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  • 101.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity.

    Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome.

    This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs.

    The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.

  • 102.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Berglund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Screening of mortality in transplant patients using an assay for immune function2011In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 24, no 4, p. 246-250Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS: In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS: The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS: In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.

  • 103.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Schneider, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation2012In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 26, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation.

    Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Tr1 cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry.

    Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8–19.2% of the baseline stimulated leukocyte activity, p<0.05). Tr1 cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275–11,038% of the baseline IL-10 secretion, pb0.05).

    Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation.

  • 104.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindvall, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Green plasma2015In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 55, no 2, p. 245-245Article in journal (Other academic)
  • 105.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Cilio, Corrado M
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
    Penha-Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Lamhamedi-Cherradi, Salah-Eddine
    INSERM U25, Hopital Necker, Paris, France.
    Löfgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Colucci, Francesco
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Garchon, Henri-Jean
    INSERM U25, Hopital Necker, Paris, France.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed)
    Abstract [en]

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

  • 106.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 7, p. 1677-1682Article in journal (Refereed)
    Abstract [en]

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

  • 107.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha-Gonçalves, Carlos
    Gulbenkian Institute for Science, Oeiras, Portugal, PT.
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 108.
    Bergqvist, Ingela
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Björn
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Corneliussen, Brit
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development2000In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 30, no 10, p. 2857-2863Article in journal (Refereed)
    Abstract [en]

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

  • 109.
    Bergseth, Grethe
    et al.
    Nordland Hospital, Bodø, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway.
    Thomas, Anub Mathew
    Radboud University Medical Center, The Netherlands.
    Gustavsen, Alice
    University of Oslo, Rikshospitalet, Norway.
    Volokhina, Elena B
    Radboud University Medical Center, The Netherlands.
    van den Heuvel, Lambertus P
    Radboud University Medical Center, The Netherlands.
    Barratt-Due, Andreas
    University of Oslo, Rikshospitalet, Norway.
    Mollnes, Tom E
    University of Oslo, Rikshospitalet, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Neoepitope based assays to detect C5a – Pitfalls and interpretations2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 201-201Article in journal (Refereed)
  • 110.
    Bergström, Ida
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Pro- and anti-inflammatory actions in coronary artery disease: with focus on CD56+ T cells and Annexin A12015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ¨The atherosclerotic process is considered to be driven by an imbalance between proand anti-inflammatory actions. Still, the inflammatory state in patients with coronary artery disease (CAD) remains to be clarified. Annexin A1 (AnxA1) is a glucocorticoidinduced protein which may have a key role in the anti-inflammatory response as a mediator of glucocorticoid effects.

    The general aim of this thesis was to deepen the knowledge of pro- and antiinflammatory mechanisms in CAD via phenotypic assessments of immune cell subsets, in particular CD56+ T cells, and exploration of AnxA1. The long-term goal is to reveal basic mechanisms that will lead to the development of biomarkers, which may be used for individualized treatment and monitoring.

    The AnxA1 protein was constitutively expressed in both neutrophils and peripheral blood mononuclear cells (PBMCs). However, it varied considerably across PBMC subsets, being most abundantly expressed in monocytes. The AnxA1 expression was also higher in CD56+ T cells than in CD56- T cells.

    The expression of total AnxA1 protein in neutrophils was higher in patients with stable angina (SA) compared with controls. However, this was not accompanied by altered neutrophil activation status. Instead, the neutrophils from patients exhibited an enhanced anti-inflammatory response to exogenous AnxA1, emphasizing the potential of AnxA1 as an inhibitor of neutrophil activity. Only patients with acute coronary syndrome (ACS) showed an increase in cell surface-associated AnxA1.

    CAD patients, independent of clinical presentation, had increased proportions of CD56+ T cells compared with controls, a phenomenon likely to represent immunological aging. The CD56+ T cells were found to exhibit a distinct proinflammatory phenotype compared with CD56- T cells. In all T cell subsets, the expression of cell surface-associated AnxA1 was significantly increased in ACS patients, while it tended to be increased in post-ACS patients. In addition, dexamethasone clearly inhibited activation of CD56+ T cells in in vitro assays, whereas AnxA1 did not. The findings highlight the need to clarify whether the role of AnxA1 is different in T cells than in innate immune cells.

    In PBMCs, the mRNA levels of AnxA1 were increased in CAD patients, particularly in ACS patients. Correspondingly, the monocytes in ACS patients exhibited increased AnxA1 protein levels, both totally and on the cell surface. However, only cell surface-associated AnxA1 in monocytes correlated with the glucocorticoid sensitivity of PBMCs ex vivo. We propose the expression of cell surfaceassociated AnxA1 to be a promising candidate marker of glucocorticoid sensitivity, which needs further investigations in larger cohorts and intervention trials. Furthermore, the fact that PBMCs in post-ACS patients exhibited pro-inflammatory activity but no increase in cell surface-associated AnxA1 allow us to speculate that the glucocorticoid action and/or availability might be insufficient in these patients.

  • 111.
    Bergström, Ida
    et al.
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lundberg, Anna K.
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Jönsson, Simon
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. IRiSC - Inflammatory Response and Infection Susceptibility Centre.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jonasson, Lena
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174177Article in journal (Refereed)
    Abstract [en]

    Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  • 112.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Search for the Masked Mechanism Behind IgG-Mediated Suppression of Antibody Responses2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibodies passively administered together with their specific antigen can enhance or suppress the specific antibody response. This phenomenon is known as antibody feedback regulation. Whether this modulation causes up- or downregulation of the antibody response depends both on the antibody isotype and the antigen used. IgG antibodies passively administered together with particulate antigens, e.g. erythrocytes, can completely prevent the induction of an antibody response to the antigen. The suppressive capacity of IgG has been routinely used in the clinic since the 1960’s in RhD-prophylaxis to prevent hemolytic disease of the fetus and newborn. Although studied for decades, the underlying mechanism of IgG-suppression has remained elusive. The main focus of this thesis has been to elucidate the mechanism behind IgG-suppression of antibody responses in vivo in mouse models using intravenous immunization with specific IgG together with native or haptenated sheep red blood cells, SRBC. We show that IgG-suppression of IgM and long-term serum IgG-responses operates independently of activating FcγRI, III, IV, or the inhibitory FcγRIIB, thus confirming and extending previous findings. Moreover, we demonstrate for the first time that C1q, C3 and CR1/2 are dispensable for IgG-suppression of antibody responses. These findings strongly argue against the involvement of Fc-dependent mechanisms as the explanation for IgG-suppression. Interestingly, GC formation occurs in IgG-suppressed mice although the antibody response to surface SRBC epitopes are completely suppressed. The data suggests that these GCs develop in response to intracellular SRBC epitopes as well as to the passively administered suppressive IgG. Moreover, we demonstrate that passively administered IgG suppresses several parameters of an antibody/B cell response including antigen specific GC and non-GC B cells, extra-follicular antibody secreting cells, long-lived plasma cells and induction of immunological memory. Before the onset of the present study, two mechanisms appeared compatible with the majority of experimental findings: IgG-mediated antigen clearance and epitope masking. Herein we show that the contribution of IgG-mediated antigen clearance is negligible and that suppression of IgG-responses is strictly epitope specific. This provides compelling evidence that a very important mechanism underlying IgG-suppression is epitope masking.

  • 113. Bergström, Joakim J E
    et al.
    Heyman, Birgitta
    Development of germinal centers in mice immunized with IgG anti-SRBC and SRBC in spite of a completely suppressed SRBC-specific antibody responseManuscript (preprint) (Other academic)
  • 114.
    Bergström, Joakim J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG-mediated Immune Suppression: Discrepancy between Suppression of Antibody and Germinal Center Responses?2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 210-210Article in journal (Other academic)
  • 115.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 238Article in journal (Refereed)
    Abstract [en]

    Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBCs) is intact in mice lacking Fc gamma Rs, complement factor 1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG-antigen complexes and/or that IgG "hides" the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extrafollicular antibody-secreting cells, germinal center B-cells, longlived plasma cells, long-term IgG responses, and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type, but not of Fc gamma R-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead, we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP, but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.

  • 116.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Joly, A. -L
    Seiron, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isringhausen, S.
    Modig, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Andersson, J.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 318-324Article in journal (Refereed)
    Abstract [en]

    With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients.

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

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

  • 118.
    Bexborn, Fredrik
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Engberg, Anna E.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Sandholm, Kerstin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Mollnes, Tom Eirik
    Hong, Jaan
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hirudin versus heparin for use in whole blood in vitro biocompatibility models2009In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 89A, no 4, p. 951-959Article in journal (Refereed)
    Abstract [en]

    Background: Heparin has traditionally been a widely used anticoagulant in blood research, but has been shown to be inappropriate for work with the complement system because of its complement-interacting properties. In this work, we have compared the effects of heparin with those of the specific thrombin inhibitor hirudin on complement and blood cells in vitro.

    Methods: Whole blood collected in the presence of hirudin (50 µg/mL) or heparin (1 IU/mL) was incubated in the slide chamber model. The plasma was analyzed for complement activation markers C3a and sC5b-9, and the polyvinylchloride test slides were stained for adhering cells. The integrity of the complement system was tested by incubating serum and hirudin-treated plasma in the presence of various activating agents.

    Results: In contrast to heparin, the addition of hirudin generally preserved the complement reactivity, and complement activation in hirudin plasma closely resembled that in normal serum. Importantly, immunochemical staining of surface-bound cells demonstrated the inducible expression of tissue factor on bound monocytes from hirudin-treated blood, an effect that was completely abolished in heparin-treated blood.

    Conclusion: Our results indicate that hirudin as an anticoagulant produces more physiological conditions than heparin, making hirudin well-suited for in vitro studies, especially those addressing the regulation of cellular processes.

  • 119.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Glutamate and GABA signalling components in the human brain and in immune cells2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.

    Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.

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

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

  • 121.
    Biglarnia, Ali-Reza
    et al.
    Skane Univ Hosp, Dept Transplantat, Malmo, Sweden;Lund Univ, Lund, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Inst Clin & Expt Traumaimmunol, Ulm, Germany.
    Mohlin, Camilla
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Centre of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The multifaceted role of complement in kidney transplantation2018In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 14, no 12, p. 767-781Article, review/survey (Refereed)
    Abstract [en]

    Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HL A incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.

  • 122.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Desensitization With Antigen-Specific Immunoadsorption Interferes With Complement in ABO-Incompatible Kidney Transplantation2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 1, p. 87-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Complement activation was characterized during and after desensitization treatment in 19 consecutive patients receiving ABO-incompatible (ABOi) living donor kidney transplants to assess the effect of desensitization protocol including antigen-specific immunoadsorption (IA) on complement activation.

    METHODS:

    All patients received rituximab- and tacrolimus-based triple treatment. Anti-A/B antibodies were removed by IA. Serial determinations of C3, C3a, the C3a/C3 ratio, and sC5b-9 were carried out between day -30 and postoperative day 30. C1q was measured on day -30 and the day before the transplantation. In two recipients, eluates from immunoadsorbent columns were analyzed for C3a, C1q, and immunoglobulins by western blotting. Same complement analysis was performed in eluate from a control column after in vitro perfusion of AB-plasma.

    RESULTS:

    Patient and graft survival were 100% for a median follow-up of 40 months (range, 12-60 months). There were no humoral rejections based on ABO-antigen-antibody interactions. C3a and the C3a/C3 ratio declined with the start of IA treatment, and this decline was maintained postoperatively. C1q declined from day -30 to a lower value on the day before transplantation (P<0.05). In eluates from both patient and control, immunoadsorbent column immunoglobulins together with C3a and C1q were detected.

    CONCLUSIONS:

    The current protocol including antigen-specific IA interferes with the complement system; this effect may be partially responsible for the absence of humoral rejection resulting from ABO-antigen-antibody interactions and the excellent outcomes obtained after ABO-incompatible kidney transplantation.

  • 123.
    Biglarnia, AliReza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Impact Of Duodenal Cuff Inflammation On Outcome After Clinical Pancreas Transplantation - A Survey Of A Comprehensive Follow-Up Strategy Including Serial Protocol Biopsy Of The Duodenal Cuff.2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S24-S24Article in journal (Other academic)
  • 124.
    Bitar, Aziz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Vibrio cholerae modulates the immune defense of human gut mucosa2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

  • 125.
    Bitar, Aziz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response of human intestinal epithelial cells by inducing microRNA-146a2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7212Article in journal (Refereed)
    Abstract [en]

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

  • 126.
    Bitar, Aziz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kyaw, Min Aung
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Marie-Louise, Hammarström
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wai, Sun Nynt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response ofhuman intestinal epithelial cells by inducing microRNA-146aIn: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed)
    Abstract [en]

    The small intestinal epithelium of Vibrio cholerae infected patients expresses the immunomodulatory microRNAs miR-146a and miR-155 at acute stage of disease. V. cholerae release outer membrane vesicles (OMVs) that serve as vehicles for translocation of virulencefactors including V. cholerae cytolysin (VCC). The aim was to investigate whether OMVs, with and/or without VCC-cargo could be responsible for induction of microRNAs in intestinal epithelial cells and thereby contribute to immunomodulation. Polarized tight monolayers of T84 cells were challenged with OMVs of wild-type and a VCC deletion mutant of the non-O1/non-O139 (NOVC) V. cholerae strain V:5/04 and with soluble VCC. OMVs, with and without VCC-cargo, caused significantly increased levels of miR-146a. Challenge with soluble VCC caused significant increases in interleukin-8 (IL-8), tumour necrosis factor-α(TNF-α), CCL20, IL-1β, and IRAK2 mRNA levels while challenge with OMVs did not causeany changes. Notably, OMVs from the VCC deficient mutant caused significant decreases in CCL20 and IL-18 mRNA levels. These results suggest that V. cholerae bacteria release OMVs that induce miR-146a in order to pave the way for colonization by reducing thestrength of an epithelial innate immune defence reaction and also preventing inflammation inthe mucosa that factors like VCC can evoke.

  • 127.
    Bjerg, A.
    et al.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Ekerljung, L.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Eriksson, J.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Naslund, J.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Sjölander, S.
    ThermoFisher Sci, ImmunoDiagnost, Uppsala, Sweden..
    Rönmark, E.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden.;OLIN Unit, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Dahl, Å.
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden..
    Holmberg, K.
    Sahlgrens Univ Hosp, Dept Otorhinolaryngol, Gothenburg, Sweden..
    Wennergren, G.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden.;Gothenburg Univ, Dept Pediat, Gothenburg, Sweden..
    Torén, K.
    Gothenburg Univ, Sahlgrenska Acad, Dept Publ Hlth & Community Med, Gothenburg, Sweden..
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Lötvall, J.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Lundbäck, B.
    Gothenburg Univ, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Increase in pollen sensitization in Swedish adults and protective effect of keeping animals in childhood2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 10, p. 1328-1336Article in journal (Refereed)
    Abstract [en]

    Background To date, most studies of the 'allergy epidemic' have been based on self-reported data. There is still limited knowledge on time trends in allergic sensitization, especially among adults. Objective To study allergic sensitization, its risk factors and time trends in prevalence. Methods Within West Sweden Asthma Study (WSAS), a population-based sample of 788 adults (17-60 years) underwent skin prick tests (SPTs) for 11 aeroallergens 2009-2012. Specific IgE was analysed in 750 of the participants. Those aged 20-46 years (n = 379) were compared with the European Community Respiratory Health Survey sample aged 20-46 year from the same area (n = 591) in 1991-1992. Results Among those aged 20-46 years, the prevalence of positive SPT to pollen increased, timothy from 17.1% to 29.0% (P < 0.001) and birch from 15.6% to 23.7% (P = 0.002) between 1991-1992 and 2009-2012. Measurements of specific IgE confirmed these increases. Prevalence of sensitization to all other tested allergens was unchanged. In the full WSAS sample aged 17-60 years, any positive SPT was seen in 41.9%, and the dominating sensitizers were pollen (34.3%), animals (22.8%) and mites (12.6%). Pollen sensitization was strongly associated with rhinitis, whereas indoor allergens were more associated with asthma. Growing up with livestock or furred pets decreased the risk of sensitization, adjusted odds ratio 0.53 (0.28-0.995) and 0.68 (0.47-0.98), respectively. Conclusion Pollen sensitization has increased in Swedish adults since the early 1990s, while the prevalence of sensitization to other allergens has remained unchanged. This is one plausible explanation for the increase in rhinitis 1990-2008 in Swedish adults, during which time the prevalence of asthma, which is more associated with perennial allergens, was stable. Contact with animals in childhood seems to reduce the risk of sensitization well into adulthood. One major factor contributing to the rise in pollen allergy is a significant increase in levels of birch and grass pollen over the past three decades.

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

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

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

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

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

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

  • 130.
    Bjerg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    Winberg, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berthold, Malin
    Mattsson, Lars
    Borres, Magnus P
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 6, p. 557-563Article in journal (Refereed)
    Abstract [en]

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

  • 131.
    Bjermo, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Dietary Fatty Acids and Inflammation: Observational and Interventional Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dietary fat quality influences the risk of type 2 diabetes and cardiovascular disease. A low-grade inflammation is suggested to contribute to the disease development, often accompanied by obesity. Whereas n-3 polyunsaturated fatty acids (PUFA) have been considered anti-inflammatory, n-6 PUFA have been proposed to act pro-inflammatory. Saturated fatty acids (SFA) act pro-inflammatory in vitro.

    This thesis aimed to investigate effects of different fatty acids on low-grade inflammation in observational and interventional studies. In Paper I and II, fatty acid composition in serum cholesterol esters was used as objective marker of dietary fat quality and related to serum C-reactive protein (CRP) and other circulating inflammatory markers in two population-based cohorts, conducted in middle-aged men and elderly men and women, respectively. In Paper III and IV, the impact of diets differing in fat quality on inflammation and oxidative stress was investigated in randomised controlled studies, in subjects with metabolic syndrome and abdominal obesity.

    In Paper I and II, a low proportion of linoleic acid (18:2 n-6) in serum was associated with higher CRP concentrations, indicating that a low intake of vegetable fats may be related to low-grade inflammation. High CRP concentrations were also associated with high proportions of palmitoleic (16:1) and oleic (18:1) acids and high stearoyl coenzymeA desaturase index, possibly reflecting altered fat metabolism and/or high SFA intake in this population. When comparing two high-fat diets rich in either saturated or monounsaturated fat, and two low-fat diets with or without long-chain n-3 PUFA supplementation during 12 weeks (Paper III), no differences in inflammation or oxidative stress markers were observed. Moreover, a 10-week intervention (Paper IV) with high linoleic acid intake showed no adverse effects on inflammation or oxidative stress. Instead, interleukin-1 receptor antagonist and tumor necrosis factor receptor-2 decreased after linoleic acid intake compared with a diet high in SFA.

    The results in this thesis indicate that dietary n-6 PUFA found in vegetable fats is associated with lower inflammation marker levels, and to some extent reduces systemic inflammation when compared with SFA. Supplementation of n-3 PUFA did not exert any systemic anti-inflammatory effects, maybe due to a relatively low dose.

  • 132. Bjornsdottir, Halla
    et al.
    Christenson, Karin
    Forsman, Huamei
    Stylianou, Marios
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Urban, Constantin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Dahlgren, Claes
    Karlsson, Anna
    Bylund, Johan
    Cytotoxic Peptides from S. aureus Cause Neutrophil Cell Death with NET-like Features2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 432-432Article in journal (Other academic)
  • 133.
    Björklund, Åsa K.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Ludwig Inst Canc Res, S-10401 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Forkel, Marianne
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden..
    Picelli, Simone
    Ludwig Inst Canc Res, S-10401 Stockholm, Sweden..
    Konya, Viktoria
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden..
    Theorell, Jakob
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden..
    Friberg, Danielle
    Karolinska Univ Hosp, Dept Otorhinolaryngol, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Stockholm, Sweden..
    Sandberg, Rickard
    Ludwig Inst Canc Res, S-10401 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Mjosberg, Jenny
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden..
    The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing2016In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 17, no 4, p. 451-460Article in journal (Refereed)
    Abstract [en]

    Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.

  • 134.
    Bjørkeng, Eva
    et al.
    Research Group for Host-Microbe Interactions, Department of Medical Biology, University of Tromsø, Tromsø, Norway.
    Rasmussen, Gunlög
    Örebro University, School of Medical Sciences.
    Sundsfjord, Arnfinn
    Research Group for Host-Microbe Interactions, Department of Medical Biology, University of Tromsø, Tromsø, Norway; Department of Microbiology and Infection Control, Reference Centre for Detection of Antimicrobial Resistance, University Hospital of North-Norway, Tromsø, Norway.
    Sjöberg, Lennart
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hegstad, Kristin
    Research Group for Host-Microbe Interactions, Department of Medical Biology, University of Tromsø, Tromsø, Norway; Department of Microbiology and Infection Control, Reference Centre for Detection of Antimicrobial Resistance, University Hospital of North-Norway, Tromsø, Norway.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences. Department of Infectious Diseases and Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Clustering of polyclonal VanB-type vancomycin-resistant Enterococcus faecium in a low-endemic area was associated with CC17-genogroup strains harbouring transferable vanB2-Tn5382 and pRUM-like repA containing plasmids with axe-txe plasmid addiction systems2011In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 4-5, p. 247-258Article in journal (Refereed)
    Abstract [en]

    VanB-type vancomycin-resistant Enterococcus faecium isolates (n = 17) from 15 patients at the Örebro University hospital in Sweden during a span of 18 months was characterized. All patients had underlying disorders and received broad-spectrum antimicrobial therapy. Pulsed-field gel electrophoresis (PFGE) grouped 14 isolates in three PFGE types and three isolates in unique PFGE patterns. All isolates had multi-locus sequence types [ST17 (n = 5); ST18 (n = 3); ST125 (n = 7); ST262 (n = 1); ST460 (n = 1)] belonging to the successful hospital-adapted clonal complex 17 (CC17), harboured CC17-associated virulence genes, were vanB2-positive and expressed diverse vancomycin minimum inhibitory concentration (MICs; 8 to > 256 mg/L). Isolate 1 had a unique PFGE type and a chromosomal transferable vanB2-Tn5382 element. Interestingly, the other five PFGE types had Tn5382 located on plasmids containing pRUM-like repA and a plasmid addiction system (axe-txe) shown by co-hybridization analysis of PFGE-separated S1-nuclease digested total DNA. The resistance plasmids were mainly of 120-kb and supported intraspecies vanB transfer. Two strains were isolated from patient 6 and we observed a possible transfer of the vanB2-resistance genes from PFGE type III ST460 to a more successful PFGE type I ST125. This latter PFGE type I ST125 became the predominant type afterwards. Our observations support the notion that vanB-type vancomycin-resistant Enterococcus faecium can persist in a low-endemic area through successful clones and plasmids with stability functions in hospital patients with known risk factors.

  • 135.
    Blomberg, Carolina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Intrathecal and Systemic Complement Activation Studies of Multiple Sclerosis and Guillan-Barré Syndrome2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Both Multiple Sclerosis (MS) and Guillan-Barré syndrome (GBS) are neurological inflammatory demyelinating autoimmune diseases, with a probable antibody contribution. Complement proteins in both MS and GBS does play a role in inflammation and demyelination at pathogenesis, according to earlier scientific evidence. The aim of this examination project work was to investigate systemic and intrathecal complement activation in MS and GBS, to gain further knowledge that might be useful for development of future therapeutics targeting immune responses during those diseases. An additional aim was to develop a new ELISA method for detection of complement iC3.

    By using sandwich ELISA, complement proteins C1q, C4, C3, fH and C3a were measured in plasma and cerebrospinal fluid (CSF) from persons within 4 different diagnostic groups; MS, other neurological diseases (OND), GBS and controls (C). An ELISA method to detect iC3 (hydrolysed C3) was also developed, including usage of SDS-PAGE. Results based on raw data and statistical analysis show significantly elevated levels of C3a (C3a/C3) in MS and decreased C3 in plasma. In CSF low levels of C4 and C3a/C3 in MS were detected, though correlation of C3a and C1q was positive. GBS reveal high levels of all complement proteins analysed in CSF except for C3, and a positive correlation of C3a and C1q as well as C3a and fH was found.

    These results indicate that MS patients have systemic complement activation; however the activation pathway is not determined. Complement activation in MS may also occur intrathecally, with correlation analysis indicating a possible activation via the classical pathway. MS patients suffering from a more acute relapsing-remitting (RR) MS have a more prominent systemic complement activation compared to MS patients responding to beta-interferon treatment. Systemic increased C3a/C3 ratio may be a possible biomarker to distinguish more acute RR MS in an earlier step of MS pathogenesis and should be further investigated. GBS patients have an intrathecal complement activation that seems to occur via the classical pathway.

  • 136.
    Blomberg, Jeanette
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Höglund, Andreas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Jacobsson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line2011In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 16, no 8, p. 783-794Article in journal (Refereed)
    Abstract [en]

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

  • 137.
    Blomberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Gottfries, Carl-Gerhard
    Gottfries Clin AB, Molndal, Sweden..
    Elfaitouri, Amal
    Benghazi Univ, Fac Publ Hlth, Dept Infect Dis & Trop Med, Benghazi, Libya..
    Rizwan, Muhammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Rosén, Anders
    Linkoping Univ, Div Cell Biol, Dept Clin & Expt Med, Linkoping, Sweden..
    Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 229Article in journal (Refereed)
    Abstract [en]

    Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

  • 138.
    Blomberg, Jonas
    et al.
    Uppsala Univ, Sweden.
    Gottfries, Carl-Gerhard
    Gottfries Clin AB, Sweden.
    Elfaitouri, Amal
    Benghazi Univ, Libya.
    Rizwan, Muhammad
    Uppsala Univ, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 229Article in journal (Refereed)
    Abstract [en]

    Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

  • 139.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammation and tendon healing2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.

    The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.

    First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.

    In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations. 

  • 140.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aspects of inflammation, angiogenesis and coagulation in preeclampsia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).

    We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.

    A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.

  • 141. Boij, Roland
    et al.
    Svensson, Judit
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lindahl, Tomas
    Palonek, Elzbieta
    Garle, Mats
    Berg, Mats
    Ernerudh, Jan
    Jenmalm, Mats
    Matthiesen, Leif
    Biomarkers of coagulation, inflammation and angiogenesis are independently associated with preeclampsia2012In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 68, no 3, p. 258-270Article in journal (Refereed)
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

  • 142. Boija, P O
    et al.
    Nilsson Ekdahl, Kristina
    Department of Medical and Physiological Chemistry, University of Uppsala.
    Nylander, G
    Ware, J
    Hemorrhagic hypotension and hepatic cell pyruvate kinase and fructose-1,6-diphosphatase activity in vivo1987In: Surgical research communications, Vol. 2, p. 119-124Article in journal (Refereed)
  • 143.
    Boiko, Iryna
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Clinical Laboratory Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Krynytska, Inna
    Department of Functional and Laboratory Diagnostics, I. Horbachevsky Ternopil State Medical University, Ternopil, Ukraine.
    Bezkorovaina, Halyna
    Outpatient Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Frankenberg, Arkadii
    Dnipropetrovsk Regional Clinical Dermatovenerologic Dispensary, Dnipro, Ukraine.
    Onuchyna, Margarita
    Clinical Laboratory Department, Dnipropetrovsk Regional Clinical Dermatovenerologic Dispensary, Dnipro, Ukraine.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and treatment of gonorrhoea patients in Ternopil and Dnipropetrovsk regions of Ukraine, 2013-20182019In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 127, no 7, p. 503-509Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern globally. However, recent gonococcal AMR data from Eastern Europe are extremely limited and no AMR data for strains spreading in Ukraine have ever been internationally published. We investigated the AMR of N. gonorrhoeae isolates in two regions of Ukraine (Ternopil 2013-2018, Dnipropetrovsk 2013-2014), and, where information was available, the treatment administered to the corresponding gonorrhoea patients. Determination of minimum inhibitory concentration (MIC) of eight antimicrobials was performed using Etest and resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied. Overall, 9.3% of the examined 150 isolates were resistant to ciprofloxacin, 6.0% to tetracycline, 2.0% to azithromycin, and 0.7% to benzylpenicillin. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or gentamicin. However, one (0.7%) isolate showed a MIC value of 0.125 mg/L for both ceftriaxone and cefixime, i.e., bordering resistance. Eighty-eight (67.2%) of 131 patients were administered dual therapy (ceftriaxone 1 g plus doxycycline/clarithromycin/azithromycin/ofloxacin) and 22 (16.8%) ceftriaxone 1 g monotherapy. Worryingly, 21 (16.0%) patients received monotherapy with clarithromycin/doxycycline/azithromycin/ofloxacin/benzylpenicillin. In conclusion, the antimicrobial susceptibility of gonococcal strains spreading in Ternopil and Dnipropetrovsk, Ukraine during 2013-2018 was high. Low levels of resistance to ciprofloxacin, tetracycline, azithromycin, and benzylpenicillin were found, but no resistance to the internationally recommended ceftriaxone, cefixime, or spectinomycin. Ceftriaxone 1 g should remain as empiric first-line treatment, in dual therapy with azithromycin or doxycycline or in monotherapy. Continued and expanded gonococcal AMR surveillance in Ukraine is essential to monitor the susceptibility to particularly extended-spectrum cephalosporins, azithromycin and doxycycline.

  • 144. Bolad, Ahmed
    et al.
    Farouk, Salah E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Israelsson, Elisabeth
    Dolo, Amagana
    Doumbo, Ogobara K.
    Nebié, Issa
    Maiga, Boubacar
    Kouriba, Bourema
    Luoni, Gaia
    Sirima, Bienveu S.
    Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 4, p. 380-386Article in journal (Refereed)
    Abstract [en]

    The well-established relative resistance to malaria observed in the Fulani as compared with other sympatric tribes in West Africa has been attributed to their higher levels of serum immunoglobulin (Ig) G antibodies to malarial antigens. In this study, we confirm and extend the previous findings by analyses of the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies in asymptomatic individuals of different sympatric tribes in Burkina Faso (Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantly higher median concentrations of anti-malarial IgG and IgM antibodies than the sympatric tribes at both locations. Although the overall subclass pattern of antibodies did not differ between the tribes, with IgG1 and IgG3 as dominant, the Fulani showed consistently significantly higher levels of these subclasses as compared with those of the non-Fulani individuals. No significant differences were seen in the levels of total IgG between the tribes, but the Fulani showed significantly higher levels of total IgM than their neighbours in both countries. While the antibody levels to some nonmalarial antigens showed the same pattern of differences seen for antibody levels to malaria antigens, no significant such differences were seen with antibodies to other nonmalarial antigens. In conclusion, our results show that the Fulani in two different countries show higher levels of anti-malarial antibodies than sympatric tribes, and this appears not to be a reflection of a general hyper-reactivity in the Fulani.

  • 145. Bolad, Ahmed
    et al.
    Farouk, Salah E.
    Modiano, David
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Dolo, Amagana
    Doumbo, Ogobara K.
    Nebié, Issa
    Maiga, Boubacar
    Kouriba, Bourema
    Luoni, Gaia
    Sirima, Bienveu Sodiomon
    Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 4, p. 380-386Article in journal (Refereed)
    Abstract [en]

    The well-established relative resistance to malaria observed in the Fulani ascompared with other sympatric tribes in West Africa has been attributed totheir higher levels of serum immunoglobulin (Ig) G antibodies to malarialantigens. In this study, we confirm and extend the previous findings by analysesof the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies inasymptomatic individuals of different sympatric tribes in Burkina Faso(Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantlyhigher median concentrations of anti-malarial IgG and IgM antibodies thanthe sympatric tribes at both locations. Although the overall subclass pattern ofantibodies did not differ between the tribes, with IgG1 and IgG3 as dominant,the Fulani showed consistently significantly higher levels of these subclasses ascompared with those of the non-Fulani individuals. No significant differenceswere seen in the levels of total IgG between the tribes, but the Fulani showedsignificantly higher levels of total IgM than their neighbours in both countries.While the antibody levels to some nonmalarial antigens showed the same patternof differences seen for antibody levels to malaria antigens, no significant suchdifferences were seen with antibodies to other nonmalarial antigens. In conclusion,our results show that the Fulani in two different countries show higherlevels of anti-malarial antibodies than sympatric tribes, and this appears not tobe a reflection of a general hyper-reactivity in the Fulani.

  • 146.
    Bolad, Ahmed Kamal
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Antibody responses in Plasmodium falciparum malaria and their relation to protection against the disease2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Protective immunity against Plasmodium falciparum may be obtained after repeated exposure to infection. Several studies indicate that immunity against the blood stages of the P. Falciparum infection is mainly antibody mediated. Protective antibodies may act either on their own, mediate antibody-dependent phagocytosis and/or cell-mediated neutralization of parasites. This thesis describes several aspects of humoral immune responses to P. falciparum infection in individuals of different age groups, different genetic background and with different degrees of malaria exposure.

    Several target antigens for antibody-mediated inhibition of parasite growth or invasion have been identified. One such antigen is Pf332, which appears on the surface of parasitized erythrocytes at late trophozoite and schizont stage. This surface exposure makes the antigen a possible target for opsonizing antibodies. We optimized an in vitro assay for studying cellmediated parasite neutralization in the presence of Pf332-reactive antibodies. Our data demonstrate that, Pf332 specific antibodies are able to inhibit parasite growth on their own and in cooperation with human monocytes.

    The P. falciparum parasites have evolved several mechanisms to evade the host neutralizing immune responses. In this thesis, we show that freshly isolated P. falciparum parasites from children living in a malaria endemic area of Burkina Faso were less sensitive for growth inhibition in vitro by autologous immunoglobulins (Ig) compared with heterologous ones. Analyses of two consecutive isolates taken 14 days apart, with regard to genotypes and sensitivity to growth inhibition in vitro, did not give any clear-cut indications on possible mechanisms leading to a reduced inhibitory activity in autologous parasite/antibody combinations. The frequent presence of persisting parasite clones in asymptomatic children indicates that the parasite possesses as yet undefined mechanisms to evade neutralizing immune responses.

    Transmission reducing measures such insecticide treated nets (ITNs) have been shown to be effective in reducing morbidity and mortality from malaria. However, concerns have been raised that ITNs usage could affect the acquisition of malaria immunity. We studied the effect of the use of insecticide treated curtains (ITC) on anti-malarial immune responses of children living in villages with ITC since birth. The use of ITC did neither affect the levels of parasite neutralizing immune responses nor the multiplicity of infection. These results indicate that the use of ITC does not interfere with the acquisition of anti-malarial immunity in children living in a malaria hyperendemic area.

    There is substantial evidence that the African Fulani tribe is markedly less susceptible to malaria infection compared to other sympatrically living ethnic tribes. We investigated the isotypic humoral responses against P. falciparum asexual blood stages in different ethnic groups living in sympatry in two countries exhibiting different malaria transmission intensities, Burkina Faso and Mali. We observed higher levels of the total malaria-specific-IgG and its cytophilic subclasses in individuals of the Fulani tribe as compared to non-Fulani individuals. Fulani individuals also showed higher levels of antibodies to measles antigen, indicating that the intertribal differences are not specific for malaria and might reflect a generally activated immune system in the Fulani.

  • 147.
    Boman, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindqvist, Helena
    Forsberg, Lars
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brief manual-based single-session Motivational Interviewing for reducing high-risk sexual behaviour in women: an evaluation2018In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 29, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

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

  • 148.
    Bondza, Sina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Ridgeview Instruments AB, Uppsala.
    Björkelund, Hanna
    Ridgeview Instruments AB, Uppsala.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Ridgeview Instruments AB, Uppsala.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Ridgeview Instruments AB, Uppsala.
    Novel Real-Time Proximity Assay for Characterizing Multiple Receptor Interactions on Living Cells2017In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, no 24, p. 13212-13218Article in journal (Refereed)
    Abstract [en]

    Cellular receptor activity is often controlled through complex mechanisms involving interactions with multiple molecules, which can be soluble ligands and/or other cell surface molecules. In this study, we combine a fluorescence-based technology for real-time interaction analysis with fluorescence quenching to create a novel time-resolved proximity assay to study protein-receptor interactions on living cells. This assay extracts the binding kinetics and affinity for two proteins if they bind in proximity on the cell surface. One application of real-time proximity interaction analysis is to study relative levels of receptor dimerization. The method was primarily evaluated using the HER2 binding antibodies Trastuzumab and Pertuzumab and two EGFR binding antibodies including Cetuximab. Using Cetuximab and Trastuzumab, proximity of EGFR and HER2 was investigated before and after treatment of cells with the tyrosine-kinase inhibitor Gefitinib. Treated cells displayed 50% increased proximity signal, whereas the binding characteristics of the two antibodies were not significantly affected, implying an increase in the EGFR-HER2 dimer level. These results demonstrate that real-time proximity interaction analysis enables determination of the interaction rate constants and affinity of two ligands while simultaneously quantifying their relative colocalization on living cells.

  • 149.
    Borres, Magnus P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Karabus, Sarah
    Red Cross War Mem Childrens Hosp, Div Allergol, Cape Town, South Africa;Netcare Christiaan Barnard Mem Hosp, Private Practice, Cape Town, South Africa.
    What is new in allergy and component tetsing?2018In: CURRENT ALLERGY & CLINICAL IMMUNOLOGY, ISSN 1609-3607, Vol. 31, no 3, p. 131-136Article, review/survey (Refereed)
  • 150.
    Borres, Magnus P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Maruyama, Nobuyuki
    Kyoto Univ, Grad Sch Agr, Lab Food Qual Design & Dev, Kyoto, Japan..
    Sato, Sakura
    Sagamihara Natl Hosp, Dept Allergy, Clin Res Ctr Allergol & Rheumatol, Sagamihara, Kanagawa, Japan..
    Ebisawa, Motohiro
    Sagamihara Natl Hosp, Dept Allergy, Clin Res Ctr Allergol & Rheumatol, Sagamihara, Kanagawa, Japan..
    Recent advances in component resolved diagnosis in food allergy2016In: Allergology International, ISSN 1323-8930, E-ISSN 1440-1592, Vol. 65, no 4, p. 378-387Article, review/survey (Refereed)
    Abstract [en]

    Due to the high prevalence of food allergic diseases globally there are increasing demands in clinical practice for managing IgE-mediated conditions. During the last decade, component resolved diagnostics has been introduced into the field of clinical allergology, providing information that cannot be obtained from extract-based tests. Component resolved data facilitate more precise diagnosis of allergic diseases and identify sensitizations attributable to cross-reactivity. Furthermore it assists risk assessment in clinical practice as sensitization to some allergenic molecules is related to persistence of clinical symptoms and systemic rather than local reactions. The information may also aid the clinician in prescription of oral immunotherapy (OIT) in patients with severe symptoms, and in giving advice on food allergen avoidance or on the need to perform food challenges. The use of allergen components is rapidly evolving and increases our possibility to treat food allergic patients with a more individual approach. Using molecular allergology, we can already now better diagnose, prognose and grade the food allergy. In summary, daily routine molecular allergy diagnostics offers a number of benefits that give us a higher diagnostic precision and allow for better management of the patient.

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