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  • 1. Abu-Elyazeed, R R
    et al.
    Heineman, T
    Dubin, G
    Fourneau, M
    Leroux-Roels, I
    Leroux-Roels, G
    Richardus, J H
    Ostergaard, L
    Diez-Domingo, J
    Poder, A
    Van Damme, P
    Romanowski, B
    Blatter, M
    Silfverdal, Sven Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, J
    Josefsson, A
    Cunningham, A L
    Flodmark, C E
    Tragiannidis, A
    Dobson, S
    Olafsson, J
    Puig-Barbera, J
    Mendez, M
    Barton, S
    Bernstein, D
    Mares, J
    Ratner, P
    Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: results from a randomised, controlled, double-blind trial2013In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 31, no 51, p. 6136-6143Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed.

    METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus.

    RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants.

    CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.

  • 2. Adderley, Jack D.
    et al.
    von Freyend, Simona John
    Jackson, Sarah A.
    Bird, Megan J.
    Burns, Amy L.
    Anar, Burcu
    Metcalf, Tom
    Semblat, Jean-Philippe
    Billker, Oliver
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
    Wilson, Danny W.
    Doerig, Christian
    Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention2020In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 4015Article in journal (Refereed)
    Abstract [en]

    Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.

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  • 3.
    Anantharajah, Ahalieyah
    et al.
    Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
    Faure, Emmanuel
    EA7366, Host-Pathogen Translational Research Group, Faculté de Médecine, Université Lille Nord de France, Lille, France.
    Buyck, Julien M.
    Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium; Focal Area Infection Biology, Biozentrum, University of Basel, Switzerland.
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Creative Antibiotics, Umeå, Sweden .
    Lindmark, Tuulikki
    Creative Antibiotics, Umeå, Sweden; Disruptivematerials, Uppsala, Sweden.
    Mecsas, Joan
    Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, United States.
    Yahr, Timothy L.
    Department of Microbiology, University of Iowa, Iowa City, United States.
    Tulkens, Paul M.
    Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
    Mingeot-Leclercq, Marie-Paule
    Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
    Guery, Benoît
    EA7366, Host-Pathogen Translational Research Group, Faculté de Médecine, Université Lille Nord de France, Lille, France.
    Van Bambeke, Françoise
    Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
    Inhibition of the injectisome and flagellar type III secretion systems by INP1855 impairs Pseudomonas aeruginosa pathogenicity and inflammasome activation2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 7, p. 1105-1116Article in journal (Refereed)
    Abstract [en]

    With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1 beta (IL-1 beta) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis. Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1 beta secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.

  • 4.
    Anderl, Ines
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere, Tampere, Finland.
    Vesala, Laura
    Ihalainen, Teemu O.
    Vanha-aho, Leena-Maija
    Andó, István
    Rämet, Mika
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere, Tampere, Finland.
    Transdifferentiation and Proliferation in Two Distinct Hemocyte Lineages in Drosophila melanogaster Larvae after Wasp Infection2016In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 7, article id e1005746Article in journal (Refereed)
    Abstract [en]

    Cellular immune responses require the generation and recruitment of diverse blood cell types that recognize and kill pathogens. In Drosophila melanogaster larvae, immune-inducible lamellocytes participate in recognizing and killing parasitoid wasp eggs. However, the sequence of events required for lamellocyte generation remains controversial. To study the cellular immune system, we developed a flow cytometry approach using in vivo reporters for lamellocytes as well as for plasmatocytes, the main hemocyte type in healthy larvae. We found that two different blood cell lineages, the plasmatocyte and lamellocyte lineages, contribute to the generation of lamellocytes in a demand-adapted hematopoietic process. Plasmatocytes transdifferentiate into lamellocyte-like cells in situ directly on the wasp egg. In parallel, a novel population of infection-induced cells, which we named lamelloblasts, appears in the circulation. Lamelloblasts proliferate vigorously and develop into the major class of circulating lamellocytes. Our data indicate that lamellocyte differentiation upon wasp parasitism is a plastic and dynamic process. Flow cytometry with in vivo hemocyte reporters can be used to study this phenomenon in detail.

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  • 5.
    Andersen, Grethe
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hägglund, M
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Petrovska, R
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J E S
    Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 3, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro-opio-melanocortin (POMC) protein mRNA were measured by the real-time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co-ordinating role for MCR subtypes and their naturally occurring ligands in the co-operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR-mediated tolerance induction in Th cells.

  • 6. Andersen, M.
    et al.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Meyer, M. K.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF- Inhibition2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 1, p. 31-39Article in journal (Refereed)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 7. Andersen, M.
    et al.
    Olesen, M. K.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Vendsyssel Hosp, Clin Res Ctr, Rheumatol Unit, Hjorring, Denmark.
    Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no Suppl. 127, p. 25-26 Meeting Abstr. PP119Article in journal (Other academic)
  • 8.
    Andersson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Bjerg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lundbäck, Bo
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    The clinical expression of asthma in schoolchildren has changed between 1996 and 20062010In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 21, no 5, p. 859-866Article in journal (Refereed)
    Abstract [en]

    Several studies have reported diverging trends in the prevalence of asthma and wheeze. The aim of this study was to investigate the clinical expression of childhood asthma in 1996 and 2006 by studying asthma morbidity, treatment, and environmental exposures in school children with physician-diagnosed asthma and wheeze, respectively. All children enrolled in first or second grade (7-8 yr-old) in three municipalities in northern Sweden were invited to a questionnaire study in 1996 and 2006, respectively. In 1996, 3430 (97%) participated; and in 2006, 2585 (96%) participated. The same parental completed questionnaire, including the ISAAC questions, was used in both surveys. Physician-diagnosed asthma was reported at 5.7% in 1996 and 7.4% in 2006. A significantly greater proportion of children with asthma were using inhaled corticosteroids (ICS) in 2006, 67% vs. 55% in 1996. This increase was parallel to a major decrease in severe asthma symptoms such as disturbed sleep because of wheeze (49% vs. 38%) and troublesome asthma (21% vs. 11%). The prevalence of current wheeze among the asthmatics decreased significantly; however, this was seen only among children not using ICS. Parental smoking decreased significantly as did the proportion living in damp buildings. In conclusion, although asthma remains a major public health issue in school age children, children with asthma had less respiratory symptoms and a better asthma control in 2006 compared to 1996. This parallels with an increase in treatment with ICS, more beneficial environmental conditions, and an increased diagnostic intensity resulting in a larger proportion of children with mild symptoms being diagnosed as having asthma.

  • 9.
    Andersson, Yvonne
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, CA 95616.
    Graverholt, Gitte
    Arla Foods Ingredients, Aarhus, Denmark.
    Fält, Helen
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Formula feeding skews immune cell composition toward adaptive immunity compared to breastfeeding2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 7, p. 4322-4328Article in journal (Refereed)
    Abstract [en]

    The ontogeny of the immune system and the effect thereon by type of infant feeding is incompletely understood. We analyzed frequencies and composition of immune cells in blood of breastfed (BF) and formula-fed (FF) infants at 1.5, 4, and 6 mo of age. Three formulas with the same protein concentration but with varying levels of alpha-lactalbumin and caseinoglycomacropeptide were compared. Twenty-nine exclusively BF infants served as reference, and 17 infants in each formula group completed the study. Whole blood and PBMCs were analyzed by flow cytometry and immunoflow cytometry, respectively. Leukocyte count of BF infants increased with time due to increased frequency of neutrophils. Lymphocyte count was high at 1.5 mo and was unchanged over time, as were the relative proportions of CD4+ alphabetaT cells, CD8+ alphabetaT cells, B cells, NK cells, and gammadeltaT cells. Most CD45R0+CD3+ cells were HLA-DR- and hence memory cells. Compared with breastfeeding, formula feeding resulted in a significant decrease in proportion of NK cells, but a significant increase in naive CD4+ alphabetaT cells and an elevated CD4-to-CD8 ratio, that is, 3.3 in the combined FF groups compared with 2.6 in the BF group. No significant differences were found between the three groups of FF infants. In conclusion, blood cells of lymphoid lineage did not change significantly in frequencies or composition from 1.5 to 6 mo of age in BF infants. In contrast, FF infants displayed an ongoing maturation of adaptive immunity cells and a delayed recruitment of innate immunity cells as compared with BF infants.

  • 10. Apcher, Sebastien
    et al.
    Martins, Rodrigo Prado
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Equipe Labellisée la Ligue Contre le Cancer, Inserm UMR1162, Université Paris, France ; RECAMO, Masaryk Memorial Cancer Institute, Czech Republic.
    The source of MHC class I presented peptides and its implications2016In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 40, p. 117-122Article, review/survey (Refereed)
    Abstract [en]

    The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-todate account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

  • 11.
    Apcher, Sebastien
    et al.
    Institut Gustave Roussy, Université Paris Sud, Villejuif, France.
    Vojtesek, Borek
    RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS1131, Institut de Génétique Moléculaire, université Paris 7, hôpital St. Louis, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    In search of the cell biology for self- versus non-self- recognition2023In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 83, article id 102334Article, review/survey (Refereed)
    Abstract [en]

    Several of today's cancer treatments are based on the immune system's capacity to detect and destroy cells expressing neoantigens on major histocompatibility class-I molecules (MHC-I). Despite this, we still do not know the cell biology behind how antigenic peptide substrates (APSs) for the MHC-I pathway are produced. Indeed, there are few research fields with so many divergent views as the one concerning the source of APSs. This is quite remarkable considering their fundamental role in the immune systems’ capacity to detect and destroy virus-infected or transformed cells. A better understanding of the processes generating APSs and how these are regulated will shed light on the evolution of self-recognition and provide new targets for therapeutic intervention. We discuss the search for the elusive source of MHC-I peptides and highlight the cell biology that is still missing to explain how they are synthesised and where they come from.

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  • 12. Arkestal, Kurt
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Enocson, Anders
    Linton, Ludvig
    Marits, Per
    Glise, Hans
    Andersson, John
    Winqvist, Ola
    CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow2018In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 88, no 6, article id e12722Article in journal (Refereed)
    Abstract [en]

    Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.

  • 13. Arnheim, L
    et al.
    Dillner, Joakim
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden.
    Sanjeevi, CB
    A population-based cohort study of KIR genes and genotypes in relation to cervical intraepithelial neoplasia2005In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 65, no 3, p. 252-259Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are involved both in control of virus infections and in elimination of tumor cells. Killer immunoglobulin-like receptors (KIRs) either activate or inhibit NK cell-mediated cytolysis, protecting healthy cells from destruction while enabling killing of abnormal cells. To investigate whether KIR genes or genotypes are associated with cervical carcinogenesis, a nested case-control study of 65 case women with cervical intraepithelial neoplasia (CIN) diagnosed during a 6-year follow-up of 15,234 women and 150 control women from the same cohort that remained healthy was performed. More than 70 different genotypes were observed, and 33 of which had not been described previously. An A-genotype including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, and KIR2DS4 was associated with increased risk of CIN (OR 6.7; 95% CI 1.7-26.3), and KIR2DL5B*002 appeared to have an inverse association with disease (OR 0.5; 95% CI 0.5-2.9). There was no association of CIN with the number of activating KIR genes. There was also no association between KIR genes and type of human papilloma virus or with other CIN-related immune response genes. It was concluded that certain KIR genes and genotypes may associate with cervical neoplasia.

  • 14.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ska obeprövade metoder få användas i svensk sjukvård?2017In: PIObladet, ISSN 1103-6249, no 2, p. 10-11Article in journal (Other academic)
  • 15. Baharom, Faezzah
    et al.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smed-Sorensen, Anna
    Human Lung Mononuclear Phagocytes in Health and Disease2017In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 499Article, review/survey (Refereed)
    Abstract [en]

    The lungs are vulnerable to attack by respiratory insults such as toxins, allergens, and pathogens, given their continuous exposure to the air we breathe. Our immune system has evolved to provide protection against an array of potential threats without causing collateral damage to the lung tissue. In order to swiftly detect invading pathogens, monocytes, macrophages, and dendritic cells (DCs)-together termed mononuclear phagocytes (MNPs)-line the respiratory tract with the key task of surveying the lung microenvironment in order to discriminate between harmless and harmful antigens and initiate immune responses when necessary. Each cell type excels at specific tasks: monocytes produce large amounts of cytokines, macrophages are highly phagocytic, whereas DCs excel at activating naive T cells. Extensive studies in murine models have established a division of labor between the different populations of MNPs at steady state and during infection or inflammation. However, a translation of important findings in mice is only beginning to be explored in humans, given the challenge of working with rare cells in inaccessible human tissues. Important progress has been made in recent years on the phenotype and function of human lung MNPs. In addition to a substantial population of alveolar macrophages, three subsets of DCs have been identified in the human airways at steady state. More recently, monocyte-derived cells have also been described in healthy human lungs. Depending on the source of samples, such as lung tissue resections or bronchoalveolar lavage, the specific subsets of MNPs recovered may differ. This review provides an update on existing studies investigating human respiratory MNP populations during health and disease. Often, inflammatory MNPs are found to accumulate in the lungs of patients with pulmonary conditions. In respiratory infections or inflammatory diseases, this may contribute to disease severity, but in cancer patients this may improve clinical outcomes. By expanding on this knowledge, specific lung MNPs may be targeted or modulated in order to attain favorable responses that can improve preventive or treatment strategies against respiratory infections, lung cancer, or lung inflammatory diseases.

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  • 16.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Chlamydia pneumoniae infection results in generalized bone loss in mice2008In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, p. 1175-1181Article in journal (Refereed)
  • 17.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse2017In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 6, p. 363-369Article in journal (Refereed)
    Abstract [en]

    The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

  • 18.
    Bas, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Extrathymic T cell receptor gene rearrangement in human alimentary tract2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    T lymphocytes regulate the initiation, duration, and magnitude of adaptive immune responses and function as effector cells in cell mediated immunity. To become immunologically competent they must generate functional antigen receptors. This process takes place in the thymus and requires somatic recombination of T cell receptor (TCR) genes. It is mediated by the endonucleases recombination activating gene-1 (RAG1) and RAG2. Although the thymus regresses at puberty, T cells are present throughout life implying that other tissues must provide the proper milieu for T cell development. This thesis describes extrathymic T cell maturation in man. RAG1, RAG2, and the preTα-chain (pTα), which is exclusively utilized in developing T cells, were used as markers for TCR gene rearrangement. Two new exons (1A and 1B) encoding sequences in the 5’ untranslated region (5’UTR) of mRNA were discovered in the human RAG1 gene. The previously described 5’UTR exon (renamed 1C) was located between the new exons and exon 2, the latter containing the entire coding sequence. We found that small intestinal lymphocytes of the T cell lineage expressed the new exons in three different splice forms. RAG1 mRNA containing the 1C exon was not expressed in small intestinal lymphocytes. In contrast, splice forms containing the 1A exon were not expressed in thymocytes. RAG1 and pTα mRNA expressing lymphocytes were seen both within the epithelium and in lamina propria. Thymocyte-like CD2+CD7+CD3-, CD4+CD8+, CD1a+, and IL7-R+ lymphocytes were identified in the small intestinal mucosa. CD2+CD7+CD3- cells had the highest expression levels of mRNA for RAG1 and pTα, suggesting that the small intestinal mucosa is indeed a site for T cell maturation. Small intestinal T lymphocytes were also shown to kill via the Fas/FasL pathway in a TCR/CD3 independent manner and via the perforin/granzyme pathway in a TCR/CD3 dependent manner. The Fas/FasL-mediated cytotoxicity may reflect an ongoing selection process of extrathymically maturated T cells.

    The nasopharyngeal tonsil is the major inductive site for immune reactions against inhaled antigens. Previous demonstration of RAG1 expression in tonsillar B cells was interpreted as antigen driven receptor revision. The present study confirms the expression of RAG1 in B cells. We also found that RAG1, RAG2, and pTa mRNAs were expressed in lymphocytes of the T cell lineage. A small population of cells with the immature phenotype CD2+CD7+CD3- was demonstrated. This population had the highest expression levels of mRNA for RAG1, RAG2, pTα and terminal deoxynucleotidyl transferase. All four splice-forms of RAG1 mRNA were expressed. RAG1 and pTα mRNA expressing cells were mainly located in the proximity of the surface epithelium and in the outer rim of the follicles. These results suggest that the nasopharyngeal tonsil is a site where extrathymic T cell development and antigen driven TCR revision are occurring in parallel.

    Celiac disease (CD) is a small intestinal enteropathy characterized by permanent intolerance to gluten. Gluten reactive intestinal T cells are central in the pathogenesis and CD can be regarded as a failure to maintain tolerance to this food antigen. Expression of the RAG1 1A/2 splice form was significantly decreased in small intestinal T cell subsets of CD patients suggesting that impaired TCR gene rearrangement could contribute to failure of maintain tolerance in CD.

    Together, these findings show that both small intestinal and nasopharyngeal tonsillar lymphocytes of T cell lineage have the molecular machinery for antigen receptor rearrangement and that thymocyte-like lymphocytes are present in both tissues. Thus these organs are likely sites of T lymphocyte ontogeny as well as for secondary T cell receptor rearrangement in man.

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  • 19.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Cilio, Corrado M
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
    Penha-Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Lamhamedi-Cherradi, Salah-Eddine
    INSERM U25, Hopital Necker, Paris, France.
    Löfgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Colucci, Francesco
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Garchon, Henri-Jean
    INSERM U25, Hopital Necker, Paris, France.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed)
    Abstract [en]

    The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

  • 20.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 7, p. 1677-1682Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

  • 21.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha-Gonçalves, Carlos
    Gulbenkian Institute for Science, Oeiras, Portugal, PT.
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development.

    Methods: We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes.

    Results: Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4 /loCD8+ cells differentiating from the CD4CD8 to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6.

    Conclusion/interpretation: Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

  • 22.
    Bergqvist, Ingela
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Björn
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Corneliussen, Brit
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development2000In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 30, no 10, p. 2857-2863Article in journal (Refereed)
    Abstract [en]

    E2A, HEB and E2-2 genes encode a group of basic helix-loop-helix (bHLH) transcription factors that are structurally and functionally similar. Deletion of the genes encoding either of these proteins leads to early lethality and a block in B lymphocyte development. Evidence for a function in T lymphocyte development has, however, only been reported for E2A and HEB. To further elucidate the role of E2-2 at developmental stages that have proven difficult to study due to the early lethality phenotype of mice defective in E2-2, we generated and analyzed mice conditionally mutated in the E2-2 gene. These mice are mosaic with respect to E2-2 expression, consisting of cells with either one functional and one null mutated E2-2 allele or two null mutated alleles. Using this experimental model, we find that cells with a homozygous null mutated E2-2 gene are under-represented in B lymphocyte as well as T lymphocyte cell lineages as compared to other hematopoietic or non-hematopoietic cell lineages. Our data suggests that E2-2 deficiency leads to a partial block in both B and T lymphocyte development. The block in T cell development appears to occur at an early stage in differentiation, since skewing in the mosaicism is observed already in CD4+8+ double-positive thymocytes.

  • 23. Bernasconi, Valentina
    et al.
    Norling, Karin
    Gribonika, Inta
    Ong, Li Ching
    Burazerovic, Sabina
    Parveen, Nagma
    Schon, Karin
    Stensson, Anneli
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Larson, Goran
    Hook, Fredrik
    Lycke, Nils
    A vaccine combination of lipid nanoparticles and a cholera toxin adjuvant derivative greatly improves lung protection against influenza virus infection2021In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 14, no 2, p. 523-536Article in journal (Refereed)
    Abstract [en]

    This is a proof-of-principle study demonstrating that the combination of a cholera toxin derived adjuvant, CTA1-DD, and lipid nanoparticles (LNP) can significantly improve the immunogenicity and protective capacity of an intranasal vaccine. We explored the self-adjuvanted universal influenza vaccine candidate, CTA1-3M2e-DD (FPM2e), linked to LNPs. We found that the combined vector greatly enhanced survival against a highly virulent PR8 strain of influenza virus as compared to when mice were immunized with FPM2e alone. The combined vaccine vector enhanced early endosomal processing and peptide presentation in dendritic cells and upregulated co-stimulation. The augmenting effect was CTA1-enzyme dependent. Whereas systemic anti-M2e antibody and CD4(+)T-cell responses were comparable to those of the soluble protein, the local respiratory tract IgA and the specific Th1 and Th17 responses were strongly enhanced. Surprisingly, the lung tissue did not exhibit gross pathology upon recovery from infection and M2e-specific lung resident CD4(+)T cells were threefold higher than in FPM2e-immunized mice. This study conveys optimism as to the protective ability of a combination vaccine based on LNPs and various forms of the CTA1-DD adjuvant platform, in general, and, more specifically, an important way forward to develop a universal vaccine against influenza.

  • 24. Berthold, Malin
    et al.
    Bjerg, Anders
    Winberg, Anna
    Mattsson, Lars
    Borres, Magnus
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Obstructive Lung Disease in Northern Sweden (OLIN) studies, Norrbotten county council, Luleå, Sweden.
    Association of Sensitization to Specific Pet Allergen Components with Asthma Symptoms in School Children2015In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 135, no 2, p. AB22-AB22Article in journal (Other academic)
    Abstract [en]

    Animal sensitization is a known determinant of asthma in children. The objective was to study the association of asthma with sensitization to pet allergen components in schoolchildren. Methods: A random sample of 696 children (11-12 y) from a Swedish population-based cohort was analyzed for sensitization (≥0.1 kUA/L) to cat, dog and horse dander extracts using ImmunoCAP. Sensitized children were further analyzed for IgE antibodies to animal allergen components using ImmunoCAP ISAC112. An expanded ISAAC questionnaire was completed by the parents. Results: Of 259 animal-sensitized children (37%) the majority (75%) were sensitized to more than one species. Among the 11 % (n=77) with current asthma 69 % were sensitized to at least one animal extract, as compared to one third of children without current asthma (p<0.001). Current asthma and asthma symptoms upon contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. Already at moderate levels of IgE antibodies to Fel d 4 (1-15 ISU), at which level most children were sensitized also to Fel d 1, the prevalence of asthma symptoms upon contact with cats was significantly increased. Dog-sensitized children were commonly sensitized to several dog components, and the greatest risk for asthma was seen in children co-sensitized to Can f 5 and Can f 1/f 2. Conclusions: Among Northern Swedish schoolchildren furry animals were the main perennial sensitizers. Asthma symptoms were associated with sensitizations to multiple components within an animal species. In particular, cat Fel d 4 sensitization was strongly related to asthma symptoms.

  • 25. Bielig, H
    et al.
    Rompikuntal, Pramod Kumar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Mitesh, Dongre
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Zurek, B
    Lindmark, B
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kufer, T A
    University of Cologne.
    NOD-like receptor activation by outer-membrane vesicles (OMVs) from non-O1 non-O139 Vibrio cholerae is modulated by the quorum sensing regulator HapR2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 4, p. 1418-1427Article in journal (Refereed)
    Abstract [en]

    Vibrio cholerae is an inhabitant of aquatic systems and one of the causative agents of severe dehydrating diarrhea in humans. It has also emerged as an important cause of different kinds of inflammatory responses and in particular, V. cholerae strains of the non-O1 non-O139 serogroups (NOVC) have been associated with such infections in human. We analyzed the potential of outer membrane vesicles (OMVs) derived from the NOVC strain V:5/04 to induce inflammatory responses in human host cells. V:5/04 OMVs were taken up by human epithelial cells and induced inflammatory responses. siRNA-mediated gene knock-down revealed that the inflammatory potential of NOVC OMVs was partially mediated by the nucleotide-binding domain, leucine rich repeat containing family member NOD1. Physiochemical analysis of the content of these OMVs, in conjunction with NOD1 and NOD2 reporter assays in HEK293T cells, confirmed the presence of both NOD1 and NOD2 active peptidoglycan in the OMVs. Furthermore, we show that deletion of the quorum sensing regulator HapR which mimics an infective life style, specifically reduced the inflammatory potential of the V:5/04 OMVs and their ability to activate NOD1 and NOD2. In conclusion, our study shows that NOVC OMVs elicit immune responses mediated by NOD1 and NOD2 in mammalian host cells. Moreover, we provide evidence that the quorum sensing machinery plays an important regulatory role in this process by attenuating the inflammatory potential of OMVs in infective conditions. This work thus identified a new facet of how Vibrio affects host immune responses and defines a role for the quorum sensing machinery in this process.

  • 26.
    Bitar, Aziz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Vibrio cholerae modulates the immune defense of human gut mucosa2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The key function of innate immunity is to sense danger signals and initiate effective responses as a defense mechanism against pathogens. Simultaneously, effector responses must be regulated to avoid excessive inflammation with resulting tissue damage. microRNAs (miRNAs), are small endogenous molecules, that has recently gained attention as important regulatory elements in the human inflammation cascade. The control over host miRNA expression may represent a previously uncharacterized molecular strategy exploited by pathogens to mitigate innate host cell responses.

    Vibrio cholerae is a Gram-negative bacterium that colonizes the human small intestine and causes life-threatening secretory diarrhea, essentially mediated by cholera toxin (CT). It is considered a non-invasive pathogen and does not cause clinical inflammation. Still, cholera is associated with inflammatory changes of the small intestine. Furthermore, CT-negative strains of V. cholerae cause gastroenteritis and are associated with extra-intestinal manifestations, suggesting that other virulence factors than CT are also involved in the pathogenesis.

    The innate immune response to V. cholerae is poorly investigated and the potential role of miRNA in cholera had not been studied before. Therefore, this thesis explores the role of intestinal epithelial cells in response to V. cholerae infection with a focus on regulatory miRNA as a potential contributor to the pathogenesis. The in vivo material was small intestinal biopsies from patients suffering from V. cholerae infection. As an in vitro model for V. cholerae attack on intestinal epithelium, we used tight monolayers of T84 cells infected with V. cholerae and their released factors. We analyzed changes in levels of cytokines, immunomodulatory microRNA and their target genes.

    We showed that miRNA-146a and miRNA-155 reached significantly elevated levels in the intestinal mucosa at acute stages of disease in V. cholerae infected patients and declined to normal levels at the convalescent stage. Low-grade inflammation was identified at the acute stage of V. cholerae infection, which correlated with elevated levels of regulatory miRNA. Furthermore, outer membrane vesicles (OMVs) released by the bacteria were shown to induce miR-146a and live bacteria induced miR-155 in intestinal epithelial cells. In addition, OMVs decreased epithelial permeability and caused mRNA suppression of pro-inflammatory cytokines, including immune cell attractant IL-8 and CLL20, and the inflammasome markers IL-1b and IL-18. These results propose that V. cholerae regulates the host expression of miRNA during infection and may set the threshold for activation of the intestinal epithelium.

    Moreover, we showed that V. cholerae also harbors inflammatory-inducing capabilities, by secreting a pore-forming toxin, Vibrio cholerae cytolysin (VCC). By using genetically modified strains as well as soluble protein challenge experiments, VCC was found solely responsible for the increased epithelial permeability and induction of several pro-inflammatory cytokines in intestinal epithelial cells. In contrast to OMVs, VCC displayed strong upregulation of the pro-inflammatory cytokines IL-8, TNF-a, CCL20 and IL-1b and IRAK2, a key signaling molecule in the IL-1 inflammasome pathway. This suggest that VCC is an important virulence factor in the V. cholerae pathogenesis, particularly in CT-negative strains. Furthermore, we showed that the bacterium could control the inflammatory actions of VCC by secreting the PrtV protease, which degraded VCC and consequently abolished inflammation.  

    In summary, we showed that V. cholerae harbors immunomodulating capabilities, both at the gene level, through induction of host regulatory miRNA, and at the protein level, through secretion of VCC and PrtV. These strategies may be relevant for V. cholerae to promote survival in the gut and cause successful infections in the human host.

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  • 27.
    Bitar, Aziz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response of human intestinal epithelial cells by inducing microRNA-146a2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 7212Article in journal (Refereed)
    Abstract [en]

    The small intestinal epithelium of Vibrio cholerae infected patients expresses the immunomodulatory microRNAs miR-146a and miR-155 at acute stage of disease. V. cholerae release outer membrane vesicles (OMVs) that serve as vehicles for translocation of virulence factors including V. cholerae cytolysin (VCC). The aim was to investigate whether OMVs, with and/or without VCC-cargo could be responsible for induction of microRNAs in intestinal epithelial cells and thereby contribute to immunomodulation. Polarized tight monolayers of T84 cells were challenged with OMVs of wildtype and a VCC deletion mutant of the non-O1/non-O139 (NOVC) V. cholerae strain V:5/04 and with soluble VCC. OMVs, with and without VCC-cargo, caused significantly increased levels of miR-146a. Increase was seen already after 2 hours challenge with OMVs and persisted after 12 hours. Challenge with soluble VCC caused significant increases in interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), CCL20, IL-1β, and IRAK2 mRNA levels while challenge with OMVs did not cause increases in expression levels of any of these mRNAs. These results suggest that V. cholerae bacteria release OMVs that induce miR-146a in order to pave the way for colonization by reducing the strength of an epithelial innate immune defence reaction and also preventing inflammation in the mucosa that factors like VCC can evoke.

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  • 28. Bjerg, A.
    et al.
    Winberg, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Johansson, R.
    Berthold, M.
    Borres, M.
    Hedman, Linnea
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Norrbotten City Council, OLIN Studies, Luleå, Sweden.
    Backman, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Norrbotten City Council, OLIN Studies, Luleå, Sweden.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Norrbotten City Council, OLIN Studies, Luleå, Sweden.
    Sensitization to animal allergen components in relation to asthma among young adults in Northern Sweden2019In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, p. 291-291Article in journal (Other academic)
  • 29. Bjerg, Anders
    et al.
    Ekerljung, Linda
    Eriksson, Jonas
    Näslund, Jonas
    Sjölander, Sigrid
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Gothenburg University, Göteborg.
    Dahl, Åslög
    Holmberg, Kenneth
    Wennergren, Göran
    Torén, Kjell
    Borres, Magnus P
    Lötvall, Jan
    Lundbäck, Bo
    Increase in pollen sensitization in Swedish adults and protective effect of keeping animals in childhood2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 10, p. 1328-1336Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To date, most studies of the "allergy epidemic" have been based on self-reported data. There is still limited knowledge on time trends in allergic sensitization, especially among adults.

    OBJECTIVE: To study allergic sensitization, its risk factors, and time trends in prevalence.

    METHODS: Within West Sweden Asthma Study (WSAS) a population-based sample of 788 adults (17-60y) underwent skin prick tests (SPT) for 11 aeroallergens 2009-2012. Specific IgE was analyzed in 750 of the participants. Those aged 20-46y (n=379) were compared with the European Community Respiratory Health Survey sample aged 20-46y from the same area (n=591) in 1991-1992.

    RESULTS: Among those aged 20-46y the prevalence of positive SPT to pollen increased; timothy from 17.1% to 29.0% (p<0.001) and birch from 15.6% to 23.7% (p=0.002) between 1991-1992 and 2009-2012. Measurements of specific IgE confirmed these increases. Prevalence of sensitization to all other tested allergens was unchanged. In the full WSAS sample aged 17-60y any positive SPT was seen in 41.9%, and the dominating sensitizers were pollen (34.3%), animals (22.8%) and mites (12.6%). Pollen sensitization was strongly associated with rhinitis, whereas indoor allergens were more associated with asthma. Growing up with livestock or furred pets decreased the risk of sensitization, adjusted odds ratio 0.53 (0.28-0.995) and 0.68 (0.47-0.98) respectively.

    CONCLUSION: Pollen sensitization has increased in Swedish adults since the early 1990's, while the prevalence of sensitization to other allergens has remained unchanged. This is one plausible explanation for the increase in rhinitis 1990-2008 in Swedish adults, during which time the prevalence of asthma, which is more associated with perennial allergens, was stable. Contact with animals in childhood seems to reduce the risk of sensitization well into adulthood. One major factor contributing to the rise in pollen allergy is a significant increase in levels of birch and grass pollen over the past three decades.

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  • 30.
    Bjerg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    Winberg, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berthold, Malin
    Mattsson, Lars
    Borres, Magnus P
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 6, p. 557-563Article in journal (Refereed)
    Abstract [en]

    Background: Animal sensitization is a major determinant of asthma in children. Component-resolved studies of unselected pediatric populations are lacking. The aim was to describe sensitization to animal components and the association with asthma and rhinitis in animal-sensitized schoolchildren. Methods: A random sample of 696 children (11-12years) from a Swedish population-based cohort was tested for sensitization to cat, dog, and horse dander using ImmunoCAP. Sera from animal-sensitized children were further analyzed by microarray including three allergen components from cat, four from dog, and two from horse. The parents completed an expanded ISAAC questionnaire. Results: Of 259 animal-sensitized children (0.1 kU(A)/l), 51% were sensitized to all three, 23% to two, and 25% to one species. Current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. This association was seen already at moderate-level sensitization (1-15 ISU) to Fel d 4, at which level most children were sensitized to Fel d 1, as well. In dog-sensitized children, the majority was sensitized to more than one dog component, and co-sensitization to Can f 5 and Can f 1/f 2 conferred the greatest risk for asthma. Sensitization to the highly cross-reactive serum albumins was uncommon and not associated with asthma. Conclusions: Among schoolchildren in northern Sweden, where mite allergy is uncommon, furry animals were the primary perennial sensitizers. Asthma was associated with higher levels of component sensitization, and sensitization to more than one component from the same animal conferred the greatest risk.

  • 31. Bjornsdottir, Halla
    et al.
    Christenson, Karin
    Forsman, Huamei
    Stylianou, Marios
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Urban, Constantin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Dahlgren, Claes
    Karlsson, Anna
    Bylund, Johan
    Cytotoxic Peptides from S. aureus Cause Neutrophil Cell Death with NET-like Features2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 432-432Article in journal (Other academic)
  • 32.
    Björmsjö, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Ekström, Nina
    Department of Health Security, Finnish Institute for Health and Welfare, Helsinki, Finland.
    Silfverdal, Sven-Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, USA.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Vaccine IgG antibody response is higher in formula-fedcompared to breastfed infants but not affected by added bovine lactoferrin or lowered iron content: results from a randomized controlled trialManuscript (preprint) (Other academic)
  • 33.
    Blomberg, Jeanette
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Höglund, Andreas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Jacobsson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line2011In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 16, no 8, p. 783-794Article in journal (Refereed)
    Abstract [en]

    Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.

  • 34.
    Boman, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindqvist, Helena
    Forsberg, Lars
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brief manual-based single-session Motivational Interviewing for reducing high-risk sexual behaviour in women: an evaluation2018In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 29, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to develop and evaluate brief Motivational Interviewing (MI) to facilitate behaviour change in women at high risk of contracting sexually transmitted infections (STIs). One hundred and seventy-three women (mean age 24.7) at high risk of contracting STIs were randomized to a brief risk-reducing MI counselling intervention (n = 74) or assigned to the control group (n = 99). MI skill was assessed using the Motivational Interviewing Treatment Integrity (MITI) Coding System. Seventeen of 74 (23%) women tested for Chlamydia trachomatis (CT) in the MI intervention group and 22 of 99 (22%) in the control group had a genital CT infection 0-24 months before baseline. All additional CT testing was monitored up to 24 months for all 173 women in the study. None of the 49 CT-retested women in the MI group was CT infected, as compared to 3 of 72 (4%) women in the control group. A generalized estimating equations model with sexual high-risk behaviour measured at baseline and at six-month follow-up produced an adjusted estimated odds ratio of 0.38 (95% confidence interval = 0.158, 0.909), indicating efficacy. Brief manual-based single-session MI counselling seems to be effective in reducing high-risk sexual behaviour in women at high risk of acquiring STIs.

  • 35.
    Bonroy, Carolien
    et al.
    Department of Diagnostic Sciences, Ghent University, Ghent, Belgium; Department of Laboratory Medicine, University Hospital Ghent, Ghent, Belgium.
    Vercammen, Martine
    Department of Laboratory Medicine, AZ Sint-Jan, Brugge, Belgium; Research Group REIM, Vrije Universiteit Brussel, Brussels, Belgium.
    Fierz, Walter
    Schweizerischer Verband der Diagnostikindustrie (SVDI-ASID), Bern, Switzerland.
    Andrade, Luis E.C.
    Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; Immunology Division, Fleury Medicine and Health Laboratories, Sao Paulo, Brazil.
    Van Hoovels, Lieve
    Department of Laboratory Medicine, OLV Hospital, Aalst, Belgium; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
    Infantino, Maria
    Immunology and Allergology Laboratory, S. Giovanni di Dio Hospital, Florence, Italy.
    Fritzler, Marvin J.
    Department of Medicine, Cumming School of Medicine, University of Calgary, AB, Calgary, Canada.
    Bogdanos, Dimitrios
    Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, University General Hospital of Larissa, Larissa, Greece.
    Kozmar, Ana
    Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
    Nespola, Benoit
    Laboratory of Immunology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Broeders, Sylvia
    Quality of Laboratories, Sciensano, Ixelles, Belgium.
    Patel, Dina
    UK NEQAS Immunology, Immunochemistry and Allergy, Sheffield Teaching Hospitals, Sheffield, United Kingdom.
    Herold, Manfred
    Department of Internal Medicine II, Rheumatology Laboratory, Medical University of Innsbruck, Innsbruck, Austria.
    Zheng, Bing
    Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
    Chan, Eric Y.T.
    Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong.
    Uibo, Raivo
    Department of Immunology, Medical Faculty, University of Tartu, Tartu, Estonia.
    Haapala, Anna-Maija
    Department of Immunology, Fimlab Laboratories, Tampere, Finland.
    Musset, Lucile
    Department of Immunology, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
    Sack, Ulrich
    Medical Faculty, Leipzig University, Leipzig, Germany.
    Nagy, Gabor
    Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
    Sundic, Tatjana
    Department of Immunology and Transfusion Medicine, Haugesund Hospital, Helse Fonna, Haugesund, Norway.
    Fischer, Katarzyna
    Individual Laboratory for Rheumatologic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland.
    Rego De Sousa, Maria-José
    Immunopathology and Autoimmunity Department, Centro de Medicina Laboratorial Germano de Sousa, Lisbon, Portugal.
    Vargas, Maria Luisa
    Immunology, Hospital Universitario de Badajoz, Badajoz, Spain.
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Heijnen, Ingmar
    Immunology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.
    García-De La Torre, Ignacio
    Department of Immunology and Rheumatology, Hospital General de Occidente, Universidad de Guadalajara, Guadalajara, Mexico.
    Carballo, Orlando Gabriel
    Laboratory of Immunology, Hospital Carlos G. Durand, Buenos Aires, Argentina; Department of Microbiology and Immunology, Instituto Universitario, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
    Satoh, Minoru
    Department of Human, Information and Life Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan; Department of Medicine, Kitakyushu Yahata-Higashi Hospital, Kitakyushu, Japan.
    Kim, Kyeong-Hee
    Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, South Korea.
    Chan, Edward K.L.
    Department of Oral Biology, University of Florida, FL, Gainesville, United States.
    Damoiseaux, Jan
    Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands.
    Lopez-Hoyos, Marcos
    Immunology Service, University Hospital Marques de Valdecilla-IDIVAL, University of Cantabria, Santander, Spain.
    Bossuyt, Xavier
    Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Laboratory Medicine, University Hospital Leuven, Leuven, Belgium.
    The European Autoimmune Standardization Initiative (EASI), (Contributor)
    The International Consensus on ANA Patterns (ICAP), (Contributor)
    Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP2023In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 61, no 7, p. 1167-1198Article in journal (Refereed)
    Abstract [en]

    Objectives: Antinuclear antibodies (ANA) are important for the diagnosis of various autoimmune diseases. ANA are usually detected by indirect immunofluorescence assay (IFA) using HEp-2 cells (HEp-2 IFA). There are many variables influencing HEp-2 IFA results, such as subjective visual reading, serum screening dilution, substrate manufacturing, microscope components and conjugate. Newer developments on ANA testing that offer novel features adopted by some clinical laboratories include automated computer-assisted diagnosis (CAD) systems and solid phase assays (SPA).

    Methods: A group of experts reviewed current literature and established recommendations on methodological aspects of ANA testing. This process was supported by a two round Delphi exercise. International expert groups that participated in this initiative included (i) the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group “Autoimmunity Testing”; (ii) the European Autoimmune Standardization Initiative (EASI); and (iii) the International Consensus on ANA Patterns (ICAP).

    Results: In total, 35 recommendations/statements related to (i) ANA testing and reporting by HEp-2 IFA; (ii) HEp-2 IFA methodological aspects including substrate/conjugate selection and the application of CAD systems; (iii) quality assurance; (iv) HEp-2 IFA validation/verification approaches and (v) SPA were formulated. Globally, 95% of all submitted scores in the final Delphi round were above 6 (moderately agree, agree or strongly agree) and 85% above 7 (agree and strongly agree), indicating strong international support for the proposed recommendations.

    Conclusions: These recommendations are an important step to achieve high quality ANA testing.

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  • 36.
    Bortz, Robert H.
    et al.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Florez, Catalina
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, NY, United States.
    Laudermilch, Ethan
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Wirchnianski, Ariel S.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lasso, Gorka
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Malonis, Ryan J.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Georgiev, George I.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Vergnolle, Olivia
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Herrera, Natalia G.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Morano, Nicholas C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Campbell, Sean T.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Orner, Erika P.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Mengotto, Amanda
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Dieterle, M. Eugenia
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Fels, J. Maximilian
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Haslwanter, Denise
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Jangra, Rohit K.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Celikgil, Alev
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Kimmel, Duncan
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lee, James H.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Mariano, Margarette C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Nakouzi, Antonio
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Quiroz, Jose
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Rivera, Johanna
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Szymczak, Wendy A.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Tong, Karen
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Barnhill, Jason
    Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, NY, United States.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Stein, Daniel T.
    Montefiore Medical Center, NY, Bronx, United States; Division of Endocrinology and Diabetes, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Pirofski, Liise-Anne
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Goldstein, D Yitzchak
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Garforth, Scott J.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Almo, Steven C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Daily, Johanna P.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Prystowsky, Michael B.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Faix, James D.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Fox, Amy S.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Weiss, Louis M.
    Montefiore Medical Center, NY, Bronx, United States; Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lai, Jonathan R.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Chandran, Kartik
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Single-Dilution COVID-19 Antibody Test with Qualitative and Quantitative Readouts2021In: mSphere, E-ISSN 2379-5042, Vol. 6, no 2, article id e00224-21Article in journal (Refereed)
    Abstract [en]

    The coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to place an immense burden on societies and health care systems. A key component of COVID-19 control efforts is serological testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior SARS-CoV-2 infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this sensitive test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test make it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.IMPORTANCE Serological surveillance has become an important public health tool during the COVID-19 pandemic. Detection of protective antibodies and seroconversion after SARS-CoV-2 infection or vaccination can help guide patient care plans and public health policies. Serology tests can detect antibodies against past infections; consequently, they can help overcome the shortcomings of molecular tests, which can detect only active infections. This is important, especially when considering that many COVID-19 patients are asymptomatic. In this study, we describe an enzyme-linked immunosorbent assay (ELISA)-based qualitative and quantitative serology test developed to measure IgG and IgA antibodies against the SARS-CoV-2 spike glycoprotein. The test can be deployed using commonly available laboratory reagents and equipment and displays high specificity and sensitivity. Furthermore, we demonstrate that IgG titers in patient samples can be estimated from a single measurement, enabling the assay's use in high-throughput clinical environments.

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  • 37. Brenner, David
    et al.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Univ Ulm, Dept Neurol, Ulm, Germany.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice"2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 2, p. 530-Article in journal (Refereed)
  • 38. Browall, Sarah
    et al.
    Norman, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bioinformatics Infrastructure for Life Sciences, Computational Life Science Cluster.
    Galanis, Ilias
    Sjöstrom, Karin
    Dagerhamn, Jessica
    Hellberg, Christel
    Pathak, Anuj
    Spadafina, Tiziana
    Sandgren, Andreas
    Bättig, Patrick
    Franzén, Oscar
    Andersson, Björn
    Örtqvist, Åke
    Normark, Staffan
    Henriques-Normark, Birgitta
    Intraclonal Variations Among Streptococcus pneumoniae Isolates Influence the Likelihood of Invasive Disease in Children2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 3, p. 377-388Article in journal (Refereed)
    Abstract [en]

    Background. Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated. Methods. A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed. Results. Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness. Conclusions. Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

  • 39. Bruening, Janina
    et al.
    Weigel, Bettina
    Gerold, Gisa
    Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Hannover, Germany.
    The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy2017In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 7232361Article in journal (Refereed)
    Abstract [en]

    The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

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  • 40.
    Brundin, Peik
    et al.
    S:t Görans Sjukhus, Infektionsenheten.
    Landgren, Britt-Marie
    Kvinnohälsan, Karolinska University Hospital.
    Fjällström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Gustafsson, Jan-Åke
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Johansson, Anders F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Nalvarte, Ivan
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Expression of sex hormone receptor and immune response genes in peripheral blood mononuclear cells during the menstrual cycleManuscript (preprint) (Other academic)
  • 41.
    Brundin, Peik M. A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Department of Biosciences and Nutrition, Karolinska Institutet.
    Sex differences in immune response and sex hormone receptor expression in healthy individuals and during viral infection2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is sex-bias in morbidity and mortality from infectious diseases. Infections kill more men than women and several studies have pointed out differences in the immune system as a reason. The sex hormones estrogen, progesterone and testosterone all shape the effect of the immune response on multiple levels. Women at fertile age have been suggested to have higher proinflammatory responses from inflammatory stimuli compared to men and post-menopausal women, which has been ascribed to their higher estrogen levels. This could possibly lead to a more active pathogen response but may also result in a detrimental immunopathology to infections or development of autoimmune reaction.

    The overall aim of this thesis is to study the contribution of sex hormones and sex hormone receptors (SHR) to sex differences in immune response. We focus on peripheral blood mononuclear cells (PBMCs) to study such relationships in healthy individuals, as well as in individuals with asymptomatic Torque Teno Virus infection, and individuals with acute Puumala virus infection.

    In Paper I, we investigated expression of SHR and immune response genes in PBMC from healthy premenopausal (pre-MP) women during the menstrual cycle. The expression levels were estimated using a qPCR Array (Taqman low-density array, TLDA). SHR expression did not change significantly during the menstrual cycle, but several key immune regulatory genes were significantly more expressed during the ovulatory and mid luteal phase. Further, we separated PBMC into cell subsets (CD4+ T-cells, CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) and analyzed the expression through qPCR of estrogen receptors (ERs), ERα, ERβ1 (wildtype) and the isoform ERβ2. For the first time and unexpectedly, we demonstrate that the isoform ERβ2 was more abundant than wildtype ERβ1. The data from this paper provides new knowledge on the contribution of the menstrual cycle on immune response.

    In Paper II, we explored the use of Torque Teno Virus as a secondary functional immune marker in men and women. Expression of viral TTV DNA in PBMCs was estimated using a qPCR kit from Argene (R-gene) and analyzed in relation to serum sex hormone levels. The results showed that 50% of the men, 25% the post-MP women, and 18% of the pre-MP women were TTV+. Interestingly, all pre-MP women that were TTV+ had hormonal aberrances and were either anovulatory and/or hypothyroid. TTV+ pre-MP women also had significantly lower progesterone levels than TTV- pre-MP women. This paper indicates that the prevalence of TTV in PBMC differs between men, pre-MP and post-MP women. Furthermore, hormonal aberrances (at least in pre-MP women) will lead to increased prevalence of TTV.

    In Paper III we investigated the expression of ERα, ERβ1 and ERβ2 in PBMC from patients with Nephropathia epidemica, the viral zoonotic disease caused by Puumala virus, a Hanta virus known to affect more men than women. Expression of ERs in PBMCs and clinical laboratory results during the acute and convalescent phases were analyzed using a principal component analysis (PCA). The results show differences in ER expression and support previous findings that men and women have a different clinical picture

    In conclusion, the results in this thesis reveal distinct patterns of immune response related to sex hormone levels, SHR expression and the phases of the menstrual cycle supporting that there a link between sex hormone levels and immune responses. Further, we show that the ER isoform ERβ2 is more abundant in PBMCs than what was previously described. The data in this thesis adds to the knowledge to the sex differences in immune response and exemplifies the importance of taking these differences into account in the clinic.

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  • 42.
    Brundin, Peik M.A.
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; S:t Görans Hospital, Dept of Medicine, Unit of Infectious Diseases, Stockholm, Sweden.
    Landgren, Britt-Marie
    Fjällström, Peter
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Anders F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nalvarte, Ivan
    Blood hormones and torque teno virus in peripheral blood mononuclear cells2020In: Heliyon, E-ISSN 2405-8440, Vol. 6, no 11, article id e05535Article in journal (Refereed)
    Abstract [en]

    Men and women respond differently to infectious diseases. Women show less morbidity and mortality, partially due to the differences in sex hormone levels which can influence the immune response. Torque teno virus (TTV) is non-pathogenic and ubiquitously present in serum from a large proportion (up to 90%) of adult humans with virus levels correlating with the status of the host immune response. The source of TTV replication is unknown, but T-lymphocytes have been proposed. In this study we investigated the presence and levels of TTV in peripheral blood mononuclear cells (PBMCs) in premenopausal (pre-MP) women, post-menopausal (post-MP) women, and men, and determined their serum sex hormone levels. Of the examined subjects (n = 27), we found presence of TTV in PMBC from 17.6% pre-MP (n = 17), 25.0% post-MP (n = 4) and 50.0% men (n = 6). The levels of TTV/μg DNA were lower among TTV-positive men and post-MP women compared to pre-MP women. All the positive pre-MP women were either anovulatory, hypothyroid, or both. In addition, the TTV-positive pre-MP women had significantly lower progesterone levels compared to TTV-negative pre-MP women. Although our study was performed on a limited number of subjects, the data suggests that TTV in PBMC is associated with an anovulatory menstrual cycle with low progesterone levels, and possibly with male sex.

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  • 43.
    Bråbäck, Lennart
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Department of Research and Development, Västernorrland County Council and Sundsvalls sjukhus, Sundsvall.
    Ekéus, Cecilia
    Lowe, Adrian J
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Murdoch Childrens Research Institute and Centre for MEGA Epidemiology , School of Population Health, The University of Melbourne, Melbourne, Australia.
    Hjern, Anders
    Confounding with familial determinants affects the association between mode of delivery and childhood asthma medication: a national cohort study2013In: Allergy, Asthma & Clinical Immunology, ISSN 1710-1484, E-ISSN 1710-1492, Vol. 9, no 1, p. 14-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mode of delivery may affect the risk of asthma but the findings have not been consistent and factors shared by siblings may confound the associations in previous studies. METHODS: The association between mode of delivery and dispensed inhaled corticosteroid (ICS) (a marker of asthma) was examined in a register based national cohort (n=199 837). A cohort analysis of all first born children aged 2-5 and 6-9 years was performed. An age-matched sibling-pair analysis was also performed to account for shared genetic and environmental risk factors. RESULTS: Analyses of first-borns demonstrated that elective caesarean section was associated with an increased risk of dispensed ICS in both 2-5 (adjusted odds ratio (aOR)=1.19, 95% confidence interval (CI) 1.09-1.29) and 6-9 (aOR=1.21, 1.09-1.34) age groups. In the sibling-pair analysis, the increased risk associated with elective caesarean section was confirmed in 2-5 year olds (aOR=1.22, 1.05-1.43) but not in 6-9 year olds (aOR=1.06, 0.78-1.44). Emergency caesarean section and vacuum extraction had some association with dispensed ICS in the analyses of first-borns but these associations were not confirmed in the sibling-pair analyses. CONCLUSIONS: Confounding by familial factors affects the association between mode of delivery and dispensed ICS. Despite this confounding, there was some evidence that elective caesarean section contributed to a modestly increased risk of dispensed ICS but only up to five years of age.

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  • 44.
    Bröms, Jeanette E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    IglG and IglI of the Francisella pathogenicity island are important virulence determinants of Francisella tularensis LVS2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 9, p. 3683-3696Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia, a disease intimately associated with the multiplication of the bacterium within host macrophages. This in turn requires the expression of Francisella pathogenicity island (FPI) genes, believed to encode a type VI secretion system. While the exact functions of many of the components have yet to be revealed, some have been found to contribute to the ability of Francisella to cause systemic infection in mice as well as to prevent phagolysosomal fusion and facilitate escape into the host cytosol. Upon reaching this compartment, the bacterium rapidly multiplies, inhibits activation of the inflammasome, and ultimately causes apoptosis of the host cell. In this study, we analyzed the contribution of the FPI-encoded proteins IglG, IglI, and PdpE to the aforementioned processes in F. tularensis LVS. The ΔpdpE mutant behaved similarly to the parental strain in all investigated assays. In contrast, ΔiglG and ΔiglI mutants, although they were efficiently replicating in J774A.1 cells, both exhibited delayed phagosomal escape, conferred a delayed activation of the inflammasome, and exhibited reduced cytopathogenicity as well as marked attenuation in the mouse model. Thus, IglG and IglI play key roles for modulation of the intracellular host response and also for the virulence of F. tularensis.

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  • 45.
    Bunne, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hedman, Linnea
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Perzanowski, Matthew
    Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, NY, New York, United States.
    Bjerg, Anders
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Winberg, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Lundbäck, Bo
    Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Platts-Mills, Thomas
    Division of Allergy & Clinical Immunology, University of Virginia, Va, Charlottesville, United States.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    The Majority of Children Sensitized Before School-Age Develop Allergic Disease Before Adulthood: A Longitudinal Population-Based Study2022In: Journal of Allergy and Clinical Immunology: In Practice, ISSN 2213-2198, E-ISSN 2213-2201, Vol. 10, no 2, p. 577-585.e3Article in journal (Refereed)
    Abstract [en]

    Background: Allergic sensitization increases the risk of asthma and allergic rhinitis, but the impact of age at onset of sensitization is less studied.

    Objective: To examine the cumulative incidence of asthma and rhinitis up to age 19 years in relation to age at onset of sensitization to airborne allergens.

    Method: All children in grade 1 and 2 (median age, 8 years) in 2 municipalities in Northern Sweden were invited to undergo skin prick tests and answer a questionnaire about allergic diseases, and 88% participated. At ages 12 and 19 years, the protocol was repeated, and 1510 individuals participated in all 3 examinations. Specific IgE data were collected in a random sample at age 19 years (n = 770). Onset of sensitization was defined: 8 years or less, 8 to 12 years, 12 to 19 years, and never sensitized. Adjusted Poisson regression was used to calculate risk ratios (RRs).

    Results: At 19 years, those sensitized at 8 years of age or earlier had the highest risk of asthma (RR, 4.68; 95% CI, 3.15-6.97) and rhinitis (RR, 22.3; 95% CI, 13.3-37.6), and 84% had developed either asthma or rhinitis. The combination of sensitization at age 8 years or earlier and family history of allergic diseases rendered high risks for asthma (RR, 10.6; 95% CI, 6.71-16.7) and rhinitis (RR, 36.3; 95% CI, 18.9-69.7). Individuals sensitized at age 8 years or earlier showed significantly highest level of sensitization, as judged by number of positive skin test results and titers of specific IgE.

    Conclusions: Most individuals with sensitization at age 8 years or earlier developed asthma or rhinitis before young adulthood. The high level of sensitization in those sensitized early contributes to the high incidence of allergic airway conditions.

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  • 46.
    Cagigi, Alberto
    et al.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Yu, Meng
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Österberg, Björn
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Julia
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Falck-Jones, Sara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Vangeti, Sindhu
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Åhlberg, Eric
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Azizmohammadi, Lida
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Warnqvist, Anna
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Falck-Jones, Ryan
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Gubisch, Pia C.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ödemis, Mert
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ghafoor, Farangies
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Eisele, Mona
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Lenart, Klara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bell, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Johansson, Niclas
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Albert, Jan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Microbiology, Karolinska University Laboratory, Karolinska University Hospital Solna, Stockholm, Sweden.
    Sälde, Jörgen
    Närakut SLSO, Karolinska University Hospital Solna, Stockholm, Sweden.
    Pettie, Deleah D.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Murphy, Michael P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Carter, Lauren
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    King, Neil P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Ols, Sebastian
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Forsell, Mattias N.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Färnert, Anna
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Loré, Karin
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Smed-Sörensen, Anna
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination2021In: JCI Insight, ISSN 2379-3708, Vol. 6, no 22, article id e151463Article in journal (Refereed)
    Abstract [en]

    Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.

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  • 47.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindström, Richard
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lundqvist, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Asking about condom use: a key to individualized care when screening for chlamydia2011In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 22, no 8, p. 436-441Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis (CT) infection has been a target for both selective and national screening programmes, and Sweden has an opportunistic approach. A national plan of action states that risk groups should be identified and offered risk reduction counselling. Patients attending a drop-in sexually transmitted infection (STI) clinic reception at the University Hospital, Umeå, Sweden, were invited to complete a questionnaire regarding sociodemographic characteristics, symptoms and sexual risk behaviour; all had a CT test taken. A total of 1305 patients were included, 58% men, mean age 27.8 years. CT prevalence was 11%; 51% of those with CT were ≥ 25 years old. Only 5% used a condom during the entire sexual intercourse with their last new/temporary partner. Sexually active inconsistent condom users comprised 62% of the study population and contributed to 81% of the chlamydia infections. Asking whether a condom was used could quickly triage patients into groups with a 'higher risk' (none or inconsistent use of condoms and at least one new/temporary partners), and 'lower risk' (with more consistent condom use, although not always accurate) allowing for individualized care and counselling when screening for chlamydia. Evaluating whether a condom was used throughout the sexual intercourse did not add any useful information.

  • 48.
    Casabona, Giacomo
    et al.
    GSK, Wavre, Belgium.
    Habib, Md Ahsan
    GSK, Wavre, Belgium.
    Povey, Michael
    GSK, Wavre, Belgium.
    Riise Bergsaker, Marianne A.
    The Norwegian Institute of Public Health, Oslo, Norway.
    Flodmark, Carl-Erik
    Department of Paediatrics, Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Espnes, Ketil Arne
    Risvollan Legesenter, Trondheim, Norway; Department of Clinical Pharmacology, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway.
    Tøndel, Camilla
    Department of Paediatrics, Haukeland University Hospital, Bergen, Norway.
    Silfverdal, Sven-Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Randomised controlled trial showed long-term efficacy, immunogenicity and safety of varicella vaccines in Norwegian and Swedish children2022In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 111, no 2, p. 391-400Article in journal (Refereed)
    Abstract [en]

    Aim: Several countries, such as Norway and Sweden, have not implemented universal varicella vaccination. We present data for Norway and Sweden that were generated by a paediatric multi-country Phase III study over a 10-year period. This assessed the efficacy, antibody persistence and safety of two varicella vaccines containing the same Oka strain.

    Methods: This was an observer-blind, controlled trial conducted in 10 European countries. Children aged 12–22 months (n = 5803) were randomised 3:3:1 and vaccinated between 1 September 2005 and 10 May 2006. The two-dose group received two tetravalent measles-mumps-rubella-varicella vaccine doses. The one-dose group received one monovalent varicella vaccine dose after a measles-mumps-rubella vaccine dose. Control group participants received two measles-mumps-rubella vaccine doses. Main study outcomes were vaccine efficacy against confirmed varicella cases and incidence of adverse events.

    Results: Vaccine efficacy in the two-dose group was ≥92.1% in both Norwegian and Swedish children compared to 72.3% in Norway and 58.0% in Sweden in the one-dose group. Incidences of adverse events and serious adverse events were similar in the Norwegian and Swedish study populations.

    Conclusion: Consistent with overall study results, high efficacy against varicella and acceptable safety profiles of the two varicella vaccines were observed in Norwegian and Swedish populations. These findings highlight the benefits of varicella vaccines, particularly when administered as a two-dose schedule.

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  • 49.
    Castro Dopico, Xaquin
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Muschiol, Sandra
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Grinberg, Nastasiya F.
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom.
    Aleman, Soo
    Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden.
    Sheward, Daniel J.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hanke, Leo
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Ahl, Marcus
    Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden.
    Vikström, Linnea
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Coquet, Jonathan M.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    McInerney, Gerald
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Dillner, Joakim
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Bogdanovic, Gordana
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom.
    Murrell, Ben
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Albert, Jan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Wallace, Chris
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Probabilistic classification of anti-SARS-CoV-2 antibody responses improves seroprevalence estimates2022In: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 11, no 3, article id e1379Article in journal (Refereed)
    Abstract [en]

    Objectives: Population-level measures of seropositivity are critical for understanding the epidemiology of an emerging pathogen, yet most antibody tests apply a strict cutoff for seropositivity that is not learnt in a data-driven manner, leading to uncertainty when classifying low-titer responses. To improve upon this, we evaluated cutoff-independent methods for their ability to assign likelihood of SARS-CoV-2 seropositivity to individual samples. Methods: Using robust ELISAs based on SARS-CoV-2 spike (S) and the receptor-binding domain (RBD), we profiled antibody responses in a group of SARS-CoV-2 PCR+ individuals (n = 138). Using these data, we trained probabilistic learners to assign likelihood of seropositivity to test samples of unknown serostatus (n = 5100), identifying a support vector machines-linear discriminant analysis learner (SVM-LDA) suited for this purpose. Results: In the training data from confirmed ancestral SARS-CoV-2 infections, 99% of participants had detectable anti-S and -RBD IgG in the circulation, with titers differing > 1000-fold between persons. In data of otherwise healthy individuals, 7.2% (n = 367) of samples were of uncertain serostatus, with values in the range of 3-6SD from the mean of pre-pandemic negative controls (n = 595). In contrast, SVM-LDA classified 6.4% (n = 328) of test samples as having a high likelihood (> 99% chance) of past infection, 4.5% (n = 230) to have a 50–99% likelihood, and 4.0% (n = 203) to have a 10–49% likelihood. As different probabilistic approaches were more consistent with each other than conventional SD-based methods, such tools allow for more statistically-sound seropositivity estimates in large cohorts. Conclusion: Probabilistic antibody testing frameworks can improve seropositivity estimates in populations with large titer variability.

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  • 50. Cerveny, Lukas
    et al.
    Straskova, Adela
    Dankova, Vera
    Hartlova, Anetta
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ceckova, Martina
    Staud, Frantisek
    Stulik, Jiri
    Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 3, p. 629-635Article, review/survey (Refereed)
    Abstract [en]

    The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while high-lighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.

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