| 1. |
- Arvidsson, Ida, et al.
(författare)
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Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:4, s. 1276-1286
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Tidskriftsartikel (refereegranskat)abstract
- Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
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| 2. |
- Békássy, Zivile D., et al.
(författare)
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Aliskiren inhibits renin-mediated complement activation
- 2018
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 94:4, s. 689-700
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Tidskriftsartikel (refereegranskat)abstract
- Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.
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| 3. |
- Burlaka, Ievgeniia, et al.
(författare)
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Ouabain Protects against Shiga Toxin-Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL
- 2013
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:9, s. 1413-1423
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Tidskriftsartikel (refereegranskat)abstract
- Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-B pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-B antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.
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| 4. |
- Chao, Yashuan, et al.
(författare)
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Distinct phenotypes of platelet, monocyte, and neutrophil activation occur during the acute and convalescent phase of COVID-19
- 2021
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 32:8, s. 1092-1102
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Tidskriftsartikel (refereegranskat)abstract
- SARS-CoV-2 has spread rapidly worldwide, causing the COVID-19 pandemic. Platelet activation and platelet-leukocyte complex formation are proposed to contribute to disease progression. Here, we report platelet and leukocyte activation during acute and convalescent COVID-19 in patients recruited between May-July 2020. Blood samples were analyzed by flow cytometry and ELISA using paired comparison between inclusion (day 0) and 28 days later. The majority of patients were mildly or moderately ill with significantly higher cytokine levels (IL-6 and IL-10) on day 0 as compared with day 28. Platelet activation and granule release were significantly higher on day 0 compared with day 28, as determined by ADP- or thrombin-induced surface CD62P expression, baseline released CD62P, and thrombin-induced platelet-monocyte complex formation. Monocyte activation and procoagulant status at baseline and post activation were heterogeneous but generally lower on day 0 compared with day 28. Baseline and thrombin- or fMLF-induced neutrophil activation and procoagulant status were significantly lower on day 0 compared with day 28. We demonstrate that during the acute phase of COVID-19 compared with the convalescent phase, platelets are more responsive while neutrophils are less responsive. COVID-19 is associated with thromboembolic events where platelet activation and interaction with leukocytes may play an important role.
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| 5. |
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| 6. |
- Johansson, Karl E., et al.
(författare)
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Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli (EHEC), that cause gastrointestinal infection leading to hemolytic uremic syndrome. The aim of this study was to investigate if Stx signals via ATP and if blockade of purinergic receptors could be protective. Stx induced ATP release from HeLa cells and in a mouse model. Toxin induced rapid calcium influx into HeLa cells, as well as platelets, and a P2X1 receptor antagonist, NF449, abolished this effect. Likewise, the P2X antagonist suramin blocked calcium influx in Hela cells. NF449 did not affect toxin intracellular retrograde transport, however, cells pre-treated with NF449 exhibited significantly higher viability after exposure to Stx for 24 hours, compared to untreated cells. NF449 protected HeLa cells from protein synthesis inhibition and from Stx-induced apoptosis, assayed by caspase 3/7 activity. The latter effect was confirmed by P2X1 receptor silencing. Stx induced the release of toxin-positive HeLa cell- and platelet-derived microvesicles, detected by flow cytometry, an effect significantly reduced by NF449 or suramin. Suramin decreased microvesicle levels in mice injected with Stx or inoculated with Stx-producing EHEC. Taken together, we describe a novel mechanism of Stx-mediated cellular injury associated with ATP signaling and inhibited by P2X receptor blockade.
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| 7. |
- Jongruamklang, Philaiphon, et al.
(författare)
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Platelets inhibit erythrocyte invasion by Plasmodium falciparum at physiological platelet:erythrocyte ratios
- 2022
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Ingår i: Transfusion Medicine. - : Wiley. - 0958-7578 .- 1365-3148. ; 32:2, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the effect of platelet:erythrocyte (P:E) ratios on Plasmodium falciparum erythrocyte invasion.BACKGROUND: Recent reports have shown that platelets are directly involved in the immune response towards P. falciparum during erythrocyte invasion. However, the literature both supports and conflicts with a role for platelets in limiting invasion. Also, the effect of platelet numbers on invasion (parasitemia) has not been thoroughly investigated.METHODS/MATERIALS: The P. falciparum strains FCR3S1.2 and W2mef were cultured with group O erythrocytes. The cultures were synchronised and supplemented with pooled platelets at P:E ratios ranging from 1:100 to 1:2. Parasitemia was measured at 40 h by flow cytometry and by microscopy of blood smears.RESULTS: A linear relationship was observed between reduced invasion and increased platelet numbers at P:E ratios ranging from 1:100 to 1:20. However, this effect was reversed at lower ratios (1:10-1:2). Microscopic evaluation revealed aggregation and attachment of platelets to erythrocytes, but not specifically to parasitised erythrocytes.CONCLUSION: We have shown that under physiological P:E ratios (approx. 1:10-1:40), platelets inhibited P. falciparum invasion in a dose-dependent manner. At ratios of 1:10 and below, platelets did not further increase the inhibitory effect and, although the trend was reversed, inhibition was still maintained.
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| 8. |
- Järås, Marcus, et al.
(författare)
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Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression.
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:3, s. 1084-1091
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Tidskriftsartikel (refereegranskat)abstract
- Telomerase activity has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. However, it has been unclear whether human HSCs have telomerase activity and how telomerase activity is regulated within the HSC and progenitor pool. Here, we isolated living cord-blood (CB) CD34+ cells with up-regulated human telomerase reverse transcriptase (hTERT) expression by using an hTERT-reporting adenoviral vector encoding destabilized green fluorescent protein (dGFP) driven by the hTERT promoter, and functionally characterized them in comparison with control vector–transduced CD34+ cells expressing GFP. Following a 2-day serum-free transduction protocol, cells were sorted into a dGFP+ and a GFP+ fraction. Cell-cycle analysis revealed that the dGFP+ cells had a greater proportion of cells in S/G2/M phase compared with the GFP+ cells, (56% ± 1.8% vs 35% ± 4.3%; P < .001) and fewer cells in G0 phase (8.1% ± 3.0% vs 20% ± 4.7%; P < .01) However, the colony-forming and short-term nonobese diabetic/severe combined immunodeficient (NOD/SCID) B2m–/– mice bone marrow–repopulating capacities were similar between the dGFP+ and the GFP+ cells. Interestingly, the dGFP+ cells had a 6-fold lower repopulating capacity in NOD/SCID mice compared with the GFP+ cells and lacked secondary NOD/SCID B2m–/– mice bone marrow–repopulating capacity. Thus, up-regulation of hTERT expression within the CB HSC pool is accompanied by decreased self-renewal capacity.
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| 9. |
- Kapur, Rick, et al.
(författare)
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Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:13, s. 1651-1663
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.
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| 10. |
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| 11. |
- Kapur, Rick, et al.
(författare)
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Osteopontin mediates murine transfusion-related acute lung injury through stimulation of pulmonary neutrophil accumulation.
- 2019
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 134:1, s. 74-84
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within 6 hours of a blood transfusion. There are no specific therapies available and the pathogenesis remains unclear. Pre-existing inflammation is a risk factor for TRALI and neutrophils (PMNs) are considered to be the major pathogenic cells mediating lung damage. Osteopontin (OPN) is a multifunctional protein expressed at sites of inflammation and, for example, is involved in pulmonary disorders, can regulate cellular migration and can function as a PMN-chemoattractant. We investigated whether OPN is involved in TRALI-induction by promoting PMN-recruitment to the lungs. Using a previously established murine TRALI model, we found that in contrast to wildtype (WT) mice, OPN knock-out (KO) mice were resistant to antibody-mediated PMN-dependent TRALI induction. Administration of purified OPN to the OPN KO mice, however, restored the TRALI response and pulmonary PMN-accumulation. Alternatively, blockade of OPN in WT mice using an anti-OPN antibody prevented the onset of TRALI induction. Using pulmonary immunohistochemistry, OPN could be specifically detected in the lungs of mice that suffered from TRALI. The OPN-mediated TRALI responses were independent from other PMN-chemoattractants including macrophage inflammatory protein (MIP)-2. These data indicate that OPN is critically required for induction of antibody-mediated murine TRALI through localization to the lungs and stimulation of pulmonary PMN-recruitment. This suggests that anti-OPN antibody-therapy may be a potential strategy to explore in targeting TRALI in patients.
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| 12. |
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| 13. |
- Kapur, Rick, et al.
(författare)
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Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP)
- 2020
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 31:3, s. 399-402
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies and/or autoreactive T cells destroy platelets and megakaryocytes in the spleen and bone marrow, respectively. Thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag) have made a substantial contribution to the treatment of patients with ITP, which are refractory to first-line treatments and approximately 30% demonstrate sustained elevated platelet counts after drug tapering. How TPO-RA induce these sustained responses is not known. We analyzed the efficacy of a murine TPO-RA in a well-established murine model of active ITP. Treatment with TPO-RA (10 ug/kg, based on pilot dose escalation experiments) significantly raised the platelet counts in ITP-mice. Immunomodulation was assessed by measuring serum IgG anti-platelet antibody levels; TPO-RA-treated mice had significantly reduced IgG anti-platelet antibodies despite the increasing platelet counts. These results suggest that TPO-RA is not only an efficacious therapy but also reduces anti-platelet humoral immunity in ITP.
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| 14. |
- Karlsson, Christine, et al.
(författare)
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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.
- 2007
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 33:4, s. 440-454
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.
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| 15. |
- Maouia, Amal, et al.
(författare)
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The Immune Nature of Platelets Revisited
- 2020
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Ingår i: Transfusion Medicine Reviews. - : Elsevier BV. - 0887-7963. ; 34:4, s. 209-220
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Forskningsöversikt (refereegranskat)abstract
- Platelets are the primary cellular mediators of hemostasis and this function firmly acquaints them with a variety of inflammatory processes. For example, platelets can act as circulating sentinels by expressing Toll-like receptors (TLR) that bind pathogens and this allows platelets to effectively kill them or present them to cells of the immune system. Furthermore, activated platelets secrete and express many pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. In addition, platelets can directly influence adaptive immune responses via secretion of, for example, CD40 and CD40L molecules. Platelets are also the source of most of the microvesicles in the circulation and these miniscule elements further enhance the platelet's ability to communicate with the immune system. More recently, it has been demonstrated that platelets and their parent cells, the megakaryocytes (MK), can also uptake, process and present both foreign and self-antigens to CD8+ T-cells conferring on them the ability to directly alter adaptive immune responses. This review will highlight several of the non-hemostatic attributes of platelets that clearly and rightfully place them as integral players in immune reactions.
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| 16. |
- Marcoux, Genevieve, et al.
(författare)
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Platelet EVs contain an active proteasome involved in protein processing for antigen presentation via MHC-I molecules
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 138:25, s. 2607-2620
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Tidskriftsartikel (refereegranskat)abstract
- In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by the budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery are transferred to PEVs by activated platelets. Using molecular and functional assays, we found that the active 20S proteasome was enriched in PEVs, along with major histocompatibility complex class I (MHC-I) and lymphocyte costimulatory molecules (CD40L and OX40L). Proteasome-containing PEVs were identified in healthy donor blood, but did not increase in platelet concentrates that caused adverse transfusion reactions. They were augmented, however, after immune complex injections in mice. The complete biodistribution of murine PEVs after injection into mice revealed that they principally reached lymphoid organs, such as spleen and lymph nodes, in addition to the bone marrow, and to a lesser extent, liver and lungs. The PEV proteasome processed exogenous ovalbumin (OVA) and loaded its antigenic peptide onto MHC-I molecules, which promoted OVA-specific CD8+ T-lymphocyte proliferation. These results suggest that PEVs contribute to adaptive immunity through cross-presentation of antigens and have privileged access to immune cells through the lymphatic system, a tissue location that is inaccessible to platelets.
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| 17. |
- Na, Manli, et al.
(författare)
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Adenovirus assembly is impaired by BMI1-related histone deacetylase activity.
- 2014
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Ingår i: Virology. - : Elsevier BV. - 1096-0341 .- 0042-6822. ; 456:Apr 17, s. 227-237
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb ring finger oncogene BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) plays a critical role in development of several types of cancers. Here, we report an inverse relationship between levels of BMI1 expression and adenovirus (Ad) progeny production. Enforced BMI1 expression in A549 cells impaired Ad progeny production. In contrast, knocking-down of endogenous BMI1 expression enhanced progeny production of a conditionally replicating Ad and wild-type Ad5 and Ad11p. Ad vectors overexpressing BMI1 were not impaired in the replication of progeny genomes and in the expression of E1A and Ad structural proteins. However, 293 cells infected by Ad vector overexpressing BMI1 contained a large proportion of morphologically irregular Ad particles. This effect was reversed in 293 cells pre-treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in parallel with the production of infectious Ad particles. Our findings suggest an inhibitory role of BMI1 in Ad morphogenesis that can be implied in Ad tropism and Ad-mediated cancer therapy.
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| 18. |
- Rebetz, Johan
(författare)
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Challenges in the treatment of malignant glioma with oncolytic adenovirus
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant glioma is a tumor that spreads rapidly throughout brain and is almost impossible to remove completely by surgery. It is resistant to chemo- and radiotherapy and the prognosis is very poor. As a result, there is a desperate need for development of novel therapies against this devastating disease. Because of the heterogeneity in this cancer success has been limited, but a recent concept in cancer biology suggests that a small sub-population of cells within the tumor is responsible for initiation and maintenance of the whole tumor, the so-called cancer stem cells (CSC), a fact that could lead to new ways to treat cancer in the future. More specifically, a successful therapy has to target these CSC and in this way inhibit the re-growth of the tumor creating the possibilities for a more effective treatment against cancers such as malignant glioma. However, there is a lot of controversy surrounding this concept and in this thesis I have tried to clarify some of the uncertainties. Thus, since the CSC share many properties with normal neural stem cells (NSC) it could be that such a NCS gone awry is responsible for the CSC and the tumor. As a result, in my thesis, I have tried to look at cell surface markers for any similarities, or variations between the normal NSC and the CSC because this may give us an indication of the type of cells that are prone to transformation. In that case it would be easier to investigate which kind of changes lead to the development of a cancer cell. Additionally, in order to develop a new therapy against malignant glioma based on these possible findings we have chosen to use an adenovirus as a tool. Adenoviral infections are normally not dangerous to healthy individuals, and they are easy to manipulate so this makes them a good choice for cancer therapy. However, there is a common problem in viral treatment of cancer, which is one of the main reasons why treatments fail to give satisfactory results. This problem is the poor spread of the virus when injected into a tumor and I have as part of my work tried to identify mechanisms in order to solve it. Identifying such a mechanism can also answer some questions concerning the general problem in adenoviral biology, namely one of the reasons behind chronic adenoviral infections. We have discovered that during an adenovirus infection viral fiber proteins are secreted from the infected cell, which bind to and masks adjacent cells. Subsequently, because of this masking, as infected cells lyses and newly formed viral particles are released into the extra cellular space they infect new cells at a lower frequency. Identifying the type of cells where transformation takes place, and solving the problem of the poor spread of the virus when injected into a tumor, we hope to contribute to the development of new treatment regimes for malignant glioma in the future.
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| 19. |
- Rebetz, Johan, et al.
(författare)
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Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.
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| 20. |
- Rebetz, Johan, et al.
(författare)
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Glial Progenitor-Like Phenotype in Low-Grade Glioma and Enhanced CD133-Expression and Neuronal Lineage Differentiation Potential in High-Grade Glioma
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6, s. 1107-1107
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Tidskriftsartikel (refereegranskat)abstract
- Background: While neurosphere-as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified. Methodology/Principal Findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFR alpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRa, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype. Conclusions/Significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas.
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| 21. |
- Rebetz, Johan, et al.
(författare)
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The Pathogenic Involvement of Neutrophils in Acute Respiratory Distress Syndrome and Transfusion-Related Acute Lung Injury
- 2018
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Ingår i: Transfusion Medicine and Hemotherapy. - : S. Karger AG. - 1660-3796 .- 1660-3818. ; 45:5, s. 290-298
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Tidskriftsartikel (refereegranskat)abstract
- The acute respiratory distress syndrome (ARDS) is a serious and common complication of multiple medical and surgical interventions, with sepsis, pneumonia, and aspiration of gastric contents being common risk factors. ARDS develops within 1 week of a known clinical insult or presents with new/worsening respiratory symptoms if the clinical insult is unknown. Approximately 40% of the ARDS cases have a fatal outcome. Transfusion-related acute lung injury (TRALI), on the other hand, is characterized by the occurrence of respiratory distress and acute lung injury, which presents within 6 h after administration of a blood transfusion. In contrast to ARDS, acute lung injury in TRALI is not attributable to another risk factor for acute lung injury. 'Possible TRALI', however, may have a clear temporal relationship to an alternative risk factor for acute lung injury. Risk factors for TRALI include chronic alcohol abuse and systemic inflammation. TRALI is the leading cause of transfusionrelated fatalities. There are no specific therapies available for ARDS or TRALI as both have a complex and incompletely understood pathogenesis. Neutrophils (polymorphonuclear leukocytes; PMNs) have been suggested to be key effector cells in the pathogenesis of both syndromes. In the present paper, we summarize the literature with regard to PMN involvement in the pathogenesis of both ARDS and TRALI based on both human data as well as on animal models. The evidence generally supports a strong role for PMNs in both ARDS and TRALI. More research is required to shed light on the pathogenesis of these respiratory syndromes and to more thoroughly establish the nature of the PMN involvement, especially considering the heterogeneous etiologies of ARDS.
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| 22. |
- Rosenblad, Therese, et al.
(författare)
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Eculizumab treatment for rescue of renal function in IgA nephropathy.
- 2014
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 29:11, s. 2225-2228
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin A (IgA) nephropathy is a chronic glomerulonephritis with excessive glomerular deposition of IgA1, C3 and C5b-9, which may lead to renal failure.
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| 23. |
- Schmitt, Roland, et al.
(författare)
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The Combined Role of Galactose-Deficient IgA1 and Streptococcal IgA-Binding M Protein in Inducing IL-6 and C3 Secretion from Human Mesangial Cells: Implications for IgA Nephropathy.
- 2014
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 193:1, s. 317-326
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Tidskriftsartikel (refereegranskat)abstract
- IgA nephropathy (IgAN) is characterized by mesangial cell proliferation and extracellular matrix expansion associated with immune deposits consisting of galactose-deficient polymeric IgA1 and C3. We have previously shown that IgA-binding regions of streptococcal M proteins colocalize with IgA in mesangial immune deposits in patients with IgAN. In the present study, the IgA-binding M4 protein from group A Streptococcus was found to bind to galactose-deficient polymeric IgA1 with higher affinity than to other forms of IgA1, as shown by surface plasmon resonance and solid-phase immunoassay. The M4 protein was demonstrated to bind to mesangial cells not via the IgA-binding region but rather via the C-terminal region, as demonstrated by flow cytometry. IgA1 enhanced binding of M4 to mesangial cells, but not vice versa. Costimulation of human mesangial cells with M4 and galactose-deficient polymeric IgA1 resulted in a significant increase in IL-6 secretion compared with each stimulant alone. Galactose-deficient polymeric IgA1 alone, but not M4, induced C3 secretion from the cells, and costimulation enhanced this effect. Additionally, costimulation enhanced mesangial cell proliferation compared with each stimulant alone. These results indicate that IgA-binding M4 protein binds preferentially to galactose-deficient polymeric IgA1 and that these proteins together induce excessive proinflammatory responses and proliferation of human mesangial cells. Thus, tissue deposition of streptococcal IgA-binding M proteins may contribute to the pathogenesis of IgAN.
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| 24. |
- Semple, John W., et al.
(författare)
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An update on the pathophysiology of immune thrombocytopenia
- 2020
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Ingår i: Current Opinion in Hematology. - 1531-7048. ; 27:6, s. 423-429
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that either destroy platelets peripherally in the spleen or impair platelet production in the bone marrow. There have been a plethora of publications relating to the pathophysiology of ITP and since January of 2019, at least 50 papers have been published on ITP pathophysiology. PURPOSE OF REVIEW: To summarize the literature relating to the pathophysiology of ITP including the working mechanisms of therapies, T-cell and B-cell physiology, protein/RNA/DNA biochemistry, and animal models in an attempt to unify the perceived abnormal immune processes. RECENT FINDINGS: The most recent pathophysiologic irregularities associated with ITP relate to abnormal T-cell responses, particularly, defective T regulatory cell activity and how therapeutics can restore these responses. The robust literature on T cells in ITP points to the notion that ITP is a disease initiated by faulty self-tolerance mechanisms very much like that of other organ-specific autoimmune diseases. There is also a large literature on new and existing animal models of ITP and these will be discussed. It appears that understanding how to specifically modulate T cells in patients with ITP will undoubtedly lead to effective antigen-specific therapeutics. CONCLUSIONS: ITP is predominately a T cell disorder which leads to a breakdown in self tolerance mechanisms and allows for the generation of anti-platelet autoantibodies and T cells. Novel therapeutics that target T cells may be the most effective way to perhaps cure this disorder.
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| 25. |
- Semple, John W, et al.
(författare)
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Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies
- 2018
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Ingår i: Critical Care Medicine. - 1530-0293. ; 46:5, s. 452-458
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Forskningsöversikt (refereegranskat)abstract
- Objectives: Transfusion-related acute lung injury is characterized by the onset of respiratory distress and acute lung injury following blood transfusion, but its pathogenesis remains poorly understood. Generally, a two-hit model is presumed to underlie transfusion-related acute lung injury with the first hit being risk factors present in the transfused patient (such as inflammation), whereas the second hit is conveyed by factors in the transfused donor blood (such as antileukocyte antibodies). At least 80% of transfusion-related acute lung injury cases are related to the presence of donor antibodies such as antihuman leukocyte or antihuman neutrophil antibodies. The remaining cases may be related to nonantibody-mediated factors such as biolipids or components related to storage and ageing of the transfused blood cells. At present, transfusion-related acute lung injury is the leading cause of transfusion-related fatalities and no specific therapy is clinically available. In this article, we critically appraise and discuss recent preclinical (bench) insights related to transfusion-related acute lung injury pathogenesis and their therapeutic potential for future use at the patients’ bedside in order to combat this devastating and possibly fatal complication of transfusion.Data Sources: We searched the PubMed database (until August 22, 2017).Study Selection: Using terms: “Transfusion-related acute lung injury,” “TRALI,” “TRALI and therapy,” “TRALI pathogenesis.”Data Extraction: English-written articles focusing on transfusion-related acute lung injury pathogenesis, with potential therapeutic implications, were extracted.Data Synthesis: We have identified potential therapeutic approaches based on the literature.Conclusions: We propose that the most promising therapeutic strategies to explore are interleukin-10 therapy, down-modulating C-reactive protein levels, targeting reactive oxygen species, or blocking the interleukin-8 receptors; all focused on the transfused recipient. In the long-run, it may perhaps also be advantageous to explore other strategies aimed at the transfused recipient or aimed toward the blood product, but these will require more validation and confirmation first.
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| 26. |
- Semple, John W, et al.
(författare)
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Transfusion-associated circulatory overload and transfusion-related acute lung injury.
- 2019
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 133:17, s. 1840-1853
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Forskningsöversikt (refereegranskat)abstract
- Transfusion-associated circulatory overload (TACO) and Transfusion-related acute lung injury (TRALI) are syndromes of acute respiratory distress which occur within 6 hours of blood transfusion. TACO and TRALI are the leading causes of transfusion-related fatalities and specific therapies are unavailable. Diagnostically, it remains very challenging to distinguish TACO and TRALI from underlying causes of lung injury and/or fluid overload as well as from each other. TACO is characterized by pulmonary hydrostatic (cardiogenic) edema, while TRALI presents as pulmonary permeability edema (noncardiogenic). The pathophysiology of both syndromes is complex and incompletely understood. A 2-hit model is generally assumed to underlie TACO and TRALI disease pathology where the first hit represents the clinical condition of the patient and the second hit is conveyed by the transfusion product. In TACO, cardiac- or renal impairment and positive fluid balance appear first hits while suboptimal fluid management or other components in the transfused product may enable the second hit. Remarkably, other factors beyond volume play a role in TACO. In TRALI, the first hit can, for example, be represented by inflammation while the second hit is assumed to be caused by anti-leukocyte antibodies or biological response modifiers (e.g. lipids). In this review, we provide an up-to-date overview of TACO and TRALI regarding clinical definitions, diagnostic strategies, pathophysiological mechanisms and potential therapies. More research is required to better understand the TACO and TRALI pathophysiology and more biomarker studies are warranted. Collectively, this may result in improved diagnostics and development of therapeutic approaches for these life-threating transfusion reactions.
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| 27. |
- Ståhl, Anne-lie, et al.
(författare)
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A Novel Mechanism of Bacterial Toxin Transfer within Host Blood Cell-Derived Microvesicles.
- 2015
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli, which are non-invasive strains that can lead to hemolytic uremic syndrome (HUS), associated with renal failure and death. Although bacteremia does not occur, bacterial virulence factors gain access to the circulation and are thereafter presumed to cause target organ damage. Stx was previously shown to circulate bound to blood cells but the mechanism by which it would potentially transfer to target organ cells has not been elucidated. Here we show that blood cell-derived microvesicles, shed during HUS, contain Stx and are found within patient renal cortical cells. The finding was reproduced in mice infected with Stx-producing Escherichia coli exhibiting Stx-containing blood cell-derived microvesicles in the circulation that reached the kidney where they were transferred into glomerular and peritubular capillary endothelial cells and further through their basement membranes followed by podocytes and tubular epithelial cells, respectively. In vitro studies demonstrated that blood cell-derived microvesicles containing Stx undergo endocytosis in glomerular endothelial cells leading to cell death secondary to inhibited protein synthesis. This study demonstrates a novel virulence mechanism whereby bacterial toxin is transferred within host blood cell-derived microvesicles in which it may evade the host immune system.
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| 28. |
- Tati, Ramesh, et al.
(författare)
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Complement Activation Associated with ADAMTS13 Deficiency in Human and Murine Thrombotic Microangiopathy.
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 191:5, s. 2184-2193
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Tidskriftsartikel (refereegranskat)abstract
- This study addressed the contribution of ADAMTS13 deficiency to complement activation in thrombotic thrombocytopenic purpura (TTP). Renal tissue and blood samples were available from 12 TTP patients. C3 and C5b-9 deposition were demonstrated in the renal cortex of two TTP patients, by immunofluorescence and immunohistochemistry, respectively. C3 was also demonstrated in the glomeruli of Shiga toxin-2-treated Adamts13(-/-) mice (n = 6 of 7), but less in mice that were not Shiga toxin-2 treated (n = 1 of 8, p < 0.05) or wild-type mice (n = 0 of 7). TTP patient plasma (n = 9) contained significantly higher levels of complement-coated endothelial microparticles than control plasma (n = 13), as detected by flow cytometry. Exposure of histamine-stimulated primary glomerular endothelial cells to platelet-rich plasma from patients, or patient platelet-poor plasma combined with normal platelets, in a perfusion system, under shear, induced C3 deposition on von Willebrand factor-platelet strings (on both von Willebrand factor and platelets) and on endothelial cells. Complement activation occurred via the alternative pathway. No C3 was detected when cells were exposed to TTP plasma that was preincubated with EDTA or heat-inactivated, or to control plasma. In the perfusion system, patient plasma induced more release of C3- and C9-coated endothelial microparticles compared with control plasma. The results indicate that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and the endothelium, which may contribute to formation of thrombotic microangiopathy.
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| 29. |
- Yan, Yuhua, et al.
(författare)
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Active and separate secretion of fiber and penton base during the early phase of Ad2 or Ad5 infection
- 2017
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Ingår i: Virology. - : Elsevier BV. - 0042-6822. ; 505, s. 172-180
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Tidskriftsartikel (refereegranskat)abstract
- Fiber and penton base overproduced in adenovirus (Ad) infected cells can be secreted prior to progeny release and thereby regulate progeny spread. We aimed to investigate the mechanisms of fiber and penton base secretion in Ad2- or Ad5-infected A549 cells. Our flow cytometry analyses detected abundant surface fiber molecules, but little penton base molecules at 12 h post infection. Immunogold staining combined with transmission electron microscopic analyses revealed separate, non-co-localized release of fiber and penton base in the proximity of the plasma membrane. Depolymerization of microtubule and actin cytoskeletons, and inhibition of Rock kinase and myosin II activity together demonstrated cytoskeletal network-dependent fiber secretion. Inhibition of intracellular calcium [Ca2+]i signaling caused diminished fiber secretion, which was associated with diminished progeny production. Thus, fiber and penton base are actively and separately secreted during the early stages of Ad2 or Ad5 infection, their secretion may play important role in Ad life cycle.
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