| 51. |
- Martner, Anna, 1979, et al.
(författare)
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Pneumolysin released during Streptococcus pneumoniae autolysis is a potent activator of intracellular oxygen radical production in neutrophils
- 2008
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Ingår i: Infection and Immunity. - 1098-5522. ; 76:9, s. 4079-87
-
Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae is a major cause of otitis media, pneumonia, meningitis, and septicemia in humans. The host defense against this pathogen largely depends on bacterial killing by neutrophils. A peculiar property of pneumococci is their tendency to undergo autolysis, i.e., autoinduced disruption of the bacterial cell wall mediated by activation of the enzyme LytA, under stationary growth conditions. LytA is a virulence factor, but the molecular background for this has not been fully clarified. Here we examine how bacterial compounds released upon autolysis affect the production of reactive oxygen species (ROS) in neutrophils. We found that the S. pneumoniae strains A17 and D39 induced activation of the NADPH oxidase and the production of ROS in human neutrophils and that this activation was blocked when LytA was inactivated. The ROS-inducing bacterial substance released from autolyzed bacteria was identified as the cytoplasmic toxin pneumolysin. Further screening of clinical pneumococcal strains of various sero- and genotypes revealed that selected strains expressing toxins with reduced pneumolysin-dependent hemolytic activity had decreased abilities to induce ROS in neutrophils. Furthermore, a mutated form of purified pneumolysin lacking hemolytic and complement binding functions (PdT) did not induce any oxygen radical production. The ROS produced in response to pneumolysin formed mainly intracellularly, which may explain why this production was not detected previously. ROS released intracellularly may function as signaling molecules, modifying the function of neutrophils in bacterial defense.
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| 52. |
- Martner, Anna, 1979
(författare)
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Regulation of innate and adaptive immune responses by Gram-positive and Gram-negative bacteria
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacteria are classified as Gram-positive or Gram-negative, depending on their cell wall structure. The role of the bacterial cell wall in immune regulation is the focus of the current work. Most Gram-positive bacteria stimulate monocytes to produce large amounts of IL-12. IL-12 induces production of IFN-γ in T cells and NK cells, which, in turn, activates the bactericidal capacity of the phagocyte in synergy/concert with TNF, produced by macrophages. We studied the bacterial structures and signalling pathways involved in IL-12 production in response to intact Gram-positive bacteria. This production depended on phagocytosis and activation of the JNK, NF-κB and PI3K pathways. Gram-positive bacterial fragments inhibited IL-12 production, which may serve as a negative feedback to turn off phagocyte activation when the bacteria have been destroyed. S. pneumoniae is a Gram-positive pathogen with a peculiar habit to disintegrate in stationary culture, due to activation of autolytic enzymes that degrade the cell wall. We demonstrated that pneumococci undergoing autolysis generate bacterial fragments that shut off monocyte production of TNF, IFN-γ and IL-12, thereby counteracting phagocyte activation. Further, the cytoplasmic pneumococcal toxin pneumolysin that was released upon autolysis dramatically augmented radical oxygen production in human neutrophils. Notably, ROS were foremost produced into intracellular compartments, probably affecting neutrophil function. We also studied differences in how Gram-positive and Gram-negative bacteria modulate presentation of a model antigen to naïve T cells. Different subsets of mouse antigen-presenting cells were fed soluble ovalbumin (OVA), or OVA produced inside transgenic Gram-positive (lactobacilli/lactococci) or Gram-negative (E. coli) bacteria. Proliferation and cytokine production by OVA-specific transgenic T cells (DO11.10) was used as read-out system. “Bacterial” OVA much more efficiently activated OVA-specific CD4+ T cells, than did soluble OVA. Further, E. coli-OVA induced a greater T cell proliferation than did OVA expressed by Gram-positive bacteria. Splenic APCs pulsed with soluble OVA induced IL-13 production, while E. coli-OVA induced both IFN-γ and IL-13 and lactobacilli-OVA induced a weak IFN-γ response in the T cell culture. We also noted that peritoneal DCs induced a different T cell polarisation pattern compared to splenic DCs, supporting production of more IL-17 and IL-10, but less IL-13. Furthermore, the presence of peritoneal macrophages inhibited CD4+ T cell activation to bacterial, but not to soluble, antigens.
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| 53. |
- Martner, Anna, 1979, et al.
(författare)
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Streptococcus pneumoniae autolysis prevents phagocytosis and production of phagocyte-activating cytokines.
- 2009
-
Ingår i: Infection and immunity. - 1098-5522. ; 77:9, s. 3826-37
-
Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-gamma), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-gamma, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-gamma, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.
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| 54. |
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| 55. |
- Martner, Anna, 1979, et al.
(författare)
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Transient and durable T cell reactivity after COVID-19
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 119:30
-
Tidskriftsartikel (refereegranskat)abstract
- This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until similar to 70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-gamma remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (T-H) cells followed by an equally synchronous and durable T(H)1-like reactivity reflecting long-lasting T cell memory.
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| 56. |
- Mukanyangezi, Marie Francoise, et al.
(författare)
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Persistence rate of cervical human papillomavirus infections and abnormal cytology in Rwanda
- 2019
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Ingår i: HIV Medicine. - : Wiley. - 1464-2662 .- 1468-1293. ; 20:7, s. 485-495
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives In this study, we determined the incidence and persistence of human papillomavirus (HPV) strains and of squamous intraepithelial lesions (SIL) or worse cytology in 237 HIV-positive and HIV-negative Rwandan women and whether the interleukin (IL)-28B single nucleotide polymorphism (SNP) at rs12979860 correlated with susceptibility to and persistence of HPV infection. Methods Cervical samples were collected at baseline and after 9, 18 and 24 months for a 40-HPV DNA screening test and a ThinPrep Pap test. Genotyping of the IL-28B SNP rs12979860 was performed using real-time polymerase chain reaction (PCR). Results Chronic high-risk (HR) HPV infections occurred in 56% of HIV-positive women, while no HIV-negative women developed HPV chronicity. High-grade SIL (HSIL) or cancer was diagnosed in 38% of HIV-positive women with persistent HR-HPV infections. HIV and HR-HPV positivity at baseline were factors associated with an increased risk of HPV persistence. Additionally, HR-HPV positivity at baseline was associated with an increased risk of developing HSIL or worse cytology. The unfavourable T/x genotype at rs12979860 is common among Africans, and women with this genotype were found to be more commonly infected with HPV. Conclusions HPV screening in Rwanda may help to identify women at risk of developing cervical cancer and polymorphism in IL-28B may be associated with risk of contracting HPV infection.
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| 57. |
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| 58. |
- Nilsson, Staffan, 1956, et al.
(författare)
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Immunotherapy with HDC/IL-2 may be clinically efficacious in acute myeloid leukemia of normal karyotype
- 2020
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Ingår i: Human Vaccines & Immunotherapeutics. - : Informa UK Limited. - 2164-5515 .- 2164-554X. ; 16:1, s. 109-111
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) reduces the risk of relapse in the post-chemotherapy phase of acute myeloid leukemia (AML). Here we report the results of exploratory analyses of the clinical efficacy of HDC/IL-2 in AML with focus on the impact of karyotype aberrations in leukemic cells. Post-hoc analyses of phase III trial data suggested that HDC/IL-2 is primarily beneficial for patients with AML of normal karyotype. These results may be helpful in the selection of patients who are suitable for therapy and in the design of future immunotherapy protocols aiming at further defining the mechanism of relapse prevention by HDC/IL-2.
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| 59. |
- Ortiz, M. L., et al.
(författare)
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Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4(+) T cells
- 2015
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 212:3, s. 351-367
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Tidskriftsartikel (refereegranskat)abstract
- Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33(+)S100A9(+) cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4(+) T cells. This chemokine was released by activated IMCs. Elimination of CD4(+) T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4(+) T cells.
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| 60. |
- Rembeck, Karolina, et al.
(författare)
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Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3.
- 2014
-
Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 59:6, s. 2131-2139
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Tidskriftsartikel (refereegranskat)abstract
- The present study evaluated the impact of variations in the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) on treatment outcome in patients with hepatitis C virus (HCV) genotype 2/3 infection receiving peginterferon-α2a and lower, conventional 800 mg daily dose of ribavirin. Previous studies using higher, weight-based ribavirin dosing report that patients carrying polymorphisms encoding reduced predicted ITPase activity show decreased risk of ribavirin-induced anemia but increased risk of thrombocytopenia, with no impact on elimination of virus. Three hundred fifty-four treatment naïve HCV genotype 2/3 infected patients, enrolled in a phase III trial (NORDynamIC), were genotyped for ITPA (rs1127354 and rs7270101). Homo- or heterozygosity at Ars1127354 or Crs7270101, entailing reduced ITPase activity, was observed in 37% of patients and was associated with increased likelihood of achieving sustained virological response (SVR) (P=0.0003 in univariate and multivariate analyses) accompanied by a reduced risk of relapse among treatment-adherent patients. The association between ITPA variants and SVR remained significant when patients were subdivided by the 12- and 24-week treatment duration arms, HCV genotype, fibrosis stage and IL28B genotype, and was not secondary to improved adherence to therapy or less pronounced anemia. Gene variants predicting reduced predicted ITPase activity also were associated with decreased risk of anemia (P<0.0001), increased risk of thrombocytopenia (P=0.007), and lower ribavirin concentrations (P=0.02). Conclusion: These findings demonstrate a novel ribavirin-like association between polymorphisms at ITPA and treatment efficacy in chronic hepatitis C mediated by reduced relapse risk. We hypothesize that patients (63%) being homozygous for both major alleles, leading to normal ITPase activity, may benefit more from the addition of ribavirin to present and future treatment regimens for HCV in spite of concomitant increased risk of anemia.
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| 61. |
- Riise, Rebecca E, 1987, et al.
(författare)
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TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses
- 2015
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 195:3, s. 1121-1128
-
Tidskriftsartikel (refereegranskat)abstract
- Polymorphonuclear neutrophils (PMNs) are innate effector cells with pivotal roles in pathogen recognition, phagocytosis, and eradication. However, their role in the development of subsequent immune responses is incompletely understood. This study aimed to identify mechanisms of relevance to the cross talk between human neutrophils and NK cells and its potential role in promoting adaptive immunity. TLR-stimulated PMNs were found to release soluble mediators to attract and activate NK cells in vitro. PMN-conditioned NK cells displayed enhanced cytotoxicity and cytokine production, and responded vigorously to ensuing stimulation with exogenous and endogenous IL-12. The neutrophil-induced activation of NK cells was prevented by caspase-1 inhibitors and by natural antagonists to IL-1 and IL-18, suggesting a role for the NOD-like receptor family pyrin domain containing-3 inflammasome. In addition, PMN-conditioned NK cells triggered the maturation of monocyte-derived dendritic cells, which promoted T cell proliferation and IFN-gamma production. These data imply that neutrophils attract NK cells to sites of infection to convert these cells into an active state, which drives adaptive immune responses via maturation of dendritic cells. Our results add to a growing body of evidence that suggests a sophisticated role for neutrophils in orchestrating the immune response to pathogens.
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| 62. |
- Ringlander, Johan, et al.
(författare)
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Impact of ADAR-induced editing of minor viral RNA populations on replication and transmission of SARS-CoV-2
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 119:6
-
Tidskriftsartikel (refereegranskat)abstract
- Adenosine deaminases acting on RNA (ADAR) are RNA-editing enzymes that may restrict viral infection. We have utilized deep sequencing to determine adenosine to guanine (AfiG) mutations, signifying ADAR activity, in clinical samples retrieved from 93 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)- infected patients in the early phase of the COVID-19 pandemic. AfiG mutations were detected in 0.035% (median) of RNA residues and were predominantly nonsynonymous. These mutations were rarely detected in the major viral population but were abundant in minor viral populations in which AfiG was more prevalent than any other mutation (P < 0.001). The AfiG substitutions accumulated in the spike protein gene at positions corresponding to amino acids 505 to 510 in the receptor binding motif and at amino acids 650 to 655. The frequency of AfiG mutations in minor viral populations was significantly associated with low viral load (P < 0.001). We additionally analyzed AfiG mutations in 288,247 SARSCoV- 2 major (consensus) sequences representing the dominant viral population. The AfiG mutations observed in minor viral populations in the initial patient cohort were increasingly detected in European consensus sequences between March and June 2020 (P < 0.001) followed by a decline of these mutations in autumn and early winter (P < 0.001). We propose that ADAR-induced deamination of RNA is a significant source of mutated SARS-CoV-2 and hypothesize that the degree of RNA deamination may determine or reflect viral fitness and infectivity. © 2022 National Academy of Sciences. All rights reserved.
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| 63. |
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| 64. |
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| 65. |
- Rugwizangoga, Belson, et al.
(författare)
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Experience and Perception of Patients and Healthcare Professionals on Acute Leukemia in Rwanda: A Qualitative Study
- 2022
-
Ingår i: Cancer Management and Research. - 1179-1322. ; 14, s. 1923-1934
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To explore challenges associated with the timely diagnosis, therapy, and prognosis of acute leukemia in Rwanda. Methods: This is a qualitative study using a phenomenological approach that involved patients, patients' guardians, and healthcare professionals such as physicians from district hospitals and specialists from referral hospitals, as well as healthcare administrators. The primary data were collected from district and referral hospitals and central healthcare administration in Rwanda. The data were collected between July and October 2019. In-depth interviews were conducted, and thematic analysis was employed to interpret the results. Results: We identified barriers to seeking healthcare such as (i) insufficient knowledge within the population may lead patients and their guardians to consult traditional healers before seeking qualified medical care, and (ii) financial constraints that preclude payment of healthcare fees or other out-of-pocket cost related to diagnosis and treatment. We also observed that the referral system is tedious and primary healthcare facilities lack the competence and resources for the necessary diagnostic practices. Both may further delay diagnosis and therapy. Accordingly, healthcare professionals at the referral hospitals stated that most patients were seen at an advanced stage of the disease. For the treatment of acute lymphoblastic leukemia (ALL), only chemotherapy is utilized in Rwanda, while bone marrow (BM) transplantation is not available. Palliation is the only available treatment for the vast majority of Rwandan acute myeloid leukemia (AML) patients. Conclusion: ALL and AML are likely under-reported in Rwanda and diagnosis may be delayed, which may be explained by patient related factors (lack of knowledge, financial constraints), a tedious referral system, and suboptimal diagnostic resources.
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| 66. |
- Rugwizangoga, Belson, et al.
(författare)
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IFNL4 Genotypes Predict Clearance of RNA Viruses in Rwandan Children With Upper Respiratory Tract Infections
- 2019
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media SA. - 2235-2988. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms in the interferon lambda gene locus (IFNL) such as the IFNL4 genetic variants rs12979860 and rs368234815 are predictive of resolution of hepatitis C virus infection, but information about the impact of these variants in other infections is scarce. This study aimed at determining the potential impact of IFNL4 variation for the clearance of respiratory tract pathogens in Rwandan children (<= 5 years old, n = 480) seeking medical care for acute respiratory infections. Nasopharyngeal swabs were retrieved from all children at the first hospital referral and from 161 children at follow-up visits 2 weeks later. The swabs were analyzed for pathogens by real-time PCR and for host cell IFNL4 genotype at rs12979860 and rs368234815. Approximately 1/3 of the children were homozygous for the rs12979860 T allele and the rs368234815 Delta G allele, which are overrepresented in subjects of African descent. These IFNL4 variants were significantly associated with reduced clearance of RNA viruses. Our results suggest that IFNL4 genotypes that are common among subjects of African descent may determine inefficacious clearance of RNA viruses from the respiratory tract.
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| 67. |
- Skovbjerg, Susann, 1973, et al.
(författare)
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Gram-positive and gram-negative bacteria induce different patterns of cytokine production in human mononuclear cells irrespective of taxonomic relatedness.
- 2010
-
Ingår i: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. - New York, USA : Mary Ann Liebert Inc. - 1557-7465 .- 1079-9907. ; 30:1, s. 23-32
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Tidskriftsartikel (refereegranskat)abstract
- Upon bacterial stimulation, tissue macrophages produce a variety of cytokines that orchestrate the immune response that clears the infection. We have shown that Gram-positives induce higher levels of interleukin-12 (IL-12), interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF) from human peripheral blood mononuclear cells (PBMCs) than do Gram-negatives, which instead induce more of IL-6, IL-8, and IL-10. Here, we study whether these patterns follows or crosses taxonomic borders. PBMCs from blood donors were incubated with UV-inactivated bacteria representing 37 species from five phyla. IL-12, TNF, IL-1beta, IL-6, IL-8, and IL-10 were measured in the supernatants after 24 h and IFN-gamma after 5 days. Irrespective of phylogenetic position, Gram-positive bacteria induced much more IL-12 (nine times more on average) and IFN-gamma (seven times), more TNF (three times), and slightly more IL-1beta (1.5 times) than did Gram-negatives, which instead induced more IL-6 (1.5 times), IL-8 (1.9 times), and IL-10 (3.3 times) than did Gram-positives. A notable exception was the Gram-positive Listeria monocytogenes, which induced very little IL-12, IFN-gamma, and TNF. The results confirm the fundamental difference in innate immune responses to Gram-positive and Gram-negative bacteria, which crosses taxonomic borders and probably reflects differences in cell wall structure.
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| 68. |
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| 69. |
- Skovbjerg, Susann, 1973, et al.
(författare)
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Intact Pneumococci Trigger Transcription of Interferon-Related Genes in Human Monocytes, while Fragmented, Autolyzed Bacteria Subvert This Response
- 2017
-
Ingår i: Infection and Immunity. - 0019-9567. ; 85:5
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Tidskriftsartikel (refereegranskat)abstract
- A peculiar trait of pneumococci (Streptococcus pneumoniae) is their propensity to undergo spontaneous lysis during stationary growth due to activation of the enzyme autolysin (LytA), which fragments the peptidoglycan cell wall. The fragments that are generated upon autolysis impair phagocytosis and reduce production of interleukin-12 (IL-12) and gamma interferon (IFN-gamma) by human leukocytes in response to intact pneumococci, thereby impeding crucial host defenses. The objective was to identify additional monocyte genes whose transcription is induced by intact pneumococci and subverted by autolyzed bacteria. Monocytes were isolated from healthy blood donors and stimulated for 3 h with UV-inactivated S. pneumoniae (Rx1PLY(-) LytA(+) strain), which is capable of autolyzing, its LytA(-) isogenic autolysin-deficient mutant, or a mixture of the two (containing twice the initial bacterial concentration). Gene expression was assessed by Illumina microarray, and selected findings were confirmed by reverse transcription-quantitative real-time PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. In all, we identified 121 genes that were upregulated to a significantly higher degree by intact than autolyzed pneumococci. These included IFNB1 and a large set of interferon-induced genes, such as IFIT3, RSAD2, CFCL1, and CXCL10 genes, as well as IL12B and CD40 genes. RT-qPCR revealed that transcription of these genes in response to intact pneumococci diminished when autolyzed pneumococci were admixed and that this pattern was independent of pneumolysin. Thus, transcription of interferon-related genes is triggered by intact pneumococci and subverted by fragments generated by spontaneous bacterial autolysis. We suggest that interferon-related pathways are important for elimination of pneumococci and that autolysis contributes to virulence by extinguishing these pathways.
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| 70. |
- Törnell, Andreas, 1994, et al.
(författare)
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CYBA allelic variants are associated with severity and recovery in Guillain-Barré syndrome
- 2023
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Ingår i: Journal of the peripheral nervous system. - 1085-9489. ; 28:3, s. 407-414
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Guillain–Barré syndrome (GBS) is a rare, acute neuropathy characterized by ascending muscle weakness. Age, axonal GBS variants, and antecedent Campylobacter jejuni infection are associated with severe GBS, but the detailed mechanisms of nerve damage are only partly explored. Pro-inflammatory myeloid cells express NADPH oxidases (NOX) that generate tissue-toxic reactive oxygen species (ROS) that are implicated in neurodegenerative diseases. This study analyzed the impact of variants of the gene encoding the functional NOX subunit CYBA (p22phox) on acute severity, axonal damage, and recovery in adult GBS patients. Methods: Extracted DNA from 121 patients was genotyped for allelic variation at rs1049254 and rs4673 within CYBA using real-time quantitative polymerase chain reaction. Serum neurofilament light chain was quantified by single molecule array. Patients were followed for severity and motor function recovery for up to 13 years. Results: CYBA genotypes linked to reduced formation of ROS, i.e. rs1049254/G and rs4673/A, were significantly associated with unassisted ventilation, shorter time to normalization of serum neurofilament light chain and shorter time to regained motor function. Residual disability at follow-up was confined to patients carrying CYBA alleles associated with high formation of ROS. Interpretation: These findings implicate NOX-derived ROS in GBS pathophysiology and CYBA alleles as biomarkers of severity.
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| 71. |
- Törnell, Andreas, 1994, et al.
(författare)
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Impact of CYBA genotypes on severity and progression of multiple sclerosis
- 2022
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:5, s. 1457-1464
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The NOX2 enzyme of myeloid cells generates reactive oxygen species (ROS) that have been implicated in the pathology of multiple sclerosis (MS). We aimed to determine the impact of genetic variation within CYBA, which encodes the functional CYBA/p22phox subunit of NOX2, on MS severity and progression. Methods: One hundred three MS patients with up to 49 (median = 17) years follow-up time from first MS diagnosis were genotyped at the single nucleotide polymorphisms rs1049254 and rs4673 within CYBA. Results were matched with disease severity and time to diagnosis of secondary progressive MS (SPMS). NOX2-mediated formation of ROS was measured by chemiluminescence in blood myeloid cells from healthy donors (n=55) with defined genotypes at rs1049254 and rs4673. Results: The rs1049254/G and rs4673/A CYBA alleles were associated with reduced formation of ROS and were thus defined as low-ROS alleles. Patients carrying low-ROS alleles showed reduced multiple sclerosis severity score (p=0.02, N=103, linear regression) and delayed onset of SPMS (p=0.02, hazard ratio [HR] = 0.46, n=100, log-rank test). In a cohort examined after 2005, patients carrying low-ROS CYBA alleles showed >20years longer time to secondary progression (p=0.003, HR = 0.29, n=59, log-rank test). Conclusions: These results implicate NOX2 in MS, in particular for the development of secondary progressive disease, and point toward NOX2-reductive therapy aiming to delay secondary progression.
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| 72. |
- Törnell, Andreas, 1994, et al.
(författare)
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Induction and subsequent decline of S1-specific T cell reactivity after COVID-19 vaccination
- 2023
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616. ; 248
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed magnitude and duration of SARS-CoV-2-specific T cell responses in healthy, infection-naive subjects receiving COVID-19 vaccines. Overlapping peptides spanning the N-terminal spike 1 (S1) domain of the spike protein triggered secretion of the T cell-derived cytokine interleukin-2 ex vivo in 94/94 whole blood samples from vaccinated subjects at levels exceeding those recorded in all 45 pre-vaccination samples. S1-specific T cell reactivity was stronger in vaccinated subjects compared with subjects recovering from natural COVID-19 and decayed with an estimated half-life of 134 days in the first six months after the 2nd vaccination. We conclude that COVID-19 vaccination induces robust T cell immunity that subsequently declines.EudraCT 2021-000349-42. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-000349-42
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| 73. |
- Törnell, Andreas, 1994, et al.
(författare)
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Presence of MDSC associates with impaired antigen-specific T cell reactivity following COVID-19 vaccination in cirrhotic patients
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Cirrhosis entails high risk of serious infections and abated efficiency of vaccination, but the underlying mechanisms are only partially understood. This study aimed at characterizing innate and adaptive immune functions, including antigen-specific T cell responses to COVID-19 vaccination, in patients with compensated and decompensated cirrhosis. Methods: Immune phenotype and function in peripheral blood from 42 cirrhotic patients and 44 age-matched healthy controls were analysed after two doses of the mRNA-based COVID-19 vaccines [BNT162b2 (Pfizer BioNTech) or mRNA-1273 (Moderna)]. Results: Cirrhotic patients showed significantly reduced blood counts of antigen-presenting dendritic cells (DC) and high counts of monocytic myeloid-derived suppressor cells (M-MDSC) as compared to healthy controls. In addition, monocytic cells recovered from cirrhotic patients showed impaired expression of the antigen-presenting molecule HLA-DR and the co-stimulatory molecule CD86 upon Toll-like receptor (TLR) stimulation. These features were more prominent in patients with decompensated cirrhosis (Child-Pugh classes B & C). Interestingly, while patients with compensated cirrhosis (Child-Pugh class A) showed an inflammatory profile with myeloid cells producing the proinflammatory cytokines IL-6 and TNF, decompensated patients produced reduced levels of these cytokines. Cirrhotic patients, in particular those with more advanced end-stage liver disease, mounted reduced antigen-specific T cell reactivity to COVID-19 vaccination. Vaccine efficiency inversely correlated with levels of M-MDSC. Conclusion: These results implicate MDSC as mediators of immunosuppression, with ensuing deficiency of vaccine-specific T cell responses, in cirrhosis.
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| 74. |
- Törnell, Andreas, 1994, et al.
(författare)
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Rapid cytokine release assays for analysis of SARS-CoV-2-specific T cells in whole blood.
- 2022
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 226:2, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Waning of IgG antibodies against SARS-CoV-2 complicates diagnosis of past infection. Durability of T cell memory against SARS-CoV-2 remains unclear, and most current T cell protocols are unsuited for large-scale automation.Whole blood samples from 31 patients with verified past COVID-19 and 46 controls, out of which 40 received SARS-CoV-2 vaccine were stimulated with peptides spanning the nucleocapsid (NC) or spike 1 (S1) regions of SARS-CoV-2 and analyzed for interferon-γ (IFN-γ) in supernatant plasma. Diagnostic accuracy of these assays was evaluated against serum anti-NC and anti-receptor-binding domain S1 IgG.Induction of IFN-γ in whole blood by NC or S1 peptides diagnosed past COVID-19 with high accuracy (AUC=0.93, AUC=0.95, respectively). In accordance with previous studies, NC-IgG levels rapidly waned with only 5/17 patients (29%) remaining seropositive >180 days after infection. By contrast, NC-peptide-induced T cell memory responses remained in 13/17 (76%) subjects >180 days after infection (P=0.012 vs. NC-IgG, McNemar test). After two vaccine doses, 18/18 donors exhibited S1-specific T cell memory.Cytokine release assays for the monitoring of T cell memory in whole blood may be useful for evaluation of complications following unverified past COVID-19 and for long-term assessment of vaccine-induced T cell immunity.
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- Werlenius, Olle, et al.
(författare)
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Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:22, s. 32046-32053
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Tidskriftsartikel (refereegranskat)abstract
- The antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells is assumed to contribute to the clinical efficacy of monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL) and other hematopoietic malignancies of B cell origin. We sought to determine whether reactive oxygen species (ROS)-producing monocytes regulate the ADCC of NK cells against primary CLL cells using anti-CD20 as the linking antibody. The monoclonal CD20 antibodies rituximab and ofatumumab were found to trigger substantial release of ROS from monocytes. Antibody-exposed monocytes induced NK cell apoptosis and restricted NK cell-mediated ADCC against autologous CLL cells. The presence of inhibitors of ROS formation and scavengers of ROS preserved NK cell viability and restored NK cell-mediated ADCC against primary CLL cells. We propose that limiting the antibody-induced induction of immunosuppressive ROS may improve the anti-leukemic efficacy of anti-CD20 therapy in CLL.
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