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  • 1.
    Edston, Erik
    et al.
    Linköping University, Department of health and environment. Linköping University, Faculty of Health Sciences.
    Perskvist , Nasrin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Histiocytoid cardiomyopathy and ventricular non-compaction in a case of sudden death in a female infant2009In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 123, no 1, p. 47-53Article in journal (Refereed)
    Abstract [en]

    A case of sudden infant death with histiocytoid cardiomyopathy and ventricular non-compaction was investigated with immunohistochemical methods. Histiocytoid cardiomyopathy is thought to be a developmental defect of the cardiomyocytes of the conduction system. In contrast to mature cardiomyocytes, the histiocytoid cells showed only weak reactions to desmin and myosin antibodies. They lacked cross-striation but reacted strongly to enolase and myoglobin antibodies. The protein Pax-7, seen only in cells undergoing differentiation, and the proliferation marker Ki-67 were not expressed in the histiocytoid cells. In areas of altered myocardium, clusters of CD4-, CD8-, and CD68-positive inflammatory cells were seen as well an abundance of mast cells. With the TUNEL method, it was found that many of the histiocytoid cells were undergoing apoptosis. Our results confirm that the histiocytoid cells are defective cardiomyocytes. The apoptotic and inflammatory changes point to a degenerative process rather than defective maturation of cardiomyocytes as has been suggested in some earlier studies. Ventricular non-compaction is a developmental defect of the subendocardial tissue with hypertrabeculation and weak development of the papillary muscles. Only one case combined with histiocytoid cardiomyopathy has been described previously. A causal connection between the two conditions cannot be established until more cases have been analyzed.

  • 2.
    Majeed, Meytham
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Perskvist, Nasrin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ernst, Joel D.
    Division of Infectious Diseases and Rosalind Russell Research Laboratory, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, U.S.A..
    Orselius, Kristina
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosisin human neutrophils1998In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 24, no 5, p. 309-320Article in journal (Refereed)
    Abstract [en]

    The phagocytic function of neutrophils is a crucial element in the host defence against invading microorganisms. We investigated phagocytosis and intracellular killing of an attenuated strain of Mycobacterium tuberculosis(H37Ra) by human neutrophils focusing on the role of the cytosolic free calcium concentration [Ca2+]iand certain cytosolic calcium-dependent membrane-binding proteins annexins. Phagocytic uptake did not trigger a calcium rise and occurred independently of different calcium conditions, and in a serum-dependent manner. Changes in the viability of H37Ra were determined by agar plate colony count and a radiometric assay. Neutrophils showed a capacity to kill ingested mycobacteria and this occurred without a rise in [Ca2+]i. The ability to kill H37Ra decreased in the absence of extracellular calcium and when intra-extracellular calcium was reduced. Immunofluorescence staining revealed that during phagocytosis of H37Ra, annexins III, IV and VI translocated from cytoplasm to the proximity of the H37Ra-containing phagosomes, whereas the localization of annexin I and V remained unchanged. The translocation of annexin IV occurred even when Ca2+-depleted neutrophils ingested H37Ra in the absence of extracellular calcium. We concluded that neutrophil-mediated killing of mycobacteria is a Ca2+-dependent process. The fact that the association of certain annexins to the membrane vesicle containing H37Ra differ from other phagosomes suggests a selective regulatory mechanism during phagocytosis of mycobacteria by neutrophils.

  • 3.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Perskvist, Nasrin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    An in vitro model for assessment of the biological activity of hepatocyte growth factor2007In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 25, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a multifunctional growth factor with potent wound-healing properties that functions in the healing of chronic injuries. However, there may be a loss of HGF activity in certain chronic cases; this might be indicated by the presence of high amounts of HGF in body fluids and by the elevated expression of the HGF receptor in tissue biopsies. In such cases, a reliable means of assessing the activity of endogenous HGF would be valuable in allowing clinicians to decide if treatment with HGF would be useful. In this study, we developed an in vitro wound assay that used a mouse skin epithelial cell line to evaluate the biological activity of HGF. We showed that HGF accelerated the motility of the epithelial cells in a dose-dependent fashion with high sensitivity and specificity. This in vitro assay might be used to determine the activity of both endogenous and recombinant HGF.

  • 4.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Perskvist, Nasrin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Holmgren-Pettersson, Kajsa
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Hepatocyte growth factor accelerates restitution of damaged mouse melanocyte monolayer in vitroManuscript (preprint) (Other academic)
    Abstract [en]

    In a recent pilot study we observed enhanced wound repair properties in chronic leg ulcers after HGF administration. The aim of the present study was to assess the mechanism of HGF in the wound-healing process by an in vitro study of HGF on a transformed mouse skin epithelial cell line (CCL-53. 1) that expresses the HGF receptor, c-Met. HGF did not enhance cell proliferation, judged by [3H}thymidine incorporation. The restitution of injured epithelial cells was significantly increased by HGF. This effect was dose-dependant, beginning at low concentrations (1ng/ml) of HGF, and was inhibited by heparin. HGF enhanced migration of epithelial cells compared to untreated controls. The actin structure was changed by HGF, with less F-actin in the dense peripheral structures compared to untreated cells. Corresponding morphological changes in cells were found showing spread morphology with smaller intracellular spaces after HGF addition. We conclude that HGF may contribute to restitution of the damaged mouse epithelial cell monolayer by morphologic changes and enhanced motility of cells towards the injured area.

  • 5.
    Perskvist, Nasrin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Interaction Between Mycobacterium tuberculosis and Human Neutrophils2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is responsible for more deaths each year than any other single pathogen. Mononuclear phagocytes and T cells are crucially involved in the control and local containment of this infection. Less is known about the contribution of neutrophils to control tuberculosis. As one of the most efficient phagocytic cells of the immune system, neutrophils restrict the initial, local replication of numerous pathogens and thereby delay their systemic spread. Neutrophils immigrate quickly to the site of mycobacterial entry and are found in granulomas after infection with M. tuberculosis. The aims of this study were to investigate how neutrophils control M. tuberculosis in the acute phase of mycobacterial infection and the signaling pathways regulating these processes.

    When neutrophils are exposed to mycobacteria, they exhibit the typical early bactericidal responses: phagocytosis, generation of reactive oxygen intermediate (ROI), degranulation and the killing of mycobacteria. While production of ROI and M. tuberculosis killing in neutrophils are calcium dependent events, phagocytosis of M. tuberculosis is a calcium-independent process. Measuring intracellular calcium concentration [(Ca+2)]i, revealed that there is no increase in the level of [(Ca+2)]i in single neutrophils upon ingestion of M. tuberculosis. Investigation of the M. tuberculosis-induced phagocytic pathway showed that stimulation of neutrophils by M. tuberculosis triggers tyrosine phosphorylation of PLCγ2 and its association with sch, an adapter protein, and that such association are critical for the M. tuberculosis-stimulated ROI production through activating p38 MAPK. During phagolysosome biogenesis, phagosomes containing M. tuberculosis fused sequentially with secondary granule and late endosomal vacuoles, while delivery of azurophil granule was inhibited. A complex of Rab5a-GTP and syntaxin-4 controlled this fusion process. We suggested that the retention of this complex on the mycobacterial phagosome might allow mycobacteria to avoid the usual physiological destination of phagocytic maturation. Neutrophils infected by M. tuberculosis underwent rapid apoptosis that was mediated by activation of caspase-3 and the expression of Bax and Bcl-x1, two antagonizing members of Bcl-2 family. The level of ROI production controlled this M. tuberculosis induced apoptotic pathway. Apoptotic neutrophils are removed by macrophages, which leads to an augmented mycobactericidal effect in these cells. The results from this work show that neutrophils play an efficient and important role in the early innate immune response against mycobacterial infection, a process that may influence the subsequent specific immune response at the site of infection.

    List of papers
    1. Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosisin human neutrophils
    Open this publication in new window or tab >>Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosisin human neutrophils
    Show others...
    1998 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 24, no 5, p. 309-320Article in journal (Refereed) Published
    Abstract [en]

    The phagocytic function of neutrophils is a crucial element in the host defence against invading microorganisms. We investigated phagocytosis and intracellular killing of an attenuated strain of Mycobacterium tuberculosis(H37Ra) by human neutrophils focusing on the role of the cytosolic free calcium concentration [Ca2+]iand certain cytosolic calcium-dependent membrane-binding proteins annexins. Phagocytic uptake did not trigger a calcium rise and occurred independently of different calcium conditions, and in a serum-dependent manner. Changes in the viability of H37Ra were determined by agar plate colony count and a radiometric assay. Neutrophils showed a capacity to kill ingested mycobacteria and this occurred without a rise in [Ca2+]i. The ability to kill H37Ra decreased in the absence of extracellular calcium and when intra-extracellular calcium was reduced. Immunofluorescence staining revealed that during phagocytosis of H37Ra, annexins III, IV and VI translocated from cytoplasm to the proximity of the H37Ra-containing phagosomes, whereas the localization of annexin I and V remained unchanged. The translocation of annexin IV occurred even when Ca2+-depleted neutrophils ingested H37Ra in the absence of extracellular calcium. We concluded that neutrophil-mediated killing of mycobacteria is a Ca2+-dependent process. The fact that the association of certain annexins to the membrane vesicle containing H37Ra differ from other phagosomes suggests a selective regulatory mechanism during phagocytosis of mycobacteria by neutrophils.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81105 (URN)10.1006/mpat.1997.0200 (DOI)
    Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
    2. Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase
    Open this publication in new window or tab >>Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase
    2000 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 164, no 2, p. 959-965Article in journal (Refereed) Published
    Abstract [en]

    Recent studies have shown that human neutrophils play a significant protective role in mycobacteria infection. When encountered with mycobacteria, neutrophils exhibit the typical early bactericidal responses including phagocytosis and generation of reactive oxygen intermediates (ROI), but the underlying mechanisms are largely unknown. The present study shows that stimulation of neutrophils with an attenuated strain of Mycobacterium tuberculosis H37Ra (Mtb) led to a tyrosine kinase-dependent ROI production in these cells. Stimulation with Mtb induces a rapid and transient tyrosine phosphorylation of several proteins, one of which was identified as phospholipase Cγ2 (PLCγ2). Several tyrosine-phosphorylated proteins were associated with the PLCγ2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein. A role for PLCγ2-Shc association in the generation of ROI is supported by the observations that stimulation with Mtb causes the activation of p38 mitogen-activated protein kinase (MAPK), a downstream target of the Shc/Ras signaling cascade, and that the effect of genistein on ROI production coincided with its ability to inhibit both PLCγ2-Shc association and p38 MAPK activation. Moreover, pretreatment of neutrophils with a PLC inhibitor markedly suppresses the Mtb-stimulated ROI production as well as p38 MAPK activation in these cells. Taken together, these results indicate that stimulation of neutrophils with Mtb triggers the tyrosine phosphorylation of PLCγ2 and its association with Shc, and that such association is critical for the Mtb-stimulated ROI production through activating p38 MAPK.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-49897 (URN)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved
    3. Rab5a GTPase regulates fusion between pathogen-containing phagosomes and cytoplasmic organelles in human neutrophils
    Open this publication in new window or tab >>Rab5a GTPase regulates fusion between pathogen-containing phagosomes and cytoplasmic organelles in human neutrophils
    2002 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 115, no 6, p. 1321-1330Article in journal (Refereed) Published
    Abstract [en]

    Biogenesis of phagolysosomes proceeds through a sequential series of interactions with endocytic organelles, a process known to be regulated by Rab and SNARE proteins. The molecular mechanisms underlying phagosome maturation in neutrophils are, however, not clearly understood. We investigated fusion between phagosomes containing the intracellular pathogen Mycobacterium tuberculosis versus the extracellular pathogen Staphylococcus aureus (designated MCP for mycobacteria-containing phagosome and SCP for S. aureus-containing phagosome) and cytoplasmic compartments in human neutrophils. Western blot analysis of phagosomes isolated after internalisation revealed that lactoferrin (a constituent of secondary granules) and LAMP-1 were incorporated into both SCP and MCP, whereas hck (marker of azurophil granules) interacted solely with SCP. The subcellular distribution of the proteins Rab5a and syntaxin-4 suggested a role in docking of granules and/or endosomes to the target membrane in the neutrophil. We observed that during phagocytosis, Rab5a in GTP-bound form interacted with syntaxin-4 on the membrane of MCP and were retained for up to 90 minutes, whereas the complex was recruited to the SCP within 5 minutes but was selectively depleted from these vacuoles after 30 minutes of phagocytosis. Downregulation of Rab5a by antisense oligonucleotides efficiently reduced the synthesis of Rab5a, the binding of syntaxin-4 to MCP and SCP and the capacity for fusion exhibited by the pathogen-containing phagosomes, but it had no effect on bacteria internalisation. These data indicate that the difference in granule fusion is correlated with a difference in the association of Rab5a and syntaxin-4 with the phagosomes. Intracellular pathogen-containing phagosomes retain Rab5a and syntaxin-4, whereas extracellular pathogen-containing phagosomes bind briefly to this complex. These results also identified Rab5a as a key regulator of phagolysosome maturation in human neutrophils.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26512 (URN)11069 (Local ID)11069 (Archive number)11069 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway
    Open this publication in new window or tab >>Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway
    2002 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 168, no 12, p. 6358-6365Article in journal (Refereed) Published
    Abstract [en]

    In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26523 (URN)11082 (Local ID)11082 (Archive number)11082 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 6.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Edston, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Differential accumulation of pulmonary and cardiac mast cell-subsets and eosinophils between fatal anaphylaxis and asthma death - A postmortem comparative study2007In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 169, no 1, p. 43-49Article in journal (Refereed)
    Abstract [en]

    The distribution profile of infiltrated mast cell-subpopulations and eosinophils in the lung and heart sections of the patients who died of severe allergic hyperresponsiveness, was investigated. Four study groups were designed comprising 9 cases who died in systemic anaphylaxis (Group I), 10 asthmatic individuals whose death were assigned to acute and severe bronchial asthma (Group II), 10 asthmatic cases who died from non-immunological diseases (Group III). Twenty consecutive autopsies of non-allergic subjects who died of unnatural causes (Group IV) served as control group in this study. Utilizing antibodies against human tryptase and chymase and a double immunohistochemical staining method, we distinguished successfully all three subsets of mast cells (MC), MC-TC (containing both tryptase and chymase), MC-T (containing only tryptase) and MC-C (containing only chymase) types, subdivided on the basis of the protease compositions of their secretory granules. In order to immunostaining eosinophils, we used antibody to major basic protein as a marker. We also measured postmortem blood tryptase, specific and total serum IgE. The intriguing finding of this study was the marked differences of cellular composition in the lung between fatal anaphylaxis and asthma death Significant augmentation of MCs infiltrated in lung and heart sections of anaphylaxis patients and drastic infiltration of bronchial eosinophils in asthmatic death and consequent release of their related inflammatory mediators might explain the differential expression of the associated symptoms in these two groups. The anaphylactic deaths did show neither emphysema nor significant mucous bronchial secretions whereas all asthmatic deaths did. The degree of pulmonary congestion and edema was also more severe in anaphylaxis. This corresponded with the histological findings and the location and number of mast cell-subsets and eosinophils in the different compartments of the lungs. We have demonstrated that the third type of mast cell MC-C is only found in the lungs in anaphylactic deaths. The practical consequence of our study will be that it is now possible to confirm a suspicion of anaphylaxis death not only by measurements of serum mast cell tryptase, but also by immunohistochemical methods.

  • 7.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Long, Min
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway2002In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 168, no 12, p. 6358-6365Article in journal (Refereed)
    Abstract [en]

    In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.

  • 8.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Kulyte, Agné
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rab5a GTPase regulates fusion between pathogen-containing phagosomes and cytoplasmic organelles in human neutrophils2002In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 115, no 6, p. 1321-1330Article in journal (Refereed)
    Abstract [en]

    Biogenesis of phagolysosomes proceeds through a sequential series of interactions with endocytic organelles, a process known to be regulated by Rab and SNARE proteins. The molecular mechanisms underlying phagosome maturation in neutrophils are, however, not clearly understood. We investigated fusion between phagosomes containing the intracellular pathogen Mycobacterium tuberculosis versus the extracellular pathogen Staphylococcus aureus (designated MCP for mycobacteria-containing phagosome and SCP for S. aureus-containing phagosome) and cytoplasmic compartments in human neutrophils. Western blot analysis of phagosomes isolated after internalisation revealed that lactoferrin (a constituent of secondary granules) and LAMP-1 were incorporated into both SCP and MCP, whereas hck (marker of azurophil granules) interacted solely with SCP. The subcellular distribution of the proteins Rab5a and syntaxin-4 suggested a role in docking of granules and/or endosomes to the target membrane in the neutrophil. We observed that during phagocytosis, Rab5a in GTP-bound form interacted with syntaxin-4 on the membrane of MCP and were retained for up to 90 minutes, whereas the complex was recruited to the SCP within 5 minutes but was selectively depleted from these vacuoles after 30 minutes of phagocytosis. Downregulation of Rab5a by antisense oligonucleotides efficiently reduced the synthesis of Rab5a, the binding of syntaxin-4 to MCP and SCP and the capacity for fusion exhibited by the pathogen-containing phagosomes, but it had no effect on bacteria internalisation. These data indicate that the difference in granule fusion is correlated with a difference in the association of Rab5a and syntaxin-4 with the phagosomes. Intracellular pathogen-containing phagosomes retain Rab5a and syntaxin-4, whereas extracellular pathogen-containing phagosomes bind briefly to this complex. These results also identified Rab5a as a key regulator of phagolysosome maturation in human neutrophils.

  • 9.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Edston, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Bäckström, Gerd
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    Lodestad, Iréne
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    Palm, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    TNF-α and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death2008In: Fetal & Pediatric Pathology, ISSN 1551-3815, Vol. 27, no 3, p. 149-165Article in journal (Refereed)
    Abstract [en]

    We hypothesized that genetic variations of cytokines could contribute to the risk of developing a fatal immunological reaction in the heart of infants. Thus, tumor necrosis factor (TNF)-α and interleukin (IL)-10 gene polymorphisms versus induction of cardioimmunologxical responses in victims of sudden infant death syndrome (SIDS) were explored. We genotyped 35 infants (23 cases of SIDS and 12 infants with a known cause of death), and 100 healthy adult controls for IL-10 –1082 G/A, −592 C/A and TNF-α-238 G/A, −308 G/A. We found a higher frequency of the ATA haplotype and ATA/ATA genotype of IL-10 associated with SIDS (13%). The frequency of homozygote infants for IL-10 haplotypes in SIDS was higher (52%) than the control group (34%). All SIDS cases were homozygotice for the TNF-α-238 G allele and 20 infants were homozygous for the TNF-α-308 G allele in the same group. None of the infants with higher levels of infiltrated T-cells (n=8) was homozygous for IL-10 gene polymorphisms, whereas in contrast 3 cases of the 6 that displayed higher levels of cardiac mast cells were homozygous. In this study, the increased number of interstitial T-cells, mast cells, and macrophages in the myocardial interstitium demonstrated no correlation with the genotype for either cytokines.

  • 10.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Mycobacterium tuberculosis induce rapid apoptosis in human neutrophils through oxygen-dependent pathway2000Conference paper (Other academic)
  • 11.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 164, no 2, p. 959-965Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that human neutrophils play a significant protective role in mycobacteria infection. When encountered with mycobacteria, neutrophils exhibit the typical early bactericidal responses including phagocytosis and generation of reactive oxygen intermediates (ROI), but the underlying mechanisms are largely unknown. The present study shows that stimulation of neutrophils with an attenuated strain of Mycobacterium tuberculosis H37Ra (Mtb) led to a tyrosine kinase-dependent ROI production in these cells. Stimulation with Mtb induces a rapid and transient tyrosine phosphorylation of several proteins, one of which was identified as phospholipase Cγ2 (PLCγ2). Several tyrosine-phosphorylated proteins were associated with the PLCγ2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein. A role for PLCγ2-Shc association in the generation of ROI is supported by the observations that stimulation with Mtb causes the activation of p38 mitogen-activated protein kinase (MAPK), a downstream target of the Shc/Ras signaling cascade, and that the effect of genistein on ROI production coincided with its ability to inhibit both PLCγ2-Shc association and p38 MAPK activation. Moreover, pretreatment of neutrophils with a PLC inhibitor markedly suppresses the Mtb-stimulated ROI production as well as p38 MAPK activation in these cells. Taken together, these results indicate that stimulation of neutrophils with Mtb triggers the tyrosine phosphorylation of PLCγ2 and its association with Shc, and that such association is critical for the Mtb-stimulated ROI production through activating p38 MAPK.

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