| 1. |
- Brodin, Petter, et al.
(författare)
-
Natural Killer Cell Tolerance Persists Despite Significant Reduction of Self MHC Class I on Normal Target Cells in Mice
- 2010
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:10, s. e13174-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known. Methodology/Principal Findings: In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached. Conclusion: Collectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance.
|
|
| 2. |
- Cheng, Min, et al.
(författare)
-
Distinct and overlapping patterns of cytokine regulation of thymic and bone marrow-derived NK cell development.
- 2009
-
Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:3, s. 1460-1468
-
Tidskriftsartikel (refereegranskat)abstract
- Although bone marrow (BM) represents the main site for postnatal NK cell development, recently a distinct thymic-dependent NK cell pathway was identified. These studies were designed to investigate the role of cytokines in regulation of thymic NK cells and to compare with established regulatory pathways of BM-dependent NK cell compartment. The common cytokine receptor gamma-chain (Il2rg) essential for IL-15-induced signaling, and FMS-like tyrosine kinase 3 (FLT3) receptor ligand (Flt3l) were previously identified as important regulatory pathways of the BM NK cell compartment based on lack of function studies in mice, however their complementary action remains unknown. By investigating mice double-deficient in Il2rg and Flt3l (Flt3l(-/-) Il2rg(-/-)), we demonstrate that FLT3L is important for IL2Rg-independent maintenance of both immature BM as well as peripheral NK cells. In contrast to IL-7, which is dispensable for BM but important for thymic NK cells, IL-15 has a direct and important role in both thymic and BM NK cell compartments. Although thymic NK cells were not affected in Flt3l(-/-) mice, Flt3l(-/-)Il2rg(-/-) mice lacked detectable thymic NK cells, suggesting that FLT3L is also important for IL-2Rg-independent maintenance of thymic NK cells. Thus, IL-2Rg cytokines and FLT3L play complementary roles and are indispensable for homeostasis of both BM and thymic dependent NK cell development, suggesting that the cytokine pathways crucial for these two distinct NK cell pathways are largely overlapping.
|
|
| 3. |
- Abdellah, Tebani, et al.
(författare)
-
Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
|
|
| 4. |
|
|
| 5. |
- Asenjo, Felipe A., et al.
(författare)
-
Semi-relativistic effects in spin-1/2 quantum plasmas
- 2012
-
Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 14, s. 073042-
-
Tidskriftsartikel (refereegranskat)abstract
- Emerging possibilities for creating and studying novel plasma regimes, e. g. relativistic plasmas and dense systems, in a controlled laboratory environment also require new modeling tools for such systems. This motivates theoretical studies of the kinetic theory governing the dynamics of plasmas for which both relativistic and quantum effects occur simultaneously. Here, we investigate relativistic corrections to the Pauli Hamiltonian in the context of a scalar kinetic theory for spin-1/2 quantum plasmas. In particular, we formulate a quantum kinetic theory for the collective motion of electrons that takes into account effects such as spin-orbit coupling and Zitterbewegung. We discuss the implications and possible applications of our findings.
|
|
| 6. |
- Borgström, Emilie W., et al.
(författare)
-
Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors
- 2023
-
Ingår i: Journal of Clinical Immunology. - : Springer. - 0271-9142 .- 1573-2592. ; 43, s. 136-150
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose; The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors.Methods: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans.Results: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-gamma and CXCL10 were downregulated.Conclusions: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.
|
|
| 7. |
- Bose, Aneesh, et al.
(författare)
-
Pharmaceutical pollution disrupts the behaviour and predator–prey interactions of two widespread aquatic insects
- 2022
-
Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25
-
Tidskriftsartikel (refereegranskat)abstract
- Pharmaceutical pollution represents a rapidly growing threat to ecosystems worldwide. Drugs are now commonly detected in the tissues of wildlife and have the potential to alter the natural expression of behavior, though relatively little is known about how pharmaceuticals impact predator-prey interactions. We conducted parallel laboratory experiments using larval odonates (dragonfly and damselfly nymphs) to investigate the effects of exposure to two pharmaceuticals, cetirizine and citalopram, and their mixture on the outcomes of predator-prey interactions. We found that exposure to both compounds elevated dragonfly activity and impacted their predation success and efficiency in complex ways. While exposure to citalopram reduced predation efficiency, exposure to cetirizine showed varied effects, with predation success being enhanced in some contexts but impaired in others. Our findings underscore the importance of evaluating pharmaceutical effects under multiple contexts and indicate that these compounds can affect predator-prey outcomes at sublethal concentrations.
|
|
| 8. |
- Brodin, Petter
(författare)
-
MHC class I molecules in natural killer cell education and tolerance
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The immune system needs to respond to danger but remain tolerant to normal cells and tissues. Natural killer cells achieve tolerance to self by the use of inhibitory receptors recognizing MHC class I molecules on healthy cells. Only NK cells expressing such inhibitory receptors for self-MHC class I molecules are allowed to be fully functional through a process of education. Here we have studied this process of education and the nature of the MHC class I mediated influence. We have found that MHC class I molecules exert a quantitative rather than a binary influence on NK cells. This means that NK cells are not “on” or “off” but also everything in-between. We have also found MHC class I molecules to regulate NK cells at multiple levels, such as setting the threshold for activation and determining the quality of NK cell responses to stimulation. Also the formation of the NK cell repertoire is regulated by MHC class I. We propose that this reflects a process in which NK cells continuously sense MHC class I and other relevant inputs and adapt to them. This could serve to maintain NK cell sensitivity to relative changes in stimuli also in a context that is highly dynamic. We have termed this the Rheostat model for NK cell education.
|
|
| 9. |
- Consiglio, Camila, et al.
(författare)
-
Immune system adaptation during gender-affirming testosterone treatment
- 2023
-
Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 159, s. 29-30
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Biological sex impacts human immune responses, modulating susceptibility and severity to immune-related diseases. Female generally mount more robust immune responses than males, resulting in lower infection severity and greater autoimmunity incidence. Here, we addressed the contribution of testosterone to human immune function by analyzing a cohort of subjects undergoing gender-affirming testosterone treatment. We performed systems-level immunomonitoring through mass cytometry, scRNA and scA-TAC-Sequencing, and proteome profiling of blood samples at baseline and following 3 and 12 months of treatment. Testosterone treatment was associated with a low-grade inflammatory profile, evidenced by upregulation of proinflammatory plasma proteome (e.g., EN-RAGE, OSM, TNF), and induction of an inflammatory transcriptional program associated with NFkB signaling, and TNF signaling. Following testosterone treatment, higher NFkB activity was revealed in CD4 T, CD8 T, and NK cells in scATACseq analyses. Further, testosterone increased monocytic inflammatory responses upon bacterial stimulation in vitro. Although testosterone was associated with this inflammatory profile, it also exerted negative effects on antiviral immunity. Firstly, the percentage of plasmacytoid dendritic cells (pDC) decreased over transition, with pDC also displaying phenotypic changes associated with lower IFN responses. Secondly, bulk transcriptomics analyses show an overall reduction of IFNa responses. Thirdly, testosterone treatment led to reduced IFNa production upon PBMCs stimulation with a viral agonist. Our results show that testosterone has broad effects on the human immune system, and significantly modulates important players in antiviral immunity and inflammatory response. Identifying pathways involved in immune sexual dimorphism will help define novel targets for effective prevention and treatment of immune-mediated diseases.
|
|
| 10. |
- Consiglio, Camila Rosat, et al.
(författare)
-
The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19
- 2020
-
Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 183:4, s. 968-981
-
Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. Weapply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
|
|
| 11. |
-
Exhibition: Space Waves and a Tale : Hannes Alfvén (1908–1995). Nobel Prize laureate in physics 1970.
- 2022
-
Konstnärligt arbeteabstract
- The exhibition Space Waves and a Tale presented parts of Alfvén's extensive research, his community engagement and last but not least, his fictional story The tale of the great computing machine from 1966. In 1970 KTH professor Hannes Alfvén (1908 – 1995) was awarded the Nobel Prize in physics for his discoveries and applications in plasma physics. The exhibition Space Waves and a Tale presented parts of Alfvén's extensive research, his community engagement and his fictional story The tale of the great computing machine from 1966.Alfvén's research allow us to explore all corners of the universe – from the auroras on earth to the auroras on other planets, from solar wind to stellar wind, from plasma phenomena in the laboratory to astrophysical plasma phenomena in ours and other galaxies.The tale of the great computing machine is a satirical tale that tells the story of a future society controlled by computers and is also the source of inspiration for an opera with the same name.As part of the exhibition Space Waves and a Tale visitors were invited to share their visions of how future technology will shape our lives and societies. Two students from the KTH School of Architecture have contributed to the exhibition by designing and building a flexible and sustainable exhibition module. Students from BOOMERANG REXUS participated with objects related to aerospace research.Space Waves and a Tale was produced by the project group for KTH 200 years anniversary celebration together with KTH Library, The Opera: The Tale of the Great Computing Machine, the Division of Space and Plasma Physics and the KTH School of Architecture.In connection with the exhibithion there was a book discussion, popular science lecture and a class visit.
|
|
| 12. |
- Gustafsson, Anna, et al.
(författare)
-
Antisecretory factor in breastmilk is associated with reduced incidence of sepsis in preterm infants
- 2023
-
Ingår i: Pediatric Research. - 0031-3998 .- 1530-0447. ; 95:3, s. 762-69
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Antisecretory Factor (AF) is a protein present in breastmilk that regulates inflammatory processes. We aimed to investigate the level of AF in mothers’ own milk (MOM) in relation to sepsis and other neonatal morbidities in preterm infants. Methods: Samples of breastmilk and infant plasma were collected at 1, 4, and 12 weeks after birth from 38 mothers and their 49 infants born before 30 weeks gestation. AF-compleasome in MOM was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) and inflammatory markers in infant plasma by a panel of 92 inflammatory proteins. Neonatal treatments and outcomes were recorded. Results: The level of AF in MOM week 1 was lower for infants with later sepsis compared to no sepsis (p = 0.005). Corrected for nutritional intake of MOM, higher levels of AF decreased the risk for sepsis, OR 0.24. AF in MOM week 1 was negatively correlated to inflammatory proteins in infant plasma week 4, markedly IL-8, which was also associated with infant sepsis. Overall, higher AF levels in MOM was associated with fewer major morbidities of prematurity. Conclusion: Mother’s milk containing high levels of antisecretory factor is associated with reduced risk for sepsis and inflammation in preterm infants. Impact: High level of antisecretory factor (AF) in mothers’ own milk is associated with less risk for later sepsis in preterm infants.Receiving mothers’ milk with low AF levels during the first week after birth is correlated with more inflammatory proteins in infant’s plasma 2–4 weeks later.Human breastmilk has anti-inflammatory properties, and antisecretory factor in mothers’ own milk is a component of potential importance for infants born preterm.The findings suggest that food supplementation with AF to mothers of preterm infants to increase AF-levels in breastmilk may be a means to decrease the risk of inflammatory morbidities of prematurity.
|
|
| 13. |
- Höjer, Pontus, et al.
(författare)
-
Identification of Major Immune Cell Lineages with DBS-Pro
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Proteins play a pivotal role in cellular function and heterogeneity. Understanding cellular diversity at the proteome level necessitates sensitive single-cell assays with high throughput. While current sequencing-based methods offer promise, they often face limitations, including reliance on expensive and inaccessible commercial platforms. Here, we have adopted the DBS-Pro method, utilizing site-specific oligonucleotide-conjugated antibodies, to analyze surface proteins in single cells. The method uses cheap degenerated barcode oligonucleotides and a simple microfluidics setup for cell encapsulation. A sample of PBMCs was examined using a panel targeting six separate immune cell markers. Using this panel we could quantify marker expression on 1,307 cells, identifying major immune cell lineages including CD4+ T-cells, CD8+ T-cells, monocytes, and B-cells. While recognizing the need for protocol improvements, our results present a promising approach for single-cell proteomics.
|
|
| 14. |
- Johannes, Erik, et al.
(författare)
-
Sustainable Timber Transport : Economic Aspects of Aerodynamic Reconfiguration
- 2018
-
Ingår i: Sustainability. - : MDPI. - 2071-1050. ; 10:6, s. 1-18
-
Tidskriftsartikel (refereegranskat)abstract
- There is a need to reduce fuel consumption, and thereby reduce CO2-emissions in all parts of the transport sector. It is also well known that aerodynamic resistance affects the fuel consumption in a major way. By improving the aerodynamics of the vehicles, the fuel consumption will also decrease. A special type of transportation is that of timber, which is performed by specialized trucks with few alternative uses. This paper follows up on earlier papers concerning Swedish timber trucks where aerodynamic improvements for timber trucks were tested. By mapping the entire fleet of timber trucks in Sweden and investigating reduced fuel consumption of 2–10%, financial calculations were performed on how these improvements would affect the transport costs. Certain parameters are investigated, such as investment cost, extra changeover time and weight of installments. By combining these results with the mapping of the fleet, it can be seen under which circumstances these improvements would be sustainable. The results show that it is possible through aerodynamics to lower the transportation costs and make an investment plausible, with changeover time being the most important parameter. They also show that certain criteria for a reduced transportation cost already exist within the vehicle fleet today.
|
|
| 15. |
- Just, David, et al.
(författare)
-
Autoantibodies against the C-terminus of Lipopolysaccharide binding protein are elevated in young adults with psychiatric disease
- 2021
-
Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 126
-
Tidskriftsartikel (refereegranskat)abstract
- Growing evidence implies interactions between infections, the immune system and vulnerability for psychiatric disease. This study applies an affinity proteomic-based method to investigate potential disease associated autoantibody signatures in serum from patients from the "Young Adults" section of the Department of General Psychiatry at Uppsala University Hospital (n = 395) and population-based controls (n = 102). We found serum levels of antibodies against Lipopolysaccharide Binding Protein (LBP), a protein that is important for mediating innate immune responses involving the toll-like receptor-4 (TLR-4), to be higher in patients compared to controls (Mann Whitney U-test p = 5.248 x 10(-10)). The patients were divided into three groups based on their relative levels of autoantibodies against LBP. The distribution of autism spectra disorders (p = 2.0 x 10(-4)) and hospital care for an infection as adults (p = 0.036) differed between the anti-LBP groups, with low incidence in the group of patients with the highest levels of anti-LBP who were diagnosed with primarily affective and anxiety disorders. In a sub-group analysis, the controls who screened positive for current or previous psychiatric diagnosis (n = 20) had higher anti-LBP compared to non-psychiatric controls with negative screening for psychiatric disorders (Mann Whitney U-test p = 0.006). Inflammatory markers were found to differ across anti-LBP groups and several pro-inflammatory markers, including IL-1 beta, were low in patients with high anti-LBP and serum LBP levels were lowest in patients with the highest levels of antibodies against LBP (p = 3.5 x 10(-5)). A cell-based model showed that polyclonal rabbit anti-LBP, obtained through purification via the same protein fragment used in the initial autoantibody analysis, could interfere with LBP signaling since addition of anti-LBP to the assay reduced both IL-1 beta and IL-6 release from activated monocytes in response to LBP and LPS (p = 0.0001 and p = 0.02). This novel finding of antibodies against LBP, where high levels were only found in young adults with psychiatric disease, merits further study. Our results suggest that these antibodies may have relevance for TLR4 based immune responses and vulnerability for both infection and psychiatric disorders.
|
|
| 16. |
- Kahn, Robin, et al.
(författare)
-
Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms
- 2022
-
Ingår i: Acta Paediatrica, International Journal of Paediatrics. - : Wiley. - 0803-5253 .- 1651-2227. ; 111:2, s. 354-62
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Our aim was to describe the outcomes of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Methods: This national, population-based, longitudinal, multicentre study used Swedish data that were prospectively collected between 1 December 2020 and 31 May 2021. All patients met the World Health Organization criteria for MIS-C. The outcomes 2 and 8weeks after diagnosis are presented, and follow-up protocols are suggested. Results: We identified 152 cases, and 133 (87%) participated. When followed up 2weeks after MIS-C was diagnosed, 43% of the 119 patients had abnormal results, including complete blood cell counts, platelet counts, albumin levels, electrocardiograms and echocardiograms. After 8weeks, 36% of 89 had an abnormal patient history, but clinical findings were uncommon. Echocardiogram results were abnormal in 5% of 67, and the most common complaint was fatigue. Older children and those who received intensive care were more likely to report symptoms and have abnormal cardiac results. Conclusion: More than a third (36%) of the patients had persistent symptoms 8weeks after MIS-C, and 5% had abnormal echocardiograms. Older age and higher levels of initial care appeared to be risk factors. Structured follow-up visits are important after MIS-C.
|
|
| 17. |
- Landegren, Nils, 1986-, et al.
(författare)
-
Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'
- 2019
-
Ingår i: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.
|
|
| 18. |
|
|
| 19. |
- Lovén, Jakob, et al.
(författare)
-
MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma.
- 2010
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:4, s. 1553-8
-
Tidskriftsartikel (refereegranskat)abstract
- MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Merid, Simon Kebede, et al.
(författare)
-
Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
-
Ingår i: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
|
|
| 23. |
- Mold, Jeff E., et al.
(författare)
-
Cell generation dynamics underlying naive T-cell homeostasis in adult humans
- 2019
-
Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 17:10
-
Tidskriftsartikel (refereegranskat)abstract
- Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived C-14 in genomic DNA, we determined the turnover rates of CD4(+) and CD8(+) naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor kappa B (NF-kappa B) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-kappa B signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-kappa B phosphorylation in CD4(+)CD31(-) naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.
|
|
| 24. |
- Nilsson, Jan, et al.
(författare)
-
Långtidskomplikationer – postakut covid-19-syndrom
- 2021
-
Ingår i: Vad kan vi lära av pandemin? : Kunskapsöversikt från Kungl. Vetenskapsakademiens expertgrupp om covid-19. - Kunskapsöversikt från Kungl. Vetenskapsakademiens expertgrupp om covid-19.. ; , s. 56-64
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 25. |
- Olin, Axel, et al.
(författare)
-
Stereotypic Immune System Development in Newborn Children
- 2018
-
Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 174:5, s. 1277-
-
Tidskriftsartikel (refereegranskat)abstract
- Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 mu L of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
|
|
| 26. |
- Stikvoort, Arwen, et al.
(författare)
-
Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease
- 2017
-
Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets.
|
|
| 27. |
|
|
| 28. |
- Sundling, Christopher, et al.
(författare)
-
B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets
- 2019
-
Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:9
-
Tidskriftsartikel (refereegranskat)abstract
- Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute Plasmodium fakiporum malaria for the first time or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that approximately 80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only approximately 40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared with individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay, with a half-life of approximately 300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary and secondary B cell responses during infection.
|
|
| 29. |
- Tajvar, Pouria, 1991-, et al.
(författare)
-
Modelling Pathogen Response of the Human Immune System in a Reduced State Space
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The immune system response to pathogens is organized by a network of cells communicating through expression of a variety of proteins and signaling molecules. A high number of genes are involved in encoding these communicating agents, but the relatively low number of data points is a major challenge in modelling the gene expression response.In this work we propose a feature-selection approach based on gene expression distributions at the single-cell level that improves dynamics identification at the population level.We investigate common approaches to differential expression analysis and show that Earth Mover's Distance (EMD) is a relatively robust measure for gene selection as reflected by the coefficient of variation as well as accuracy of a naive Bayes classifier based on the selected genes.We ultimately propose the bootstrap standard deviation metric as an estimate of state uncertainty and show that statistically significant signals in pathogen response can be recovered in the reduced state space constructed with the selected genes.
|
|
| 30. |
- Tajvar, Pouria, 1991-, et al.
(författare)
-
Modelling Pathogen Response of the Human Immune System in a Reduced State Space
- 2023
-
Ingår i: 2023 62nd IEEE Conference on Decision and Control, CDC 2023. - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. 715-720
-
Konferensbidrag (refereegranskat)abstract
- The immune system response to pathogens is organized by a network of cells communicating through expression of a variety of proteins and signaling molecules. A high number of genes are involved in encoding these communicating agents, but the relatively low number of data points is a major challenge in modelling the gene expression response. In this work we propose a feature-selection approach based on gene expression distributions at the single-cell level that improves dynamics identification at the population level. We investigate common approaches to differential expression analysis and show that Earth Mover's Distance (EMD) is a relatively robust measure for gene selection as reflected by the coefficient of variation as well as accuracy of a naive Bayes classifier based on the selected genes. We ultimately propose the bootstrap standard deviation metric as an estimate of state uncertainty and show that statistically significant signals in pathogen response can be recovered in the reduced state space constructed with the selected genes.
|
|
| 31. |
- Uhlén, Mathias, et al.
(författare)
-
A genome-wide transcriptomic analysis of protein-coding genes in human blood cells
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 366:6472, s. 1471-
-
Tidskriftsartikel (refereegranskat)abstract
- Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.
|
|
| 32. |
- Xu, Ning, et al.
(författare)
-
MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
- 2011
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:7, s. 1521-9
-
Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that play important roles in the regulation of gene expression. We previously identified a characteristic miRNA expression profile in psoriasis, distinct from that of healthy skin. One of the most downregulated miRNAs in psoriasis skin was microRNA-125b (miR-125b). In this study, we aimed to identify the potential role(s) of miR-125b in psoriasis pathogenesis. In situ hybridization results showed that the major cell type responsible for decreased miR-125b levels in psoriasis lesions was the keratinocyte. Overexpression of miR-125b in primary human keratinocytes suppressed proliferation and induced the expression of several known differentiation markers. Conversely, inhibition of endogenous miR-125b promoted cell proliferation and delayed differentiation. Fibroblast growth factor receptor 2 (FGFR2) was identified as one of the direct targets for suppression by miR-125b by luciferase reporter assay. The expression of miR-125b and FGFR2 was inversely correlated in both transfected keratinocytes and in psoriatic skin. Knocking down FGFR2 expression by siRNA suppressed keratinocyte proliferation, but did not enhance differentiation. Altogether, our results demonstrate a role for miR-125b in the regulation of keratinocyte proliferation and differentiation, partially through the regulation of FGFR2. Loss of miR-125b in psoriasis skin may contribute to hyperproliferation and aberrant differentiation of keratinocytes.
|
|
| 33. |
- Yalcinkaya, Ahmet, et al.
(författare)
-
No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines
- 2024
-
Ingår i: NPJ VACCINES. - : Springer Nature. - 2059-0105. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines.
|
|
