative permissive activation state of B cell subtypes in healthy blood donors independent of age and sex2020In: BMC Immunology, E-ISSN 1471-2172, Vol. 21, no 1, article id 14Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of anti-B cell based therapies in immune-mediated diseases targeting general B cell markers or molecules important for B cell function has increased the clinical needs of monitoring B cell subpopulations.

    RESULTS: We analyzed the expression profile of cell surface markers CD86 and B and T lymphocyte attenuator (BTLA) in B cell subtypes using flow cytometry, including naïve, transitional, switched memory, non-switched memory and double-negative memory B cells and plasmablasts, and investigated the dependence of age and sex in a healthy adult blood donor population. The switched memory B cell subtype displayed a divergent expression of the markers, with increased CD86 and decreased BTLA as compared to non-switched and double negative memory cells, as well as compared to naïve B cells. Plasmablasts expressed highly increased CD86 compared to all other subtypes and a decreased expression of BTLA compared to naïve cells, but still higher compared to the memory cell populations. Transitional B cells had CD86 and BTLA expression similar to the other naïve cells.

    CONCLUSIONS: We show divergent expression of CD86 and BTLA in memory cells and plasmablasts compared to naïve B cells independent of age and sex. Furthermore, a similarly divergent difference of expression pattern was seen between the memory cell subtypes, altogether indicating that the combination of CD86 and BTLA might be markers for a permissive activation state. We suggest the combination of CD86 and BTLA expression on B cell subtypes as a potentially important tool in monitoring the status of B cell subtypes before and after treatments influencing the B cell compartment.

  • 10.
    Bachmann, Radu
    et al.
    Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Brussels, Belgium; Colorectal Surgery Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
    Van Hul, Matthias
    Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Brussels, Belgium.
    Baldin, Pamela
    Pathology Department, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
    Léonard, Daniel
    Colorectal Surgery Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
    Delzenne, Nathalie M.
    Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Brussels, Belgium.
    Belzer, Clara
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
    Ouwerkerk, Janneke P.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Kartheuser, Alex
    Colorectal Surgery Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    De Vos, Willem M.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands; Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Cani, Patrice D.
    Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, Brussels, Belgium.
    Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 17, article id 2666Article in journal (Refereed)
    Abstract [en]

    Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.

  • 11.
    Behzadi, Payam
    et al.
    Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran.
    Sameer, Aga Syed
    Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India; Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India.
    Nissar, Saniya
    Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India; Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India.
    Banday, Mujeeb Zafar
    Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India; Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India.
    Gajdács, Márió
    Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, Szeged, Hungary.
    García-Perdomo, Herney Andrés
    Division of Urology, Department of Surgery, School of Medicine, UROGIV Research Group, Universidad del Valle, Cali, Colombia.
    Akhtar, Kulsum
    Department of Clinical Biochemistry, Sher I Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India.
    Pinheiro, Marina
    Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, Porto, Portugal; CHUP, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, Porto, Portugal.
    Magnusson, Peter
    Örebro University, School of Medical Sciences. Cardiology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sarshar, Meysam
    Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
    Ambrosi, Cecilia
    IRCCS San Raffaele Roma, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy.
    The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs)2022In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, Vol. 2022, article id 2054431Article, review/survey (Refereed)
    Abstract [en]

    Interleukins (ILs)-which are important members of cytokines-consist of a vast group of molecules, including a wide range of immune mediators that contribute to the immunological responses of many cells and tissues. ILs are immune-glycoproteins, which directly contribute to the growth, activation, adhesion, differentiation, migration, proliferation, and maturation of immune cells; and subsequently, they are involved in the pro and anti-inflammatory responses of the body, by their interaction with a wide range of receptors. Due to the importance of immune system in different organisms, the genes belonging to immune elements, such as ILs, have been studied vigorously. The results of recent investigations showed that the genes pertaining to the immune system undergo progressive evolution with a constant rate. The occurrence of any mutation or polymorphism in IL genes may result in substantial changes in their biology and function and may be associated with a wide range of diseases and disorders. Among these abnormalities, single nucleotide polymorphisms (SNPs) can represent as important disruptive factors. The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.

  • 12.
    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, 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.

  • 13.
    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.

  • 14.
    Boraschi, Diana
    et al.
    Institute of Biochemistry and Cell Biology, National Research Council, Napoli, Italy.
    Alijagic, Andi
    Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy.
    Auguste, Manon
    Department of Earth, Environment and Life Sciences, University of Genova, Genova, Italy.
    Ferrari, Eleonora
    Center for Plant Molecular Biology ‐ ZMBP, Eberhard‐Karls University Tübingen, Tübingen, Germany.
    Hernadi, Szabolcs
    School of Biosciences, Cardiff University, Cardiff, England.
    Mayall, Craig
    Department of Biology, Biotechnical Faculty, University of Liubljana, Ljubljana, Slovenia.
    Michelini, Sara
    Department of Biosciences, Paris‐Lodron University Salzburg, Salzburg, Austria.
    Navarro Pacheco, Natividad I.
    Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
    Prinelli, Alessandra
    AvantiCell Science Ltd, Ayr, England.
    Swart, Elmer
    UK Centre for Ecology and Hydrology, Wallingford, England.
    Swartzwelter, Benjamin J.
    Institute of Biochemistry and Cell Biology National Research Council, Napoli, Italy.
    Bastús, Neus G.
    Institut Català de Nanosciència i Nanotecnologia (ICN2), Bellaterra, Barcelona, Spain.
    Canesi, Laura
    Department of Earth, Environment and Life Sciences, University of Genova, Genova, Italy.
    Drobne, Damjana
    Department of Biology, Biotechnical Faculty, University of Liubljana, Ljubljana, Slovenia.
    Duschl, Albert
    Department of Biosciences, Paris‐Lodron University Salzburg, Salzburg, Austria.
    Ewart, Marie‐Ann
    UK Centre for Ecology and Hydrology, Wallingford, England.
    Horejs‐Hoeck, Jutta
    Department of Biology Biotechnical Faculty, University of Liubljana, Ljubljana, Slovenia.
    Italiani, Paola
    Institute of Biochemistry and Cell Biology, National Research Council, Napoli, Italy.
    Kemmerling, Birgit
    Center for Plant Molecular Biology ‐ ZMBP, Eberhard‐Karls University Tübingen, Tübingen, Germany.
    Kille, Peter
    School of Biosciences, Cardiff University, Cardiff, England.
    Prochazkova, Petra
    Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
    Puntes, Victor F.
    Institut Català de Nanosciència i Nanotecnologia (ICN2), Bellaterra, Barcelona, Spain.
    Spurgeon, David J.
    UK Centre for Ecology and Hydrology, Wallingford, England.
    Svendsen, Claus
    UK Centre for Ecology and Hydrology, Wallingford, England.
    Wilde, Colin J.
    AvantiCell Science Ltd, Ayr, England.
    Pinsino, Annalisa
    Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy.
    Addressing Nanomaterial Immunosafety by Evaluating Innate Immunity across Living Species2020In: Small, ISSN 1613-6810, Vol. 16, no 21, article id 2000598Article, review/survey (Refereed)
    Abstract [en]

    The interaction of a living organism with external foreign agents is a central issue for its survival and adaptation to the environment. Nanosafety should be considered within this perspective, and it should be examined that how different organisms interact with engineered nanomaterials (NM) by either mounting a defensive response or by physiologically adapting to them. Herein, the interaction of NM with one of the major biological systems deputed to recognition of and response to foreign challenges, i.e., the immune system, is specifically addressed. The main focus is innate immunity, the only type of immunity in plants, invertebrates, and lower vertebrates, and that coexists with adaptive immunity in higher vertebrates. Because of their presence in the majority of eukaryotic living organisms, innate immune responses can be viewed in a comparative context. In the majority of cases, the interaction of NM with living organisms results in innate immune reactions that eliminate the possible danger with mechanisms that do not lead to damage. While in some cases such interaction may lead to pathological consequences, in some other cases beneficial effects can be identified.

  • 15.
    Cajander, Sara
    et al.
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kox, Matthijs
    Department of Intensive Care Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
    Scicluna, Brendon P.
    Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei hospital, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
    Weigand, Markus A.
    Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
    Mora, Raquel Almansa
    Department of Cell Biology, Genetics, Histology and Pharmacology, University of Valladolid, Valladolid, Spain.
    Flohé, Stefanie B.
    Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
    Martin-Loeches, Ignacio
    St James's Hospital, Dublin, Ireland; Hospital Clinic, Institut D'Investigacions Biomediques August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain.
    Lachmann, Gunnar
    Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Operative Intensive Care Medicine, Berlin, Germany.
    Girardis, Massimo
    Department of Intensive Care and Anesthesiology, University Hospital of Modena, Modena, Italy.
    Garcia-Salido, Alberto
    Hospital Infantil Universitario Niño Jesús, Pediatric Critical Care Unit, Madrid, Spain.
    Brunkhorst, Frank M.
    Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
    Bauer, Michael
    Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
    Torres, Antoni
    Pulmonology Department. Hospital Clinic of Barcelona, University of Barcelona, Ciberes, IDIBAPS, ICREA, Barcelona, Spain.
    Cossarizza, Andrea
    Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
    Monneret, Guillaume
    Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon-1, Hôpital E Herriot, Lyon, France.
    Cavaillon, Jean-Marc
    Institut Pasteur, Paris, France.
    Shankar-Hari, Manu
    Centre for Inflammation Research, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
    Giamarellos-Bourboulis, Evangelos J.
    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
    Winkler, Martin Sebastian
    Department of Anesthesiology and Intensive Care, Universitätsmedizin Göttingen, Göttingen, Germany.
    Skirecki, Tomasz
    Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland.
    Osuchowski, Marcin
    Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria.
    Rubio, Ignacio
    Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
    Bermejo-Martin, Jesus F.
    Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain; School of Medicine, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red en Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
    Schefold, Joerg C.
    Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
    Venet, Fabienne
    Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Ecole Normale Supeérieure de Lyon, Universiteé Claude Bernard-Lyon 1, Lyon, France.
    Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine2024In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 12, no 4, p. 305-322Article, review/survey (Refereed)
    Abstract [en]

    Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.

  • 16.
    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.

  • 17.
    Eklund, Daniel
    et al.
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Hans Lennart
    Division of Pulmonary Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden; Department of Respiratory Medicine UHL, Centre of Surgery and Oncology, Linköping University Hospital, Linköping, Sweden.
    Larsson, Marie
    Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Welin, Amanda
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Phagocyte Research Laboratory, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Idh, Jonna
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Paues, Jakob
    Division of Infectious Diseases, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Fransson, Sven-Göran
    Division of Radiology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Stendahl, Olle
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Schön, Thomas
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
    Lerm, Maria
    Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; Center for Infectious Medicine, Karolinska Institute, Stockholm, Sweden.
    Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients2013In: International journal of mycobacteriology, ISSN 2212-5531, Vol. 2, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.

  • 18.
    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.

  • 19.
    Ewerman, Lea
    et al.
    Department of Endocrinology, and Department of Health, Medicine; Caring Sciences, Linköping University, Linköping, Sweden.
    Landberg, Eva
    Department of Clinical Chemistry, and Department of Biomedical, Clinical Sciences, Linköping University, Linköping, Sweden.
    Hellberg, Sandra
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Hovland, Mina
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Sundin, Anna
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Jenmalm, Maria C.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Ekman, Bertil
    Department of Endocrinology, Department of Health, Medicine, Caring Sciences, Linköping University, Linköping, Sweden.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Wahlberg, Jeanette
    Department of Endocrinology, Department of Health, Medicine, Caring Sciences, Linköping University, Linköping, Sweden.
    Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia2020In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 52, no 04, p. 228-235Article in journal (Refereed)
    Abstract [en]

    Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.

  • 20.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Hiyoshi, Ayako
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Hurtig-Wennlöf, Anita
    Department of Clinical Diagnostics, School of Health and Welfare, Jönköping University, Jönköping, Sweden.
    Association between C10X polymorphism in the CARD8 gene and inflammatory markers in young healthy individuals in the LBA study2024In: BMC Cardiovascular Disorders, E-ISSN 1471-2261, Vol. 24, no 1, article id 103Article in journal (Refereed)
    Abstract [en]

    Background: The Caspase activation and recruitment domain 8 (CARD8) protein is a component of innate immunity as a negative regulator of NF- ĸB, and has been associated with regulation of proteins involved in inflammation. Expression of CARD8 mRNA and protein has been identified in human atherosclerotic lesions, and the truncated T30A variant (rs2043211) of CARD8 has been associated with lower C-reactive (CRP) and MCP-1 levels in myocardial infarction patients. The present study examines the role of a genetic variation in the CARD8 gene in relation to a selection of markers of inflammation.

    Methods: In a cross-sectional study of young healthy individuals (18.0-25.9 yrs, n = 744) the association between the rs2043211 variant in the CARD8 gene and protein markers of inflammation was assessed. Genotyping of the CARD8 C10X (rs2043211) polymorphism was performed with TaqMan real time PCR on DNA from blood samples. Protein levels were studied via Olink inflammation panel ( https://olink.com/ ). Using linear models, we analyzed men and two groups of women with and without estrogen containing contraceptives separately, due to previous findings indicating differences between estrogen users and non-estrogen using women. Genotypes were analyzed by additive, recessive and dominant models.

    Results: The minor (A) allele of the rs2043211 polymorphism in the CARD8 gene was associated with lower levels of CCL20 and IL-6 in men (CCL20, Additive model: p = 0.023; Dominant model: p = 0.016. IL-6, Additive model: p = 0.042; Dominant model: p = 0.039). The associations remained significant also after adjustment for age and potential intermediate variables.

    Conclusions: Our data indicate that CARD8 may be involved in the regulation of CCL20 and IL-6 in men. No such association was observed in women. These findings strengthen and support previous in vitro data on IL-6 and CCL20 and highlight the importance of CARD8 as a factor in the regulation of inflammatory proteins. The reason to the difference between sexes is however not clear, and the influence of estrogen as a possible factor important for the inflammatory response needs to be further explored.

  • 21.
    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)
  • 22.
    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.

  • 23.
    Ha, Van Thai
    et al.
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana, Slovenia.
    Lainšček, Duško
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Gesslbauer, Bernd
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
    Jarc-Jovičić, Eva
    Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Ilc, Nejc
    Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia.
    Lakota, Katja
    Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Mathematics, Natural Science and Information Technologies, University of Primorska, Koper, Slovenia.
    Tomšič, Matija
    Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
    van de Loo, Fons A. J.
    Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Bochkov, Valery
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
    Petan, Toni
    Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia.
    Jerala, Roman
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Manček-Keber, Mateja
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Synergy between 15-lipoxygenase and secreted PLA(2) promotes inflammation by formation of TLR4 agonists from extracellular vesicles2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 41, p. 25679-25689Article in journal (Refereed)
    Abstract [en]

    Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.

  • 24.
    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, 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.

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  • 25.
    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.

  • 26.
    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.

  • 27.
    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.

  • 28.
    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.

  • 29.
    Hutchinson, Ashley
    et al.
    Örebro University, School of Medical Sciences.
    Östlund-Lagerström, Lina
    Örebro University, School of Medical Sciences. Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    The Potential Effects of Probiotics and ω-3 Fatty Acids on Chronic Low-Grade Inflammation2020In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 8, article id E2402Article in journal (Refereed)
    Abstract [en]

    Chronic low-grade inflammation negatively impacts health and is associated with aging and obesity, among other health outcomes. A large number of immune mediators are present in the digestive tract and interact with gut bacteria to impact immune function. The gut microbiota itself is also an important initiator of inflammation, for example by releasing compounds such as lipopolysaccharides (LPS) that may influence cytokine production and immune cell function. Certain nutrients (e.g., probiotics, ω-3 fatty acids [FA]) may increase gut microbiota diversity and reduce inflammation. Lactobacilli and Bifidobacteria, among others, prevent gut hyperpermeability and lower LPS-dependent chronic low-grade inflammation. Furthermore, ω-3 FA generate positive effects on inflammation-related conditions (e.g., hypertriglyceridemia, diabetes) by interacting with immune, metabolic, and inflammatory pathways. Ω-3 FA also increase LPS-suppressing bacteria (i.e., Bifidobacteria) and decrease LPS-producing bacteria (i.e., Enterobacteria). Additionally, ω-3 FA appear to promote short-chain FA production. Therefore, combining probiotics with ω-3 FA presents a promising strategy to promote beneficial immune regulation via the gut microbiota, with potential beneficial effects on conditions of inflammatory origin, as commonly experienced by aged and obese individuals, as well as improvements in gut-brain-axis communication.

  • 30.
    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.

  • 31.
    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.

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  • 32.
    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.

  • 33.
    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.

  • 34.
    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, 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.

  • 35.
    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.

  • 36.
    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, 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.

  • 37.
    Klasson, Maria
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Occupational and Environmental Medicine.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Dermatology, University Hospital Örebro, Örebro, Sweden.
    Westberg, Håkan
    Örebro University, School of Medical Sciences. Department of Occupational and Environmental Medicine.
    Bryngelsson, Ing-Liss
    Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Tuerxun, Kaya
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Dermal exposure to cobalt studied in vitro in keratinocytes: effects of cobalt exposure on inflammasome activated cytokines, and mRNA response2021In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 26, no 8, p. 674-684Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cobalt is a dermal sensitizer, and keratinocytes respond to cobalt exposure by releasing proinflammatory mediators, regulating the immune response.

    OBJECTIVE: To determine the effect of cobalt on the inflammasome associated cytokine- and gene expression in cultured human keratinocytes (HaCaT). Cultivation in low- or high calcium conditions model separate differentiation states of keratinocytes in the skin.

    METHOD: HaCaT cells in two different states of differentiation were exposed to cobalt chloride and caspase-1 activity as well as the production of IL-1 beta, IL-18 and gene expression of IL1B, IL18, NLRP3, CASP1, and PYCARD was quantified. 

    RESULTS: High cobalt chloride exposure mediated significant increase in caspase-1 activity, cytokine levels, and IL1B and NLRP3 expression with a corresponding regulatory decrease for CASP1 and PYCARD expression. No difference between high- and low calcium culturing conditions modelling differentiation states was detected.

    CONCLUSIONS: Our data suggest that HaCaT cells respond with inflammmasome associated activity upon cobalt exposure in a concentration-dependent manner. These mechanisms could be of importance for the understanding of the pathophysiology behind allergic sensitization to dermal cobalt exposure.

  • 38.
    Krifors, Anders
    et al.
    Department of Infectious Diseases, Västmanlands Hospital, Västerås, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Centre of Clinical Research, Region Västmanland-Uppsala University, Västerås, Sweden.
    Freyhult, Elisabeth
    Department of Laboratory Medicine, Västmanlands Hospital, Västerås, Sweden.
    Rashid Teljebäck, Mulki
    Department of Infectious Diseases, Västmanlands Hospital, Västerås, Sweden.
    Wallin, Robert P. A.
    SciEd Solutions, Stockholm, Sweden.
    Winqvist, Ola
    ABC Labs, Stockholm, Sweden.
    Månsson, Emeli
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Västmanlands Hospital, Västerås, Sweden; Centre of Clinical Research, Region Västmanland-Uppsala University, Västerås, Sweden .
    Long-lasting T-cell response to SARS-CoV-2 antigens after vaccination-a prospective cohort study of HCWs working with COVID-19 patients2023In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 53, no 2, p. 142-148Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Vaccination against SARS-CoV-2 reduces the risk of hospitalisation and death, but vaccine-induced IgG antibodies against the spike protein (IgG S) decline over time. Less is known about the nature of the vaccine-induced T-cell response to SARS-CoV-2 antigens.

    METHODS: IgG antibodies against nucleocapsid protein (IgG N), IgG S, and T-cell response towards SARS-CoV-2 antigens were determined in samples taken between November 2020 and November 2021 from a cohort of healthcare workers at an Infectious Diseases Department. RT-PCR screening for SARS-CoV-2 was encouraged once every four weeks in addition to testing when symptomatic or identified through contact tracing. Vaccination data were collected at the end of the study.

    RESULTS: At inclusion, T-cell response to SARS-CoV-2 antigens was found in 10/15 (66.7%) of participants with a previous/current COVID-19 infection and in 9/54 (16.7%) of participants with no prior/current history of COVID-19 infection. All participants with complete follow-up (n = 59) received two doses of a SARS-CoV-2 vaccine during the study. All participants demonstrated detectable IgG (S) antibodies at the end of the study, in median 278 days (IQR 112) after the second vaccine dose. All but four participants displayed T-cell responses towards SARS-CoV-2 antigens. IgG S antibody levels correlated with time since the second vaccine dose. In addition, previous COVID-19 infection and the strength of the S1 T-cell response correlated with IgG S antibody levels. However, no correlation was demonstrated between the strength of the T-cell response and time since the second vaccine dose.

    CONCLUSION: COVID-19 vaccination induces robust T-cell responses that remain for at least nine months.

  • 39.
    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 0044-605X, 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.

  • 40.
    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.

  • 41.
    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)
  • 42.
    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.

  • 43.
    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.

  • 44.
    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.

  • 45.
    Maravelia, Panagiota
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Frelin, Lars
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ni, Yi
    Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
    Pérez, Noelia Caro
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlén, Gustaf
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Jagya, Neetu
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Verch, Georg
    Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
    Verhoye, Lieven
    Laboratory of Liver Infectious Diseases, Ghent University, Gent, Belgium.
    Pater, Lena
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Pasetto, Anna
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Meuleman, Philip
    Laboratory of Liver Infectious Diseases, Ghent University, Gent, Belgium.
    Urban, Stephan
    Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
    Sällberg, Matti
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Blocking entry of hepatitis B and D viruses to hepatocytes as a novel immunotherapy for treating chronic infections2021In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 223, no 1, p. 128-138Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic hepatitis B and D virus (HBV/HDV) infections can cause cancer. Current HBV therapy using nucleoside analogues (NAs) is life-long and reduces but does not eliminate the risk of cancer. A hallmark of chronic hepatitis B is a dysfunctional HBV-specific T cell response. We therefore designed an immunotherapy driven by naïve healthy T cells specific for the HDV antigen (HDAg) to bypass the need for HBV-specific T cells in order to prime PreS1-specific T cells and PreS1 antibodies blocking HBV entry.

    METHODS: Ten combinations of PreS1 and/or HDAg sequences were evaluated for induction of PreS1 antibodies and HBV- and HDV- specific T cells in vitro and in vivo. Neutralization of HBV by PreS1-specific murine and rabbit antibodies was evaluated in cell culture, and rabbit anti-PreS1 were tested for neutralization of HBV in mice repopulated with human hepatocytes.

    RESULTS: The best vaccine candidate induced T cells to PreS1 and HDAg, and PreS1 antibodies blocking HBV entry in vitro. Importantly, adoptive transfer of PreS1 antibodies prevented, or modulated, HBV infection after a subsequent challenge in humanized mice.

    CONCLUSION: We here describe a novel immunotherapy for chronic HBV/HDV that targets viral entry to complement NAs and coming therapies inhibiting viral maturation.

  • 46.
    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, 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.

  • 47.
    Midtbö, Kristine
    et al.
    Örebro University, School of Medical Sciences.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1 β and Interleukin-18 from Human Monocytes2020In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2020, article id 4651090Article in journal (Refereed)
    Abstract [en]

    Inflammasomes cleave and activate interleukin- (IL-) 1β and IL-18 which have both shared and unique biological functions. IL-1β is an important mediator of the acute phase response to infections and tissue damage, whereas IL-18 takes part in activation and tailoring of the adaptive immune response. While IL-1β has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1β and IL-18 production during inflammasome activation. Since these cytokines partake in different immune pathways, the involvement of inflammasome activity in different conditions needs to be described beyond IL-1β production alone. To address a potential heterogeneity in inflammasome functionality, ATP, chitosan, or silica oxide (SiO2) were used to induce NLRP3 inflammasome activation in THP-1 cells and the subsequent outcomes were quantified. Despite using doses of the inflammasome inducers yielding similar release of IL-1β, SiO2-stimulated cells showed a lower concentration of released IL-18 compared to ATP and chitosan. Hence, the cells stimulated with SiO2 responded with a distinctly different IL-18 : IL-1β ratio. The difference in the IL-18 : IL-1β ratio for SiO2 was constant over different doses. While all downstream responses were strictly dependent on a functional NLRP3 inflammasome, the differences did not depend on the level of gene expression, caspase-1 activity, or pyroptosis. We suggest that the NLRP3 inflammasome response should be considered a dynamic process, which can be described by taking the ratio between IL-1β and IL-18 into account and moving away from an on/off perspective of inflammasome activation.

  • 48.
    Ninyio, Nathaniel
    et al.
    Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia; Department of Microbiology, Faculty of Science, Kaduna State University, Kaduna, Nigeria.
    Lian Ho, Kok
    Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
    Kian Ong, Hui
    Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
    Yeah Yong, Chean
    Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia,Serdang, Malaysia.
    Yee Chee, Hui
    Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
    Hamid, Muhajir
    Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
    Sian Tan, Wen
    Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia; Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia.
    Immunological Analysis of the Hepatitis B Virus “a” Determinant Displayed on Chimeric Virus-Like Particles of Macrobrachium rosenbergii Nodavirus Capsid Protein Produced in Sf9 Cells2020In: Vaccines, E-ISSN 2076-393X, Vol. 8, no 2, article id 275Article in journal (Refereed)
    Abstract [en]

    Chimeric virus-like particles (VLPs) have been widely exploited for various purposes including their use as vaccine candidates, particularly due to their ability to induce stronger immune responses than VLPs consisting of single viral proteins. In the present study, VLPs of the Macrobrachium rosenbergii nodavirus (MrNV) capsid protein (Nc) displaying the hepatitis B virus “a” determinant (aD) were produced in Spodoptera frugiperda (Sf9) insect cells. BALB/c mice immunised with the purified chimeric Nc-aD VLPs elicited a sustained titre of anti-aD antibody, which was significantly higher than that elicited by a commercially available hepatitis B vaccine and Escherichia coli-produced Nc-aD VLPs. Immunophenotyping showed that the Sf9-produced Nc-aD VLPs induced proliferation of cytotoxic T-lymphocytes and NK1.1 natural killer cells. Furthermore, enzyme-linked immunospot (ELISPOT)analysis showed the presence of antibody-secreting memory B cells in the mice splenocytes stimulated with the synthetic aD peptide. The significant humoral, natural killer cell and memory B cell immune responses induced by the Sf9-produced Nc-aD VLPs suggest that they present good prospects for use as a hepatitis B vaccine candidate. 

  • 49.
    Ninyio, Nathaniel
    et al.
    Örebro University, School of Medical Sciences.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Folkhälsomyndigheten, Solna, Sweden.
    Development and analysis of prospective anti-HIV probiotic vaccines2022In: 19th Smögen Summer Symposium on Virology: Abstracts, Virus- och Pandemifonden – Swedish Society for Virology , 2022, p. 40-40Conference paper (Other academic)
    Abstract [en]

    Major improvements have been made in the treatment and prevention of HIV/AIDS. However, a prophylactic vaccine is still unavailable, and several vaccine-candidate trials yielded less than favourable results. Given that the HIV pandemic has not slowed down significantly, there is an urgent need for the development of an effective vaccine. The HIV-1 Gag protein, a key player in HIV particle assembly, is a suitable antigen for use in HIV vaccine development since antibodies targeting HIV-1 Gag will interfere with the replication of the virus. In our vaccine development strategy, it was important for us to develop a candidate for mucosal administration. This is because the mucosal route is the major site for HIV transmission and early viral replication, which is associated with extensive and rapid depletion of CD4+ T-cells in the Gut-Associated Lymphoid Tissue (GALT). Here, we transformed probiotic strains of Lactobacillus plantarum and Lactobacillus fermentum with the recombinant plasmid vectors pSIP409 and pSIP411 harbouring the HIV-1 GagM gene. Following electroporation, HIV-1 GagM expression was induced in the probiotics using peptide pheromone. Via PCR and sequencing, the presence of GagM was confirmed in the L. plantarum+ pSIP409-GagM and L. fermentum+ pSIP411-GagM clones. Protein expression was induced with peptide pheromone. Then, protein expression was confirmed by western blotting with goat anti-HIV p24 primary antibody and anti-goat secondary antibody. ELISA was also performed to confirm the antigenicity of the HIV-1 Gag antigen and to also quantify the antigen in the two Lactobacilli clones. Our results show that 1.5×109 CFU of L. plantarum+ pSIP409-GagM expressed 125μg of HIV-1 Gag and 1.9×109 CFU of L. fermentum+ pSIP411-GagM clones expressed 125μg of HIV-1 Gag respectively. In vitro digestion with pepsin, pancreatin and bile salts suggested that partial digestion of the probiotic vaccine candidates may occur when administered orally. Taken together, our probiotic HIV-1 vaccine candidates showed good prospects for further immunological analysis via animal trial.

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  • 50.
    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.

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