Change search
Refine search result
6789101112 401 - 450 of 1286
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 401.
    Gustafsson, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordström, Eva
    BioArct AB, Stockholm.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes2017In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, article id 241Article in journal (Refereed)
    Abstract [en]

    Background: Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson’s disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria.

    Methods: The aim of the present study was to investigate if the accumulation of α-syn in astrocytes can be affected by α-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to α-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies.

    Results: In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added α-syn, and consequently, the α-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer-induced mitochondrial impairment.

    Conclusions: Our results demonstrate that oligomer-selective antibodies can prevent α-syn accumulation and mitochondrial dysfunction in cultured astrocytes.

  • 402. Gustafsson, Johanna T
    et al.
    Gunnarsson, Iva
    Källberg, Henrik
    Pettersson, Susanne
    Zickert, Agneta
    Vikerfors, Anna
    Möller, Sonia
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Elvin, Kerstin
    Svenungsson, Elisabet
    Cigarette smoking, antiphospholipid antibodies and vascular events in Systemic Lupus Erythematosus2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 8, p. 1537-1543Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Smoking can induce autoantibodies in persons who are genetically predisposed to rheumatoid arthritis. We investigated the association between smoking and antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE), a question not previously addressed. Further, we explored the relationship between smoking, aPL and vascular events (arterial and venous, VE).

    METHODS: In this cross-sectional study, clinical evaluation and questionnaire data were collected from 367 prevalent SLE patients. At the same time, we measured aPL (anticardiolipin (aCL), anti-β2 glycoprotein-1 (aβ2GP1) antibodies IgG/IgM/IgA, and lupus anticoagulant (LA)), and a large set of other SLE-associated autoantibodies for comparison. Association analyses using logistic regression models with smoking, (ever, former and current with never as reference) and antibody status as outcome variable were performed. As a secondary outcome, we investigated the associations between aPL, smoking and VE.

    RESULTS: In multivariable-adjusted models ever, and in particular former, cigarette smoking was associated with the most pathogenic aPL; LA, aCL IgG and aβ2GP1 IgG. Other SLE-associated autoantibodies were not associated with smoking. The combination of smoking and aPL was strongly associated with VE. We noted a positive interaction between smoking-LA and smoking-'triple aPL' positivity for previous VE.

    CONCLUSIONS: We investigated a large set of commonly occurring autoantibodies in SLE, but only aPL were positively associated with a history of smoking. This association was especially apparent in former smokers. Among ever regular smokers who were aPL positive, we observed a strikingly high frequency of former VE. The underlying mechanisms and temporality between smoking, aPL and VE need further investigations.

  • 403.
    Gustafsson, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Calounova, Gabriela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hjelm, Fredrik
    Kriz, Vitezslav
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grönvik, Kjell-Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mostoslavsky, Gustavo
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells2011In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 12, p. 3-Article in journal (Refereed)
    Abstract [en]

    Background: Shb, a ubiquitously expressed Src homology 2 domain-containing adaptor protein has previously been implicated in the signaling of various tyrosine kinase receptors including the TCR. Shb associates with SLP76, LAT and Vav, all important components in the signaling cascade governing T cell function and develeopment. A Shb knockout mouse was recently generated and the aim of the current study was to address the importance of Shb deficiency on T cell development and function.

    Results: Shb knockout mice did not display any major changes in thymocyte development despite an aberrant TCR signaling pattern, including increased basal activation and reduced stimulation-induced phosphorylation. The loss of Shb expression did however affect peripheral CD4+ TH cells resulting in an increased proliferative response to TCR stimulation and an elevated IL-4 production level of naïve TH cells. This suggests a TH2 skewing of the Shb knockout immune system, seemingly caused by an altered TCR signaling pattern.

    Conclusion: Our results indicate that Shb appears to play an important modulating role on TCR signaling, thus regulating the peripheral CD4+ TH2 cell response.

  • 404.
    Gustafsson, Lars
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution. Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Nordling, Dag
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution. Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Andersson, Måns Sverker
    Sheldon, Ben C.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution. Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Qvarnström, Anna
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution. Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Infectious disease, reproductive effort and the cost of reproduction in birds1994In: Philosophical transactions of the Royal Society of London: Series B, no 346, p. 1655-1658Article in journal (Other (popular scientific, debate etc.))
    Abstract [en]

    Reproductive effort can have profound effects on subsequent performance. Field experiments on the collared flycatcher (Ficedula albicollis) have demonstrated a number of trade-offs between life-history traits at different ages. The mechanism by which reproductive effort is mediated into future reproductive performance remains obscure. Anti-parasite adaptations such as cell-mediated immunity may probably also be costly. Hence the possibility exists of a trade-off between reproductive effort and the ability to resist parasitic infection. Serological tests on unmanipulated collared flycatchers show that pre-breeding nutritional status correlates positively with reproductive success and negatively with susceptibility to parasitism (viruses, bacteria and protozoan parasites). Both immune response and several indicators of infectious disease correlate negatively with reproductive success. Similar relations are found between secondary sexual characters and infection parameters. For brood-size-manipulated birds there was a significant interaction between experimentally increased reproductive effort and parasitic infection rate with regard to both current and future fecundity. It seems possible that the interaction between parasitic infection, nutrition and reproductive effort can be an important mechanism in the ultimate shaping of life-history variation in avian populations.

  • 405.
    Gustafsson Lidström, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Local Immune regulation in human pregnancy: with focus on decidual macrophages2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During pregnancy, the woman carries a fetus partly foreign to her immune system, because of the expression of paternal antigens. Despite this, the fetus is normally tolerated and not rejected, as is often the case with organs in allogeneic transplantations. Systemic changes in maternal blood occur during pregnancy but, perhaps of greater importance, are changes in tissues locally in the uterus. The pregnant uterine endometrium, the decidua, is infiltrated by large numbers of leukocytes, mainly natural killer (NK) cells but also macrophages and T lymphocytes. Further, various cytokines are known to be secreted at the fetomaternal interface. However, the functions of these cells and the cytokine networks are not fully understood. The aim of this thesis was to investigate the local immune balance in normal human pregnancy decidua, both in the early phase of pregnancy and at parturition.

    First trimester decidual mononuclear cells, NK cells and macrophages were all shown to secrete IFN-γ, IL-4 and IL-10, as detected by ELISPOT. The secretion was not mirrored in blood from the same subjects. A significantly larger number of decidual macrophages secreted IL-10 than did their blood counterparts, indicating potential regulatory functions of this cell type.

    Further examination of early pregnancy decidual macrophages by microarray revealed 120 genes being differentially regulated at the transcriptional level in decidual compared to blood monocytes/macrophages. Several genes were associated with alternative activation/M2 polarization of macrophages, including CCL-18, CD209, IGF-1, MRC-1 and FN-1. Genes connected to immune regulation and tissue remodelling were common, in line with the potential functions for this cell type in utero. In addition, some molecules not previously connected to decidual macrophages, such as TREM-2, A2M and PGDS, were found to be upregulated, gaining new insights into the regulatory functions of decidual macrophages.

    Term decidual mononuclear cells spontaneously secrete IFN-γ, TNF, IL-4, IL-10, and TGF-β. No differences were seen between tissues obtained before and after the onset of labour, indicating that decidual mononuclear cells are not the main cell population responsible for plausible cytokine regulation in the process of labour induction. Placental and fetal membranes as well as cells in the maternal systemic circulation may instead contribute to a possible shift in immune balance prior to pregnancy termination.

    In conclusion, decidual leukocytes, including NK cells and macrophages, are potential producers of both Th1-like/pro-inflammatory and Th2-like/anti-inflammatory cytokines in early pregnancy as well as at parturition. Decidual macrophages are of a specialized phenotype with effector functions contributing to a proper invasion of the placenta and to immunological protection of the semi-allogeneic fetus. This thesis adds new knowledge on local immune balance during normal human pregnancy, however, the clinical significance of the presented data needs to be clarified.

  • 406.
    Gyllenfjärd, Sabina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Quantification of Tripeptidyl-peptidase II: Optimisation and evaluation of 3 assays2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Abstract

     

    Tripeptidyl-peptidase II (TPPII), is present in most eukaryotic cells. It cuts tripeptides from the N-terminus of peptides and is especially important for degrading peptides longer than 15 amino acids. TPPII also tailors long peptides into suitable substrates for the enzymes which transport and produce the peptides that MHC I present. Increased levels of TPPII have also been found in certain cancer cells, thus it is of interest to determine if TPPII could be used as a tumour marker.

    The aim of this study was to optimise and evaluate 3 different methods for quantifying TPPII. Western blot, enzyme-linked immunosorbent assay (ELISA) and fluorophore-linked immunosorbent assay (FLISA) protocols were optimised regarding incubation times and antibody dilutions. Sensitivity and linearity were the most important parameters when evaluating the results. The coefficient of determination of western blot was R2=0.98-1 within the range of 1.29-250ng TPPII/well and ELISA had a coefficient of determination of R2=0.96 within the range of 0.03-250ng TPPII/well. Presently western blot is the only one of these methods to yield reliable results with impure samples, but ELISA is superior regarding sensitivity and throughput. Thus further optimisation of ELISA is interesting to pursue.

  • 407. Gyuranecz, Miklos
    et al.
    Birdsell, Dawn N.
    Splettstoesser, Wolf
    Seibold, Erik
    Beckstrom-Sternberg, Stephen M.
    Makrai, Laszlo
    Fodor, Laszlo
    Fabbi, Massimo
    Vicari, Nadia
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Busch, Joseph D.
    Vogler, Amy J.
    Keim, Paul
    Wagner, David M.
    Phylogeography of Francisella tularensis subsp holarctica, Europe2012In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 2, p. 290-293Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis subsp. holarctica isolates from Austria, Germany, Hungary, Italy, and Romania were placed into an existing phylogeographic framework. Isolates from Italy were assigned to phylogenetic group B.FTNF002-00; the other isolates, to group B.13. Most F tularensis subsp. holarctica isolates from Europe belong to these 2 geographically segregated groups.

  • 408. Göranson, Sofie Paues
    et al.
    Thålin, Charlotte
    Lundström, Annika
    Hållström, Lars
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Wallén, Håkan
    Soop, Anne
    Mobarrez, Fariborz
    Circulating H3Cit is elevated in a human model of endotoxemia and can be detected bound to microvesicles2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12641Article in journal (Refereed)
    Abstract [en]

    Early diagnosis of sepsis is crucial since prompt interventions decrease mortality. Citrullinated histone H3 (H3Cit), released from neutrophil extracellular traps (NETs) upon binding of platelets to neutrophils following endotoxin stimulation, has recently been proposed a promising blood biomarker in sepsis. Moreover, microvesicles (MVs), which are released during cell activation and apoptosis and carry a variety of proteins from their parental cells, have also been shown to be elevated in sepsis. In a randomized and placebo-controlled human model of endotoxemia (lipopolysaccharide injection; LPS), we now report significant LPS-induced elevations of circulating H3Cit in 22 healthy individuals. We detected elevations of circulating H3Cit by enzyme-linked immunosorbent assay (ELISA), as well as bound to MVs quantified by flow cytometry. H3Cit-bearing MVs expressed neutrophil and/or platelet surface markers, indicating platelet-neutrophil interactions. In addition, in vitro experiments revealed that H3Cit can bind to phosphatidylserine exposed on platelet derived MVs. Taken together; our results demonstrate that NETs can be detected in peripheral blood during endotoxemia by two distinct H3Cit-specific methods. Furthermore, we propose a previously unrecognized mechanism by which H3Cit may be disseminated throughout the vasculature by the binding to MVs.

  • 409. Göranzon, C.
    et al.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok Kumar
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Eriksson, J.
    Bohr, J.
    Nyhlin, Nils
    Immunohistokemisk karakterisering av lymfocyter vid microscopisk kolit2011In: Gastrokuriren, ISSN 1651-0453, Vol. 16, no 29, p. PO16-PO16Article in journal (Other academic)
  • 410. Göranzon, C.
    et al.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok Kumar
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Eriksson, S.
    Bohr, Johan
    Nyhlin, Nils
    Immunohistochemical characterization of lymphocytes in microscopic colitis2010Conference paper (Other academic)
  • 411.
    Günaltay, Sezin
    Örebro University, School of Medical Sciences.
    Dysregulated mucosal immune responses in microscopic colitis patients2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

  • 412.
    Hadad, Ronza
    et al.
    WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, , Örebro University Hospital, Örebro, Sweden.
    Lagos, Amaya C.
    WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Ljungberg, Johan
    Department of Infectious Diseases, Hospital of Halmstad, Halmstad, Sweden.
    Nilsson, Peter
    Department of Clinical Microbiology & Infection Control, Hospital of Halmstad, Halmstad, Sweden.
    Jensen, Jörgen S.
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Fredlund, Hans
    WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Macrolide and fluoroquinolone resistance in Mycoplasma genitalium in two Swedish counties, 2011-20152018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 2, p. 123-127Article in journal (Refereed)
    Abstract [en]

    Mycoplasma genitalium, causing non-gonococcal non-chlamydial urethritis and associated with cervicitis, has developed antimicrobial resistance (AMR) to both the macrolide azithromycin (first-line treatment) and the fluoroquinolone moxifloxacin (second-line treatment). Our aim was to estimate the prevalence of resistance, based on genetic AMR determinants, to these antimicrobials in the M. genitalium population in two Swedish counties, Örebro and Halland, 2011-2015. In total, 672 M. genitalium positive urogenital samples were sequenced for 23S rRNA and parC gene mutations associated with macrolide and fluoroquinolone resistance, respectively. Of the samples, 18.6% and 3.2% in Örebro and 15.2% and 2.7% in Halland contained mutations associated with macrolide and fluoroquinolone resistance, respectively. The predominating resistance-associated mutations in the 23S rRNA gene was A2059G (n = 39) in Örebro and A2058G (n = 13) and A2059G (n = 13) in Halland. The most prevalent possible resistance-associated ParC amino acid alterations were S83I (n = 4) in Örebro and S83N (n = 2) in Halland. Resistance-associated mutations to both macrolides and fluoroquinolones were found in 0.7% of samples. Our findings emphasize the need for routine AMR testing, at a minimum for macrolide resistance, of all M. genitalium-positive samples and regular national and international surveillance of AMR in M. genitalium, to ensure effective patient management and rational antimicrobial use.

  • 413.
    Hadad, Ronza
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Pizza, Mariagrazia
    Novartis V&D, Siena, Italy.
    Rappuoli, Rino
    Novartis V&D, Siena, Italy.
    Fredlund, Hans
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Novel meningococcal 4CMenB vaccine antigens - prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 9, p. 750-760Article in journal (Refereed)
    Abstract [en]

    The first cross-protective Neisseria meningitidis vaccine (focus on serogroup B), the protein-based 4 component meningococcus serogroup B (4CMenB), includes the New Zealand outer membrane vesicle and three main genome-derived neisserial antigens (GNAs). These GNAs are fHbp (fused to GNA2091), NHBA (fused to GNA1030) and NadA. In this study, the prevalence and polymorphisms of the nucleotide and amino acid sequences of the 4CMenB antigens in a temporally and geographically diverse collection of N. gonorrhoeae isolates (n similar to=similar to 111) were investigated. All the examined GNA genes, except the nadA gene, were present in all gonococcal isolates. However, 25 isolates contained premature stop codons in the fHbp gene and/or the nhba gene, resulting in truncated proteins. Compared with the 4CMenB antigen sequences in reference strain MC58, the gonococcal strains displayed 67.095.4% and 60.994.9% identity in nucleotide sequence and amino acid sequence, respectively, in the equivalent GNA antigens. The absence of NadA, lack of universal expression of fHbp and NHBA and the uncertainty regarding the surface exposure of fHbp as well as the function of NHBA in N. gonorrhoeae will likely limit the use of the identical 4CMenB antigens in a gonococcal vaccine. However, possible cross-immunity of 4CMenB with gonococci and expression and function of the equivalent gonococcal GNAs, as well as of more appropriate GNAs for a gonococcal vaccine, need to be further examined.

  • 414.
    Hadad, Ronza
    et al.
    Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden; Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Marks, Ellen
    Department of Medical Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Kalbina, Irina
    Örebro University, School of Science and Technology. Örebro Life Science Center, Örebro University, Örebro, Sweden.
    Schön, Karin
    Department of Medical Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Lycke, Nils
    Department of Medical Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology. Örebro Life Science Center, Örebro University, Örebro, Sweden.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Protection against genital tract Chlamydia trachomatis infection following intranasal immunization with a novel recombinant MOMP VS2/4 antigen2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, p. 1078-1086Article in journal (Refereed)
    Abstract [en]

    The asymptomatic nature of most Chlamydia trachomatis infections and the lack of appropriate effects by current prevention and management call for vaccine development. We evaluated a recombinant subunit vaccine candidate based on the major outer membrane protein variable segments 2 and 4 (MOMP VS2/4). To achieve maximal immunogenicity and ease of production and purification, MOMP VS2/4 was constructed by using highly immunogenic sequences of MOMP only, thereby minimizing the presence of hydrophobic regions, and spacing the immunogenic epitopes with a flexible amino acid sequence. A purification tag was also added. The MOMP VS2/4 was given intranasally, with or without intravaginal boost, with cholera toxin (CT) adjuvant to C57BL/6 mice, which were screened for immunogenicity and protection against a live challenge infection with C. trachomatis serovar D. Bacterial shedding, cell-mediated responses, and antibody responses were monitored. Immunized mice exhibited significantly less bacterial shedding and were better protected against infertility as compared to unimmunized control mice. Immunizations stimulated both systemic and local specific antibody (IgG1, IgG2c, and IgA) responses, and primed T cells that produced interferon-c and interleukins 13 and 17 upon challenge with recall antigen. Thus, MOMP VS2/4, in combination with CT adjuvant, stimulated Th1, Th2, and Th17 effector cells, and generated protective immunity associated with less pathology. We regard MOMP VS2/4 as a promising candidate for further development into a mucosal chlamydial vaccine.

  • 415.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. niklas.hagberg@medsci.uu.se.
    Theorell, Jakob
    Hjorton, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bryceson, Yenan
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Autoantibodies to the CD94/NKG2A and CD94/NKG2C receptors in patients with systemic lupus erythematosusManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: To investigate the occurrence and function of autoantibodies (autoabs) targeting the CD94/NKG2A, CD94/NKG2C or NKG2D receptors in patients with systemic lupus erythematosus (SLE).

    Method: Murine Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C or NKG2D, and untransfected cells were incubated with sera from 203 patients with SLE and 90 healthy individuals. Binding of immunoglobulin (Ig) to the cells was determined by flow cytometry. Autoabs were characterized with regard to isotype, subclass, λ/κ exclusion and interference with HLA-E-binding. IgG were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 target cells, as well as their capacity to induce antibody-dependent cellular cytotoxicity (ADCC). The frequency and phenotype of NK cells from these patients were determined by flow cytometry and the exons encoding NKG2A (KLRC1), NKG2C (KLRC2) and CD94 (KLRD1) were sequenced. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were determined in longitudinally sampled sera and correlated to disease activity (SLEDAI score) and severity (SLICC/ACR damage index).

    Results: Seven patients with autoabs targeting the CD94/NKG2A receptor were identified. Two of these patients’ autoabs also recognized the CD94/NKG2C receptor. IgG from six of the patients interfered with the binding of HLA-E to CD94/NKG2A, whereas IgG from one patient increased this binding. Of the two patients with anti-CD94/NKG2C autoabs, IgG from one patient blocked, and IgG from the other patient stabilized the binding of HLA-E to CD94/NKG2C. Anti-CD94/NKG2A autoabs abrogated the HLA-E-mediated inhibition of NK cell cytotoxicity by CD94/NKG2A+ NK cells, whereas anti-CD94/NKG2C autoabs interfered with the HLA-E-mediated increased cytotoxicity of CD94/NKG2C+ NK cells. Furthermore, these autoabs induced ADCC of CD94/NKG2A- and CD94/NKG2C-expressing target cells. No uncommon non-synonymous sequence variations were found in the genes encoding NKG2A, NKG2C or CD94.  The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were associated to the SLEDAI score.

    Conclusions: Autoabs targeting the CD94/NKG2A or the CD94/NKG2C receptor are found in a subset of patients with SLE. These autoabs affects the cytotoxicity of NK cells, mediate ADCC in vitro and their titers are associated to the disease activity and a more severe SLE phenotype. Consequently, anti-CD94/NKG2A and anti-CD94/NKG2C autoabs may contribute to the pathogenesis of SLE and our findings highlight the possible importance of NK cells in the SLE disease process.

  • 416.
    Hahn-Strömberg, Victoria
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Section for Pathology, Örebro University Hospital, Örebro, Sweden.
    Askari, Shlear
    Department of Laboratory Medicine, Section for Pathology, Örebro University Hospital, Örebro, Sweden.
    Befekadu, Rahel
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Section for Pathology, Örebro University Hospital, Örebro, Sweden.
    Matthiessen, Peter
    Örebro University Hospital. Department of Clinical Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Sune
    Örebro University, Örebro University School of Business.
    Nilsson, Torbjorn K.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 7, p. 636-642Article in journal (Refereed)
    Abstract [en]

    Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue-specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease.

  • 417.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    THE INFLUENCE OF LACTOBACILLI AND STAPHYLOCOCCUS AUREUS ON IMMUNE RESPONSIVENESS IN VITRO2013Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alteration of gut microbiota has been associated with development of immune mediated diseases, such as allergy. In part, this could be due to the influence of microbes in shaping the immune response. In paper I, we investigated the association of early-life gut colonization with bacteria, and numbers of IL-4, IL-10 and IFN-γ producing cells at two years of age in response to PBMC stimulation with phytohemagglutinin (PHA) in vitro. Early Staphylococcus (S) aureus colonization was directly proportional to increased numbers of IL-4 and IL-10 secreting cells, while early co-colonization with lactobacilli and S. aureus associated with a decrease in IL-4, IL-10 and IFN-γ secreting cells compared to S. aureus alone. This was also confirmed in in vitro stimulations of PBMC with Lactobacillus and/or S. aureus strains, where S. aureus-induced IFN-γ production by Th cells was down regulated by co-stimulation with Lactobacillus. In paper II, we investigated the effects of UV-killed and/or culture supernatant (sn) of Lactobacillus strains and S. aureus strains on IEC and immune cell responses. IEC exposed to S. aureus-sn produced CXCL-1/GRO-α and CXCL-8/IL-8, while UV-killed bacteria had no effect. Further, PBMC from healthy donors exposed to Lactobacillus-sn and S. aureus-sn were able to produce a plethora of cytokines, but only S. aureus induced the T-cell associated cytokines: IL-2, IL-17, IFN-γ and TNF-α; which were down regulated by co-stimulation with any of the different Lactobacillus strains. Intracellular staining verified S. aureus-induced IFN-γ and IL-17 production by Th cells, and increased CTLA-4 expression and IL-10 production by T reg cells.

    In conclusion, we show that colonization with gut microbiota at early age modulates the cytokine response in infancy. In addition, bacterial species influence cytokine response in a species-specific manner and we demonstrate that lactobacilli modulate S. aureus-induced immune response away from an inflammatory phenotype.

  • 418. Hales, B. J.
    et al.
    Hizawa, N.
    Jenmalm, M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wardlaw, A. J.
    Developments in the field of allergy in 2014 through the eyes of Clinical and Experimental Allergy2015In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 45, no 12, p. 1723-1745Article, review/survey (Refereed)
    Abstract [en]

    The pathogenesis of asthma continues to be a major topic of interest to our authors with reviews and original papers on the role of viruses, mechanisms of inflammation, biomarkers, and phenotypes of asthma being major topics. A number of papers described new treatments for asthma focusing on blocking the Th2 response reflecting the fact that two decades of work in this area is finally bearing fruit. The pathogenesis of chronic rhinosinusitis is a growing area of interest, but there has been less on the genetics of airways disease than in previous years possibly reflecting the degree of rigour (and therefore a smaller body of work), with which these sorts of studies are now being undertaken. There continues to be a wide range of papers dealing with mechanisms of allergic disease ranging from clinical-based studies to basic research and the use of in vivo animal models especially mice. As before, mechanisms and new approaches to immunotherapy are common themes. Several were published in the allergens section investigating modification of allergens to increase their effectiveness and reduce the risk of adverse events. Risk factors for allergic disease was a common theme in the epidemiology section and food allergy a common theme in clinical allergy with papers on the development of protocols to induce tolerance and attempts to find biomarkers to distinguish sensitization from allergic disease. This was another exciting year for the editors, and we hope the readers of the journal.

  • 419.
    Hallander, Hans
    et al.
    Swedish Institute for Infectious Disease Control.
    Andersson, Mikael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Gustafsson, Lennart
    Swedish Institute for Infectious Disease Control.
    Ljungman, Margaretha
    Swedish Institute for Infectious Disease Control.
    Netterlid, Eva
    Swedish Institute for Infectious Disease Control.
    Seroprevalence of pertussis antitoxin (anti-PT) in Sweden before and 10 years after the introduction of a universal childhood pertussis vaccination program2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 12, p. 912-922Article in journal (Refereed)
    Abstract [en]

    The prevalence of IgG ELISA antibodies against pertussis toxin (anti-PT) was studied in two Swedish seroepidemiological studies. One was performed in 1997 when the new pertussis vaccination program was 1 year old (n = 3420). In 2007, when Pa vaccines had been used countrywide for 10 years in the universal child vaccination program, this study was repeated to analyze the effect of vaccination on anti-PT prevalence (n = 2379). Before the statistical analysis of seroprevalence, children vaccinated within the last 2 years before the serosurveys were excluded. The results indicate a reduced exposure to Bordetella pertussis in the population. The proportion of sera without measurable anti-PT antibodies increased significantly, aggregated over all comparable age groups, from 3.8% in people sampled in 1997 to 16.3% in people sampled in 2007. For cord blood, 1% was without measurable anti-PT antibodies in 1997 compared to a significantly higher level, 12%, in 2007. With anti-PT concentrations of ≥50 and ≥100 EU/ml as cutoff points for 'recent infection' the proportion above the cutoff points for younger children was significantly higher in 1997 than in 2007 at both cutoff points. For all adults, 20 years of age and older, the difference in proportions above the lower cutoff point was close to statistically significant, comparing 1997 with 2007. This was not the case at 100 EU/ml. In the 1997 samples of children, there was a significant downward trend of 'recent infections' at both cutoff points for three sampled age groups between 5 and 15 years of age from 21% at 5.0–5.5 years of age to 7% at 14.7–15.7 years for the lowest cutoff. In the 2007 samples of children, on the contrary, there was a significant continuous upward trend of 'recent infections', at both cutoff points, for four sampled age groups between 4 and 18 years of age – from 4% at 4–5 years of age to 16% at 17–18 years at the lowest cutoff. The continuous increase, with age of children with high anti-PT concentrations, supports the recent change in the general Swedish childhood vaccination program to include a pre-school booster at 5–6 years and a school-leaving booster at 14–16 years of age.

  • 420. Hallböök, H
    et al.
    Hägglund, H
    Stockelberg, D
    Nilsson, P-G
    Karlsson, K
    Björkholm, M
    Linderholm, M
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Linder, O
    Smedmyr, B
    Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience2005In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 35, no 12, p. 1141-1148Article in journal (Refereed)
    Abstract [en]

    Adult patients with acute lymphoblastic leukaemia (ALL) have been treated according to national protocols in Sweden since 1986. Stem cell transplantation (SCT) has been recommended in first remission for patients with risk factors for relapse, and for standard risk patients only after relapse. In this retrospective study, the results of autologous and allogeneic SCT in these populations were evaluated. In total, 187 patients with a median age of 34 years (17-66 years) underwent SCT. The 5-year disease-free survival (DFS), for all patients, was 26% (Confidence intervals (CI) 20-32%). The 5-year DFS was higher for patients transplanted in first remission 32% (CI 24-40%) compared to 14% (CI 5-23%; P<0.0001) in patients transplanted beyond first remission. No significant differences in DFS (P=0.06) were determined between autologous, related donor and unrelated donor SCT in the whole cohort. A lower relapse rate was counterbalanced by higher treatment-related mortality in patients undergoing allogeneic SCT. In Philadelphia-positive ALL, allogeneic SCT was superior to autologous SCT, with a 5-year DFS of 30% (CI 12-47%) vs 0% (P=0.04). Limited chronic graft-versus-host-disease (GVHD) was associated with an improved DFS of 53% (CI 38-69%) compared to no chronic GVHD of 22% (CI 10-36%; P=0.0008), indicating a clinically important graft-versus-leukaemia effect.

  • 421.
    Halova, Ivana
    et al.
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Rönnberg, Elin
    Karolinska Univ Hosp, Karolinska Inst & Clin Immunol & Transfus Med, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden.
    Draberova, Lubica
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Vliagoftis, Harissios
    Karolinska Univ Hosp, Karolinska Inst & Clin Immunol & Transfus Med, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden; Univ Alberta, Alberta Resp Ctr, Edmonton, AB, Canada; Univ Alberta, Dept Med, Edmonton, AB, Canada.
    Nilsson, Gunnar P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Draber, Petr
    Czech Acad Sci, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic.
    Changing the threshold-Signals and mechanisms of mast cell priming2018In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 282, no 1, p. 73-86Article in journal (Refereed)
    Abstract [en]

    Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2, sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.

  • 422.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Crosstalk Between Activated Platelets and the Complement System2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Several studies have shown that complement and thrombotic events co-exist. Platelets have been suspected to act as the bridge between the two cascade systems.

    To study the platelet-induced complement activation we developed a system in which platelets were activated by thrombin receptor activating peptide (TRAP) in platelet rich plasma (PRP) or whole blood anti-coagulated using the specific thrombin inhibitor, lepirudin.

    TRAP-activated platelets induced a fluid-phase complement activation measured as generation of C3a and sC5b-9, triggered by released chondroitin sulphate-A (CS-A) which interacted with C1q and activated the complement system through the classical pathway.

    Complement components C1q, C3, C4 and C9 were also shown to bind to TRAP-activated platelets but this binding did not seem to be due to a complement activation since blocking of complement activation at the C1q or C3 levels did not affect the binding of the complement proteins. The C3 which bound to activated platelets consisted of C3(H2O), indicating that bound C3 was not proteolytically activated. Binding of C1q was partially dependent on CS-A exposure on activated platelets. The abolished complement activation on the surface of activated platelets was suggested to be dependent on the involvement of several complement inhibitors. We confirmed the binding of C1INH and factor H to activated platelets. To this list we have added another potent complement inhibitor, C4BP. The binding of factor H and C4BP was shown to be dependent on exposure of CS-A on activated platelets.

    The physiological relevance of these reactions was reflected in an elevated expression of CD11b on leukocytes, and increased generation of platelet-leukocyte complexes. The platelets were involved in these events by at least two different mechanisms; generation of C5a which activated leukocytes and binding of C3(H2O)/iC3(H2O), a ligand to the intergrin CD11b/CD18 on their surface.

    These mechanisms add further to the understanding of how platelets interact with the complement system and will help us to understand the role of the complement system in cardiovascular disease and thrombotic conditions.

  • 423.
    Hamad, Osama A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bäck, Jennie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Per H
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Platelets, complement, and contact activation: partners in inflammation and thrombosis2012In: Current Topics In Innate Immunity II / [ed] Lambris, JD; Hajishengallis, G, 2012, p. 185-205Conference paper (Refereed)
    Abstract [en]

    Platelet activation during thrombotic events is closely associated with complement and contact system activation, which in turn leads to inflammation. Here we review the interactions between activated platelets and the complement and contact activation systems in clotting blood. Chondroitin sulfate A (CS-A), released from alpha granules during platelet activation, is a potent mediator of crosstalk between platelets and the complement system. CS-A activates complement in the fluid phase, generating anaphylatoxins that mediate leukocyte activation. No complement activation seems to occur on the activated platelet surface, but C3 in the form of C3(H2O) is bound to the surfaces of activated platelets. This finding is consistent with the strong expression of membrane-bound complement regulators present at the platelet surface. CS-A exposed on the activated platelets is to a certain amount responsible for recruiting soluble regulators to the surface. Platelet-bound C3(H2O) acts as a ligand for leukocyte CR1 (CD35), potentially enabling platelet-leukocyte interactions. In addition, platelet activation leads to the activation of contact system enzymes, which are specifically inhibited by anti-thrombin, rather than by C1INH, as is the case when contact activation is induced by material surfaces. Thus, in addition to their traditional role as initiators of secondary hemostasis, platelets also act as mediators and regulators of inflammation in thrombotic events.

  • 424.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina N
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Non-proteolytically activated C3 promotes binding of activated platelets and platelet-derived microparticles to leukocytes via CD11b/CD182012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1191-1191Article in journal (Refereed)
    Abstract [en]

    Background:

    We have previously demonstrated that complement component C3 binds to the surface of activated platelets, independent of proteolytic activation. The resulting form of C3, termed C3(H2O), was shown to be a ligand for recombinant CD35 (complement receptor 1, CR1). Previous studies by others have indicated that platelet-leukocyte complex (PLC) formation is dependent on the interaction between platelet exposed P-selectin (CD62P) and its ligand, PSGL-1, on leukocytes. In addition, CD11b/CD18 (Mac-1 or CR3) has been shown to participate in this reaction, but its ligand has not yet been identified.

    Objective:

    To test the hypothesis that C3 bound to activated platelets and platelet-derived microparticles (PMPs) can act as a ligand for CD11b/CD18 (CR3) and contribute to PLC formation.

    Methods and results:

    Blood cells were depleted of plasma proteins. After extensive washing, C3 was added, and the leukocytes were activated with C5a and the platelets with thrombin receptor-activating peptide (TRAP). PLC formation was detected by flow cytometry (monocytes: CD14+/CD42a+, granulocytes: CD16+/CD42a+). For both granulocytes and monocytes, the addition of C3 significantly enhanced PLC formation. Formation of PLC was inhibited by both anti-P-selectin and anti-CD11b monoclonal antibodies. In addition, PMPs isolated from serum, were found to expose C3(H2O) and bind to leukocytes in a fashion similar to activated platelets.

    Conclusion:

    We have identified proteolytically non-activated C3 as a ligand for CD11b in the formation of PLC and possibly the binding of PMPs to leukocytes. This observation most likely has pathophysiological implications for the recently reported links between thrombotic disease and the complement system.

  • 425.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl Nilsson, Kristina
    Contribution of chondroitin sulfate A to the binding of complement proteins to activated platelets2010In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 9, p. e12889-Article in journal (Refereed)
    Abstract [en]

    Exposure of chondroitin sulfate A (CS-A) on the surface of activated platelets is well established.  The aim of the present study was to investigate to what extent CS-A contributes to the binding of C1q and the complement regulators C1 inhibitor (C1INH), C4b-binding protein (C4BP), and factor H to platelets. Human serum was passed over Sepharose conjugated with CS-A, and bound proteins were identified by Western blotting, and mass spectrometric analysis. C1q was identified as the main protein that specifically bound to CS-A, but C4BP and factor H were also shown to interact. Binding of C1INH was dependent of the presence of C1q and not bound to CS-A from C1q-depleted serum. The specific interactions observed of these proteins with CS-A were subsequently confirmed by surface plasmon resonance analysis using purified proteins. Importantly, C1q, C4BP, and factor H were shown to bind also to activated platelets and this interaction was inhibited by a CS-A-specific monoclonal antibody, thereby linking the binding of C1q, C4BP, and factor H to exposure of CS-A on platelets. CS-A-bound C1q was also shown to amplify the binding of model immune complexes to both microtiter plate-bound CS-A and to activated platelets. In conclusion, this study supports the concept that CS-A contributes to the binding of C1q, C4BP, and factor H to platelets, thereby adding CS-A to the previously reported binding sites for these proteins on the platelet surface. CS-A-bound C1q seems to amplify the binding of immune complexes to activated platelets, suggesting a role for this molecule in immune complex diseases.

  • 426.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mitroulis, Ioannis
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Chavakis, Triantafyllos
    Ricklin, Daniel
    Lambris, John D.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD182015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 141-142Article in journal (Other academic)
  • 427.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Per H.
    Wouters, Diana
    Lambris, John D.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 12010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 5, p. 2686-2692Article in journal (Refereed)
    Abstract [en]

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfaces of nonactivated and thrombin receptor-activating peptide-activated platelets was analyzed by flow cytometry and Western blot analyses. C1q, C4, C3, and C9 were found to bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. However, inhibiting complement activation at the C1q or C3 level did not block the binding of C3 to activated platelets. Diluting PRP and chelating divalent cations also had no effect, further indicating that the deposition of complement components was independent of complement activation. Furthermore, washed, activated platelets bound added C1q and C3 to the same extent as platelets in PRP. The use of mAbs against different forms of C3 demonstrated that the bound C3 consisted of C3(H(2)O). Furthermore, exogenously added soluble complement receptor 1 was shown to bind to this form of platelet-bound C3. These observations indicate that there is no complement activation on the surface of platelets under physiological conditions. This situation is in direct contrast to a number of pathological conditions in which regulators of complement activation are lacking and thrombocytopenia and thrombotic disease are the ultimate result. However, the generation of C3(H(2)O) represents nonproteolytic activation of C3 and after factor I cleavage may act as a ligand for receptor binding.

  • 428.
    Hamad, Osama
    et al.
    Uppsala University.
    Bäck, Jennie
    Uppsala University.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Platelets, Complement, and Contact Activation: Partners in inflammation and thrombosis2012In: Current Topics in Innate Immunity II / [ed] John D. Lambris &George Hajishengallis, Springer, 2012, Vol. 946, no Current Topics in Innate Immunity II. J. D. Lambris, G. Hajishengallis (eds.), p. 185-205Conference paper (Refereed)
    Abstract [en]

    Platelet activation during thrombotic events is closely associated with complement and contact system activation, which in turn leads to inflammation . Here we review the interactions between activated platelets and the complement and contact activation systems in clotting blood. Chondroitin sulfate A (CS-A), released from alpha granules during platelet activation, is a potent mediator of crosstalk between platelets and the complement system. CS-A activates complement in the fluid phase, generating anaphylatoxins that mediate leukocyte activation. No complement activation seems to occur on the activated platelet surface, but C3 in the form of C3(H2O) is bound to the surfaces of activated platelets . This finding is consistent with the strong expression of membrane-bound complement regulators present at the platelet surface. CS-A exposed on the activated platelets is to a certain amount responsible for recruiting soluble regulators to the surface. Platelet-bound C3(H2O) acts as a ligand for leukocyte CR1 (CD35), potentially enabling platelet–leukocyte interactions. In addition, platelet activation leads to the activation of contact system enzymes, which are specifically inhibited by antithrombin, rather than by C1INH, as is the case when contact activation is induced by material surfaces. Thus, in addition to their traditional role as initiators of secondary hemostasis, platelets also act as mediators and regulators of inflammation in thrombotic events.

  • 429.
    Hamad, Tarza
    et al.
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University, Örebro, Sweden; Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University, Örebro, Sweden.
    Nilsdotter-Augustinsson, Åsa
    Department of Infectious Diseases, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University, Örebro, Sweden.
    Antibiotic susceptibility among Staphylococcus epidermidis isolated from prosthetic joint infections, with focus on doxycycline2015In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 123, no 12, p. 1055-1060Article in journal (Refereed)
    Abstract [en]

    In recent years, coagulase-negative staphylococci such as Staphylococcus epidermidis have gained importance as nosocomial pathogens, especially in immunocompromised patients and prosthetic joint infections (PJIs). These infections are often long lasting and difficult to treat due to the production of bacterial biofilm and the transformation of the bacteria into a stationary growth phase. Rifampicin is able to penetrate the biofilm, but to reduce the risk of development of rifampicin resistance it should be used in combination with an additional antibiotic. In this study we used Etest to investigate the antimicrobial susceptibility of 134 clinical isolates of S.epidermidis obtained from PJIs to six oral antibiotics: doxycycline, rifampicin, linezolid, fusidic acid, clindamycin, and ciprofloxacin. We also performed synergy testing on doxycycline in combination with each of the remaining antibiotics. Ninety-three (69%) of the 134 isolates were susceptible to doxycycline, 94/134 (70%) to rifampicin, 56/134 (42%) to clindamycin, 25/134 (19%) to ciprofloxacin, 81/134 (60%) to fusidic acid, and 100% to linezolid. Thirty-two (80%) of the 40 isolates not fully susceptible to rifampicin were susceptible to doxycycline. Doxycycline in combination with each of the other investigated antibiotics exerted an additive effect on nearly half of the isolates, with the exception of clindamycin, which displayed an even higher percentage of additive effect (69%). To conclude, as the majority of the S.epidermidis isolates were susceptible to doxycycline, this antimicrobial agent may provide a potential alternative for combination therapy together with rifampicin.

  • 430. Hamadani, Mehdi
    et al.
    Hari, Parameswaran N.
    Zhang, Ying
    Carreras, Jeanette
    Akpek, Goerguen
    Aljurf, Mahmoud D.
    Ayala, Ernesto
    Bachanova, Veronika
    Chen, Andy I.
    Chen, Yi-Bin
    Costa, Luciano J.
    Fenske, Timothy S.
    Freytes, Cesar O.
    Ganguly, Siddhartha
    Hertzberg, Mark S.
    Holmberg, Leona A.
    Inwards, David J.
    Kamble, Rammurti T.
    Kanfer, Edward J.
    Lazarus, Hillard M.
    Marks, David I.
    Nishihori, Taiga
    Olsson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Reddy, Nishitha M.
    Rizzieri, David A.
    Savani, Bipin N.
    Solh, Melhem
    Vose, Julie M.
    Wirk, Baldeep
    Maloney, David G.
    Smith, Sonali M.
    Montoto, Silvia
    Saber, Wael
    Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation2014In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 20, no 11, p. 1729-1736Article in journal (Refereed)
    Abstract [en]

    The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

  • 431.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winther, Johanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rudolfsson, Stina H
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm.
    Granfors, Torvald
    Department of Urology, Central Hospital, Västerås, Sweden.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

    METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

    CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

  • 432.
    Han, Jing
    et al.
    School of Public Health, Health Science Center, Xi’an Jiaotong University, No.76 Yanta West Road, Xi’an 710061, Shaanxi, People’s Republic of China.
    Wang, Weizhuo
    Department of Orthopedics, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, People’s Republic of China.
    Qu, Chengjuan
    Department of Applied Physics, University of Eastern Finland, 70211 Kuopio, Finland.
    Liu, Ruiyu
    Department of Orthopedics, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, People’s Republic of China.
    Li, Wenrong
    Department of Medical Imaging, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, People’s Republic of China.
    Gao, Zongqiang
    Department of Orthopedics, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, People’s Republic of China.
    Guo, Xiong
    School of Public Health, Health Science Center, Xi’an Jiaotong University, No.76 Yanta West Road, Xi’an 710061, Shaanxi, People’s Republic of China.
    Role of inflammation in the process of clinical Kashin-Beck disease: latest findings and interpretations2015In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 64, no 11, p. 853-860Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD), a particular type of osteoarthritis (OA), and an endemic disease with articular cartilage damage and chondrocytes apoptosis, can affect many joints, and the most commonly affected joints are the knee, ankle, and hand. KBD has traditionally been classified as a non-inflammatory OA. However, recent studies have shown that inflammation has played an important role in the development of KBD. Nowadays, clinical KBD is not only an endemic disease, but also a combined result of many other non-endemic factors, which contains age, altered biomechanics, joint trauma and secondary OA. The characteristics of the developmental joint failure of advanced KBD, because of the biochemical and mechanical processes, are tightly linked with the interaction of joint damage and its immune response, as well as the subsequent state of chronic inflammation leading to KBD progression. In this review, we focus on the epidemiology, pathology, imaging, cytokines and transduction pathways investigating the association of inflammation with KBD; meanwhile, a wide range of data will be discussed to elicit our current hypotheses considering the role of inflammation and immune activation in KBD development.

  • 433.
    Hanevik, Kurt
    et al.
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway.;Haukeland Hosp, Ctr Trop Infect Dis, Bergen, Norway..
    Kristoffersen, Einar
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Immunol Transfus Med, Bergen, Norway..
    Morch, Kristine
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway.;Haukeland Hosp, Ctr Trop Infect Dis, Bergen, Norway..
    Rye, Kristin Paulsen
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway..
    Sornes, Steinar
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway..
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Bruserud, Oystein
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway..
    Langeland, Nina
    Univ Bergen, Dept Clin Sci, Lab Bldg 8 Floor, N-5021 Bergen, Norway.;Haukeland Hosp, Ctr Trop Infect Dis, Bergen, Norway..
    Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome2017In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 18, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: The role of pathogen specific cellular immune responses against the eliciting pathogen in development of post-infectious chronic fatigue syndrome (PI-CFS) is not known and such studies are difficult to perform. The aim of this study was to evaluate specific anti-Giardia cellular immunity in cases that developed CFS after Giardia infection compared to cases that recovered well. Patients reporting chronic fatigue in a questionnaire study three years after a Giardia outbreak were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS and idiopathic chronic fatigue. Giardia specific immune responses were evaluated in 39 of these patients by proliferation assay, T cell activation and cytokine release analysis. 20 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Results: Patients were clinically classified into CFS (n = 15), idiopathic chronic fatigue (n = 5), fatigue from other causes (n = 9) and recovered from fatigue (n = 10). There were statistically significant antigen specific differences between these Giardia exposed groups and unexposed controls. However, we did not find differences between the Giardia exposed fatigue classification groups with regard to CD4 T cell activation, proliferation or cytokine levels in 6 days cultured PBMCs. Interestingly, sCD40L was increased in patients with PI-CFS and other persons with fatigue after Giardia infection compared to the non-fatigued group, and correlated well with fatigue levels at the time of sampling. Conclusion: Our data show antigen specific cellular immune responses in the groups previously exposed to Giardia and increased sCD40L in fatigued patients.

  • 434. Hansen, Finja C.
    et al.
    Kalle-Brune, Martina
    van der Plas, Mariena J. A.
    Stromdahl, Ann-Charlotte
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Morgelin, Matthias
    Schmidtchen, Artur
    The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 11, p. 5397-5406Article in journal (Refereed)
    Abstract [en]

    Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4-and TLR2-induced NF-kappa B activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38 alpha and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-kappa B activity and proinflammatory cytokine production in monocytes and macrophages.

  • 435.
    Hansson, Charlotta
    et al.
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Schön, Karin
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Kalbina, Irina
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Andersson, Sören
    Örebro University Hospital. Sch Sci & Technol, Orebro Life Sci Ctr, Univ Orebro, Orebro, Sweden; Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden .
    Bokarewa, Maria I.
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.
    Lycke, Nils Y.
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Feeding transgenic plants that express a tolerogenic fusion protein effectively protects against arthritis2016In: Plant Biotechnology Journal, ISSN 1467-7644, E-ISSN 1467-7652, Vol. 14, no 4, p. 1106-1115Article in journal (Refereed)
    Abstract [en]

    Although much explored, oral tolerance for treatment of autoimmune diseases still awaits the establishment of novel and effective vectors. We investigated if the tolerogenic CTA1(R7K)-COL-DD fusion protein can be expressed in edible plants and in this way induce oral tolerance and protect against arthritis. The fusion protein was recombinantly expressed in Arabidopsis thaliana plants, which were fed to H-2q restricted DBA/1 mice to assess the preventive effect on collagen-induced arthritis (CIA). The treatment resulted in fewer mice exhibiting disease and arthritis scores were significantly reduced. Immune suppression was evident in treated mice and serum biomarkers for inflammation as well as anti-collagen IgG responses were reduced. In spleen draining and lymph nodes, CD4+ T cell responses were reduced. Concomitant with a reduced effector T cell activity with lower IFNg, IL-13 and IL-17A production we observed an increase in IL-10 production to recall antigen stimulation in vitro, suggesting reduced Th1, Th2 and Th17 activity subsequent to upregulated IL-10 and regulatory T cell (Treg) functions. The present study shows that edible plants expressing a tolerogen were effective at stimulating CD4 T cell tolerance and in protecting against CIA disease. Our study conveys optimism as to the potential of using edible plants for oral treatment of rheumatoid arthritis.

  • 436.
    Hansson, Monika
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mercury-induced autoimmunity: Genetics and immunoregulation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

    In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

    We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait.

    We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

    Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

  • 437.
    Hansson, Tony
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Anneren, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjoberg, O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Klareskog, L
    Dannaeus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Celiac disease in relation to immunologic serum markers, traced DQ antigens in Swedish children with Down syndrome.1999In: J Pediatr Gastroenterol Nutr, Vol. 29, p. 286-Article in journal (Refereed)
  • 438.
    Hansson, Tony
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Dahlbom, I
    Pharmacia & Upjohn Diagnostics.
    Hall, J
    Holtz, A
    Elfman, L
    Dannaeus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Klareskog, L
    Antibody reactivity against human and guinea pig tissue transglutaminase in children with celiac disease2000In: J Pediatric Gastroenterology and Nutrition, Vol. 30, p. 379-Article in journal (Refereed)
  • 439.
    Hansson, Tony
    et al.
    Department of Rheumatology, Karolinska Institute.
    Dahlbom, I
    Rogberg, S
    Dannaeus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hopfl, P
    Gut, H
    Kraaz, W
    Klareskog, L
    Recombinant human tissue transglutaminase for diagnosis and follow-up of childhood coeliac disease.2002In: Pediatr Res, Vol. 51, p. 700-Article in journal (Refereed)
  • 440.
    Hansson, Tony
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Dannaeus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Klareskog, L
    Cytokine-producing cells in peripheral blood of children with coeliac disease secrete cytokines with a type 1 profile.1999In: Clin Exp Immunol, Vol. 116, p. 246-Article in journal (Refereed)
  • 441.
    Hansson, Tony
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Dannaeus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kraaz, W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjoberg, O
    Klareskog, L
    Production of antibodies to gliadin by peripheral blood lymphocytes in children with celiac disease: the use of an enzyme-linked immunospot technique for screening and follow-up.1997In: Pediatr Res, Vol. 41, p. 554-Article in journal (Refereed)
  • 442. Hansson, Tony
    et al.
    Ulfgren, AK
    Lindroos, E
    DannAEus, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dahlbom, I
    Pharmacia Diagnostics.
    Klareskog, L
    Transforming growth factor-beta (TGF-beta) and tissue transglutaminaseexpression in the small intestine in children with coeliac disease.2002In: Scand J Immunol, Vol. 56, p. 530-Article in journal (Refereed)
  • 443.
    Hanstock, Helen
    et al.
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences. Bangor University, Bangor, Gwynedd, Wales.
    Edwards, Jason
    Bangor University, Bangor, Gwynedd, Wales.
    Walsh, Neil
    Bangor University, Bangor, Gwynedd, Wales.
    Tear Lactoferrin and Lysozyme as Clinically Relevant Biomarkers of Mucosal Immune Competence2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1178Article in journal (Refereed)
    Abstract [en]

    Tears have attracted interest as a minimally-invasive biological fluid from which to assess biomarkers. Lactoferrin (Lf) and lysozyme (Lys) are abundant in the tear fluid and have antimicrobial properties. Since the eye is a portal for infection transmission, assessment of immune status at the ocular surface may be clinically relevant. Therefore, the aim of this series of studies was to investigate the tear fluid antimicrobial proteins (AMPs) Lf and Lys as biomarkers of mucosal immune status. To be considered biomarkers of interest, we would expect tear AMPs to respond to stressors known to perturb immunity but be robust to confounding variables, and to be lower in participants with heightened risk or incidence of illness. We investigated the relationship between tear AMPs and upper respiratory tract infection (URTI; study 1) as well as the response of tear AMPs to prolonged treadmill exercise (study 2) and dehydration (study 3). Study 1 was a prospective cohort study conducted during the common cold season whereas studies 2 and 3 used repeated-measures crossover designs. In study 1, tear Lys concentration (C) as well as tear AMP secretion rates (SRs) were lower in individuals who reported pathogen-confirmed URTI (n = 9) throughout the observation period than in healthy, pathogen-free controls (n = 17; Lys-C, P = 0.002, d = 0.85; Lys-SR, P < 0.001, d = 1.00; Lf-SR, P = 0.018, d = 0.66). Tear AMP secretion rates were also lower in contact lens wearers. In study 2, tear AMP SRs were 42–49% lower at 30 min−1 h post-exercise vs. pre-exercise (P < 0.001, d = 0.80–0.93). Finally, in study 3, tear AMPs were not influenced by dehydration, although tear AMP concentrations (but not secretion rates) displayed diurnal variation. We conclude that Lf and Lys have potential as biomarkers of mucosal immune competence; in particular, whether these markers are lower in infection-prone individuals warrants further investigation.

  • 444.
    Harboe, M.
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Johnson, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nymo, S.
    Nordland Hospital, Norway.
    Ekholt, K.
    Oslo University Hospital Rikshospitalet, Norway.
    Schjalm, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Lindstad, J. K.
    Oslo University Hospital Rikshospitalet, Norway.
    Pharo, A.
    Oslo University Hospital Rikshospitalet, Norway.
    Hellerud, B. C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Mollnes, T. E.
    Oslo University Hospital Rikshospitalet, Norway ; Nordland Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Molecular modelling showed optimal fit between TSR5 in trimeric properdin and C345C in the C3b moiety for stabilization of the alternative convertase, whereas binding to molecular patterns in myeloperoxidase, endothelial cells and Neisseria meningitides was indirectly mediated by initial C3 activation2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1205-1205Article in journal (Refereed)
  • 445.
    Harboe, M.
    et al.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Johnson, C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Lindstad, J. K.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Pharo, A.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Hellerud, B. C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nymo, S.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Mollnes, T. E.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Binding of properdin to myeloperoxidase and Neisseria meningitidis is C3-dependent2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, Special Issue, p. 142-142, article id 067Article in journal (Refereed)
  • 446.
    Harboe, Morten
    et al.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Johnson, Christina
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Nymo, Stig
    Nordland Hosp, Res Lab, Bodo, Norway..
    Ekholt, Karin
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Schjalm, Camilla
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Lindstad, Julie K.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Pharo, Anne
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Hellerud, Bernt C.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mollnes, Tom E.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway.;Nordland Hosp, Res Lab, Bodo, Norway..
    Nilsson, Per H.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway..
    Molecular modelling showed optimal fit between TSR5 in trimeric properdin and C345C in the C3b moiety for stabilization of the alternative convertase, whereas binding to molecular patterns in myeloperoxidase, endothelial cells and Neisseria meningitides was indirectly mediated by initial C3 activation2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1205-1205Article in journal (Other academic)
  • 447.
    Harboe, Morten
    et al.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Johnson, Christina
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Nymo, Stig
    Nordland Hosp, Res Lab, N-8092 Bodo, Norway..
    Ekholt, Karin
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Schjalm, Camilla
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Lindstad, Julie K.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Pharo, Anne
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Hellerud, Bernt Christian
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, S-39182 Kalmar, Sweden..
    Mollnes, Tom Eirik
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway.;Nordland Hosp, Res Lab, N-8092 Bodo, Norway.;Univ Oslo, KG Jebsen Inflammatory Res Ctr, N-0424 Oslo, Norway.;Univ Tromso, Fac Hlth Sci, KG Jebsen Thrombosis Res & Expertise Ctr, N-9037 Tromso, Norway.;Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway..
    Nilsson, Per H.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway.;Linnaeus Univ, Linnaeus Ctr Biomat Chem, S-39182 Kalmar, Sweden.;Univ Oslo, KG Jebsen Inflammatory Res Ctr, N-0424 Oslo, Norway..
    Properdin binding to complement activating surfaces depends on initial C3b deposition2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 4, p. E534-E539Article in journal (Refereed)
    Abstract [en]

    Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

  • 448.
    Hardt, Uta
    et al.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gunnarsson, Iva
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Clancy, Robert M.
    NYU, Sch Med, Dept Med, Div Rheumatol, New York, NY USA..
    Silverman, Gregg J.
    NYU, Sch Med, Dept Med, Div Rheumatol, New York, NY USA..
    Svenungsson, Elisabet
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Gronwall, Caroline
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Autoimmune reactivity to malondialdehyde adducts in SLE is associated with high disease activity2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 330-330Article in journal (Other academic)
  • 449.
    Hartana, C. A.
    et al.
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Bergman, E. Ahlen
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Broome, A.
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Berglund, S.
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Johansson, M.
    Sundsvall Hosp, Dept Urol, Sundsvall, Sweden.
    Alamdari, F.
    Vastmanland Hosp, Dept Urol, Vasteras, Sweden.
    Jakubczyk, T.
    Lanssjukhuset Ryhov, Dept Urol, Jonkoping, Sweden.
    Huge, Y.
    Linkoping Univ, Div Urol, Dept Clin & Expt Med, Linkoping, Sweden.
    Aljabery, F.
    Linkoping Univ, Div Urol, Dept Clin & Expt Med, Linkoping, Sweden.
    Palmqvist, K.
    Ostersund Cty Hosp, Dept Surg, Urol Sect, Ostersund, Sweden.
    Holmström, Benny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Glise, H.
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Riklund, K.
    Umea Univ, Dept Radiat Sci, Diagnost Radiol, Umea, Sweden.
    Sherif, A.
    Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden.
    Winqvist, O.
    Karolinska Inst, Dept Med Solna, Unit Immunol & Allergy, Stockholm, Sweden.
    Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

    Tissue-resident memory T (T-RM) cells are CD8(+) T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in T-RM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in T-RM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate T-RM cell phenotypes. We discovered that tumour T-RM cells have low DNA methylation in the PRF1 locus (32<bold></bold>9% methylation), which corresponds to increased numbers of perforin-expressing T-RM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour T-RM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that T-RM cells from tumours are not terminally exhausted. Moreover, a high number of T-RM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, T-RM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies T-RM cells as potential new targets for cancer immunotherapy.

  • 450. He, T.
    et al.
    Venema, K.
    Priebe, M. G.
    Welling, G. W.
    Brummer, Robert
    Örebro University, School of Health and Medical Sciences.
    Vonk, R. J.
    The role of colonic metabolism in lactose intolerance2008In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 38, no 8, p. 541-547Article in journal (Refereed)
    Abstract [en]

    Lactose maldigestion and intolerance affect a large part of the world population. The underlying factors of lactose intolerance are not fully understood. In this review, the role of colonic metabolism is discussed, i.e. fermentation of lactose by the colonic microbiota, colonic processing of the fermentation metabolites and how these processes would play a role in the pathophysiology of lactose intolerance. We suggest that the balance between the removal and production rate of osmotic-active components (lactose, and intermediate metabolites, e.g. lactate, succinate, etc.) in the colon is a key factor in the development of symptoms. The involvement of the colon may provide the basis for designing new targeted strategies for dietary and clinical management of lactose intolerance.

6789101112 401 - 450 of 1286
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf