| 1. |
- Bornelöv, Susanne, et al.
(author)
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Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e80080-
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Journal article (peer-reviewed)abstract
- Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children) and BAMSE (a Swedish birth-cohort including 2033 children), genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6) and 3.2 (95% CI 2.0-5.0) in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0) of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies of etiological mechanisms and may also strengthen the basis for risk assessment and prevention.
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| 2. |
- Hedman, Anna M, et al.
(author)
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Allergen-specific IgE over time in women before, during and after pregnancy
- 2018
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In: Allergy. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0105-4538 .- 1398-9995.
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Journal article (peer-reviewed)abstract
- The trajectory of IgE levels before, during and after pregnancy in sensitized individuals is characterized by significant increase in specific IgE to birch allergens but not to other allergens after multiple testing. This increase may warrant some surveillance in the antenatal care for those with clinical symptoms.
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| 3. |
- Sonkoly, Enikö, et al.
(author)
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MicroRNAs : novel regulators involved in the pathogenesis of psoriasis?
- 2007
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:7
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Journal article (peer-reviewed)abstract
- MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases.
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| 4. |
- Acevedo, Nathalie, et al.
(author)
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DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life
- 2021
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:2
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Journal article (peer-reviewed)abstract
- DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p <= 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.
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| 5. |
- Acevedo, Nathalie, et al.
(author)
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Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients
- 2020
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Journal article (peer-reviewed)abstract
- T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.
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| 6. |
- Acevedo, Nathalie, et al.
(author)
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Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 1
- 2016
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In: plos one. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
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Journal article (peer-reviewed)abstract
- Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases- related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.
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| 7. |
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| 8. |
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| 9. |
- Baptista, Marisa A. P., et al.
(author)
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Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
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| 10. |
- Barbosa-Lorenzi, Valéria C, et al.
(author)
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Curdlan induces selective mast cell degranulation without concomitant release of LTC4, IL-6 or CCL2
- 2017
-
In: Immunobiology. - : Elsevier BV. - 0171-2985 .- 1878-3279. ; 222:4, s. 647-650
-
Journal article (peer-reviewed)abstract
- Mast cells are sentinel cells with a tissue-specific localization in the interface between the host and the external environment. Their quick and selective response upon encountering pathogens is part of the innate host response and typically initiates the following adaptive immune response. Among several pattern recognition receptors (PRRs) involved in the recognition of pathogens by mast cells, the C-type lectin receptor Dectin-1 has been associated with the recognition of fungi. Our previous studies have shown that mast cells are the predominant cell type expressing Dectin-1 in human skin, and they also recognize and respond to Malassezia sympodialis by producing cytokines connected to the innate host response and upregulating the expression of Dectin-1. In the present study, we investigated mast cell responses to Curdlan, a β-glucan that acts as an agonist for the fungi receptor Dectin-1, and found a unique response pattern with induced degranulation, but surprisingly without synthesis of Leukotriene C4, IL-6 or CCL2. Since mast cells are the predominant Dectin-1 expressing cell in the human skin, this study suggests that mast cell degranulation in response to fungi is an important part of the first line of defense against these pathogens.
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| 11. |
- Bhalla, Nayanika, et al.
(author)
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Spatial transcriptomics of human placentas reveal distinct RNA patterns associated with morphology and preeclampsia
- 2023
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In: Placenta. - : Elsevier BV. - 0143-4004 .- 1532-3102. ; 139, s. 213-216
-
Journal article (peer-reviewed)abstract
- Spatial transcriptomics (ST) maps RNA level patterns within a tissue. This technology has not been previously applied to human placental tissue. We demonstrate analysis of human placental samples with ST. Unsupervised clustering revealed that distinct RNA patterns were found corresponding to different morphological structures. Additionally, when focusing upon terminal villi and hemoglobin associated structures, RNA levels differed between placentas from full term healthy pregnancies and those complicated by preeclampsia. The results from this study can provide a benchmark for future ST studies in placenta.
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| 12. |
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| 13. |
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| 14. |
- Garbani, M., et al.
(author)
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Allergen-loaded strontium-doped hydroxyapatite spheres improve allergen-specific immunotherapy in mice
- 2017
-
In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 72:4, s. 570-578
-
Journal article (peer-reviewed)abstract
- BackgroundImmunomodulatory interventions play a key role in the treatment of infections and cancer as well as allergic diseases. Adjuvants such as micro- and nanoparticles are often added to immunomodulatory therapies to enhance the triggered immune response. Here, we report the immunological assessment of novel and economically manufactured microparticle adjuvants, namely strontium-doped hydroxyapatite porous spheres (SHAS), which we suggest for the use as adjuvant and carrier in allergen-specific immunotherapy (ASIT).Methods and ResultsScanning electron microscopy revealed that the synthesis procedure developed for the production of SHAS results in a highly homogeneous population of spheres. SHAS bound and released proteins such as ovalbumin (OVA) or the major cat allergen Fel d 1. SHAS-OVA were taken up by human monocyte-derived dendritic cells (mdDCs) and murine DCs and did not have any necrotic or apoptotic effects even at high densities. In a murine model of ASIT for allergic asthmatic inflammation we found that OVA released from subcutaneously injected SHAS-OVA led to a sustained stimulation of both CD4+ and CD8+ T-cells. ASIT with SHAS-OVA as compared to soluble OVA resulted in similar humoral responses but in a higher efficacy as assessed by symptom scoring.ConclusionWe conclude that SHAS may constitute a suitable carrier and adjuvant for ASIT with great potential due to its unique protein-binding properties.
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| 15. |
- Gioti, Anastasia, et al.
(author)
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Genomic Insights into the Atopic Eczema-Associated Skin Commensal Yeast Malassezia sympodialis
- 2013
-
In: mBio. - 2161-2129 .- 2150-7511. ; 4:1, s. e00572-12-
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Journal article (peer-reviewed)abstract
- Malassezia commensal yeasts are associated with a number of skin disorders, such as atopic eczema/dermatitis and dandruff, and they also can cause systemic infections. Here we describe the 7.67-Mbp genome of Malassezia sympodialis, a species associated with atopic eczema, and contrast its genome repertoire with that of Malassezia globosa, associated with dandruff, as well as those of other closely related fungi. Ninety percent of the predicted M. sympodialis protein coding genes were experimentally verified by mass spectrometry at the protein level. We identified a relatively limited number of genes related to lipid biosynthesis, and both species lack the fatty acid synthase gene, in line with the known requirement of these yeasts to assimilate lipids from the host. Malassezia species do not appear to have many cell wall-localized glycosylphosphatidylinositol (GPI) proteins and lack other cell wall proteins previously identified in other fungi. This is surprising given that in other fungi these proteins have been shown to mediate interactions (e. g., adhesion and biofilm formation) with the host. The genome revealed a complex evolutionary history for an allergen of unknown function, Mala s 7, shown to be encoded by a member of an amplified gene family of secreted proteins. Based on genetic and biochemical studies with the basidiomycete human fungal pathogen Cryptococcus neoformans, we characterized the allergen Mala s 6 as the cytoplasmic cyclophilin A. We further present evidence that M. sympodialis may have the capacity to undergo sexual reproduction and present a model for a pseudobipolar mating system that allows limited recombination between two linked MAT loci. IMPORTANCE Malassezia commensal yeasts are associated with a number of skin disorders. The previously published genome of M. globosa provided some of the first insights into Malassezia biology and its involvement in dandruff. Here, we present the genome of M. sympodialis, frequently isolated from patients with atopic eczema and healthy individuals. We combined comparative genomics with sequencing and functional characterization of specific genes in a population of clinical isolates and in closely related model systems. Our analyses provide insights into the evolution of allergens related to atopic eczema and the evolutionary trajectory of the machinery for sexual reproduction and meiosis. We hypothesize that M. sympodialis may undergo sexual reproduction, which has important implications for the understanding of the life cycle and virulence potential of this medically important yeast. Our findings provide a foundation for the development of genetic and genomic tools to elucidate host-microbe interactions that occur on the skin and to identify potential therapeutic targets.
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| 16. |
- Greicius, Gediminas, et al.
(author)
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Microvilli structures on B lymphocytes: inducible functional domains?
- 2004
-
In: Int Immunol. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 16:2, s. 353-64
-
Journal article (peer-reviewed)abstract
- Interactive contact between B lymphocytes and T cells is necessary for their expansion during an immune response. It has been shown that B lymphocytes receive signals from T cells, such as IL-4 and cross-linking of CD40, which are crucial for their differentiation. We previously found that these factors induce formation of microvilli on B cells and that this was correlated with increased homotypic adhesion of B lymphocytes. In this study we have investigated if IL-4 induce segregation of proteins to microvilli and lipid rafts. Using immuno-electron microscopy we analyzed cell-surface distribution of molecules involved in B-T cell co-activation. Recruitment to detergent-resistant membrane fractions was analyzed using sucrose gradient centrifugation. We found that microvilli were enriched in ICAM-1 and MHC class II molecules. In contrast, LFA-1 and CD40 were more abundant on the smooth cell surfaces, while B7-2 (CD86) was randomly distributed. We also discovered that depletion of cholesterol, using beta-methyl-cyclodextrin, lowered the number of microvilli, indicating that intact lipid rafts are required for their expression. Moreover, activation of B lymphocytes by lipopolysaccharide (LPS) induced increased expression of GM(1), a marker for lipid rafts. However, although both surface and total levels of GM(1) were similar in B lymphocytes stimulated with either LPS or LPS plus IL-4, GM(1) was mainly expressed on microvilli in LPS plus IL-4-stimulated cells. Taken together, our results indicate that microvilli represent distinct inducible membrane domains that can regulate direct cell-cell interactions via grouping and three-dimensional presentation of cell-surface receptors.
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| 17. |
- Holm, Tina, et al.
(author)
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Cell-penetrating peptides as antifungals towards Malassezia sympodialis
- 2012
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In: Letters in Applied Microbiology. - 0266-8254 .- 1472-765X. ; 54:1, s. 39-44
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Journal article (peer-reviewed)abstract
- Aim: To determine whether different antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) are able to inhibit the growth of the commensal yeast Malassezia sympodialis, which can act as a trigger factor in different skin disorders, such as atopic eczema (AE), seborrhoeic eczema (SE) and dandruff. Methods and results: The antifungal activity of 21 different AMPs and CPPs was investigated by microdilution assay and plate counting to determine the number of colony forming units. Five CPPs and one AMP showed fungicidal activity at submicromolar concentrations. Importantly, no membrane damage on human keratinocytes was detected after peptide treatment. Conclusions: Several CPPs, while being nontoxic to mammalian cells, possess growth inhibitory activity on the very stringent yeast M. sympodialis. Significance and impact of study: Our findings that the CPPs and one AMP that are harmless towards mammalian cells act as antifungal agents against sympodialis opens up the possibility to use these in the treatment for AL, SE and dandruff. To our knowledge, this is the first time peptides have been identilied as antilungal agents against sympodialis. Further studies to ekicidate the mechanism are warranted.
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| 18. |
- Holmgren-Peterson, Kajsa, 1964-
(author)
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Structure and dynamics of epithelial cells : Studied with confocal microscopy and flourescence recovery after photobleaching
- 1995
-
Doctoral thesis (other academic/artistic)abstract
- Epithelial cells of the human body form a physical barrier to harmful agents and potential invading microorganisms. In the small intestine they must also produce enzymes for digestion of food and be able to absorb nutrients.The aim of this work was to study properties of epithelial cells in model systems using cell lines and toad bladder cells, and to study the effect of gluten intolerance (celiac disease, CD), viz. a pathological condition, on human small-intestine epithelial cells, enterocytes. Fluores-cence microscopy techniques, and primarily confocallaser scanning microscopy (CLSM), have beeen used as the major methods in the investigation. Part of the work has also been to develop, and apply, tools for measurements in confocal rnicroscopy images to obtain semi-quantitative information on structures.Fluorescence recovery after photobleaching (FRAP) was used to study the effect of maturation of small intestine-like epithelial cells. Lateral diffusion of membrane components was measured to reveal alterations in membrane fluidity induced by differentiation. No general effects on the lateral mobility of membrane components was observed, rather distinct effects were noticed on protein diffusion.Vasopressin induces the fusion of vesicles containing water channels with the apical membrane of toad bladder epithelial cells. This fusion is known to result in depolymerization of fllamentous actin (F-actin) of the cell. CLSM was used to assess where in the cell the depolymerization occurs. It was demonstrated that the depolymerization is not evenly distributed, but confined only to the apical region of the cells.In children suffering from celiac disease the mucosa of the small intestine is severely damaged. The damage at the enterocyte level is, however, less investigated. In the present work, CLSM was applied to compare the distributions ofF-actin and of glycoconjugates in enterocytes from children with CD to enterocytes from children not suffering from the disease. The results show that in children with active CD the distribution of both structures was altered, but also that compliance to a gluten-free diet results in the return to normal-looking enterocytes.
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| 19. |
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| 20. |
- Johansson, Catharina, et al.
(author)
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Elevated Peripheral Allergen-Specific T Cell Response Is Crucial for a Positive Atopy Patch Test Reaction
- 2009
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In: International Archives of Allergy and Immunology. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 150:1, s. 51-58
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Journal article (peer-reviewed)abstract
- Background: Atopic eczema is a chronic inflammatory skin disease in which several subgroups of cases can be identified. Atopy patch testing (APT) reveals allergen sensitization also in atopic eczema patients devoid of detectable allergen-specific IgE, suggesting the importance of factors other than IgE in the reaction. Here we investigate the relationship between APT reactions and allergen-specific peripheral IgE and T cell reactivity in atopic eczema patients. Methods: Adult patients with atopic eczema (n = 64) and healthy controls (n = 24) were analyzed for reactivity to Malassezia sympodialis extract by APT, measurement of specific plasma IgE and in vitro determination of the frequency of allergen-reactive peripheral blood mononuclear cells producing interleukin-4 and interleukin-5 using the ELISpot method. Results: When combining the results of the APT, IgE measurements and the ELISpot analyses, reactivity to M. sympodialis was found in a majority of the atopic eczema patients (69%), whereas the healthy controls were negative throughout. T cell reactivity to M. sympodialis, manifested by production of both interleukins 4 and 5, was highly predictive for a positive APT reaction and displayed a strongly positive correlation with the APT score. In contrast, the allergen-specific IgE levels did not predict the APT outcome, and no correlation could be found between the IgE levels and the APT score. Conclusion: Peripheral allergen-specific T helper 2 cell-mediated reactivity appears to be required for a positive APT reaction to M. sympodialis. The diagnostic potential of measuring peripheral allergen-specific T cell responses should be considered in atopic eczema.
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| 21. |
- Johansson, Henrik J., et al.
(author)
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Extracellular nanovesicles released from the commensal yeast Malassezia sympodialis are enriched in allergens and interact with cells in human skin
- 2018
-
In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
-
Journal article (peer-reviewed)abstract
- Malassezia sympodialis is a dominant commensal fungi in the human skin mycobiome but is also associated with common skin disorders including atopic eczema (AE). M. sympodialis releases extracellular vesicles, designated MalaEx, which are carriers of small RNAs and allergens, and they can induce inflammatory cytokine responses. Here we explored how MalaEx are involved in hostmicrobe interactions by comparing protein content of MalaEx with that of the parental yeast cells, and by investigating interactions of MalaEx with cells in the skin. Cryo-electron tomography revealed a heterogeneous population of MalaEx. iTRAQ based quantitative proteomics identified in total 2439 proteins in all replicates of which 110 were enriched in MalaEx compared to the yeast cells. Among the MalaEx enriched proteins were two of the M. sympodialis allergens, Mala s 1 and s 7. Functional experiments indicated an active binding and internalization of MalaEx into human keratinocytes and monocytes, and MalaEx were found in close proximity of the nuclei using super-resolution fluorescence 3D-SIM imaging. Our results provides new insights into host-microbe interactions, supporting that MalaEx may have a role in the sensitization and maintenance of inflammation in AE by containing enriched amounts of allergens and with their ability to interact with skin cells.
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| 22. |
- Kunzmann, Andrea, et al.
(author)
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Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells
- 2011
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In: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 253:2, s. 81-93
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Journal article (peer-reviewed)abstract
- Engineered nanoparticles are being considered for a wide range of biomedical applications, from magnetic resonance imaging to "smart" drug delivery systems. The development of novel nanomaterials for biomedical applications must be accompanied by careful scrutiny of their biocompatibility. In this regard, particular attention should be paid to the possible interactions between nanoparticles and cells of the immune system, our primary defense system against foreign invasion. On the other hand, labeling of immune cells serves as an ideal tool for visualization, diagnosis or treatment of inflammatory processes, which requires the efficient internalization of the nanoparticles into the cells of interest. Here, we compare novel monodispersed silica-coated iron oxide nanoparticles with commercially available dextran-coated iron oxide nanoparticles. The silica-coated iron oxide nanoparticles displayed excellent magnetic properties. Furthermore, they were nontoxic to primary human monocyte-derived macrophages at all doses tested whereas dose-dependent toxicity of the smaller silica-coated nanoparticles (30 nm and 50 nm) was observed for primary monocyte-derived dendritic cells, but not for the similarly small dextran-coated iron oxide nanoparticles. No macrophage or dendritic cell secretion of pro-inflammatory cytokines was observed upon administration of nanoparticles. The silica-coated iron oxide nanoparticles were taken up to a significantly higher degree when compared to the dextran-coated nanoparticles, irrespective of size. Cellular internalization of the silica-coated nanoparticles was through an active, actin cytoskeleton-dependent process. We conclude that these novel silica-coated iron oxide nanoparticles are promising materials for medical imaging, cell tracking and other biomedical applications. (C) 2011 Elsevier Inc. All rights reserved.
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| 23. |
- Kupferschmidt, Natalia, et al.
(author)
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Mesoporous silica particles potentiate antigen-specific T-cell responses
- 2014
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In: Nanomedicine. - 1743-5889 .- 1748-6963. ; 9:12, s. 1835-1846
-
Journal article (peer-reviewed)abstract
- Aim: To study the adjuvant effect of mesoporous silica particles and their capability of modifying an already existing allergic Th2-like immune response. Materials & methods: The adjuvant effect of Santa Barbara Amorphous-15 (SBA-15) mesoporous silica particles was studied in an antigen-specific ovalbumin (OVA) system in vitro and in vivo. The capacity of the OVA-loaded SBA-15 particles (SBA-15-OVA) to modify an existing immune response was assessed in a murine allergy model. Results: SBA-15-OVA induced significantly stronger OVA-specific splenocyte proliferation compared with OVA alone. Significantly higher IFN-gamma production was observed in ex vivo OVA-stimulated splenocytes from SBA-15-OVA-immunized mice compared with mice injected with only SBA-15 or OVA. Treatment of OVA-sensitized mice with SBA-15-OVA modified the immune response with significantly lower serum levels of OVA-specific IgE and higher IgG levels compared with the alum-OVA-treated group. Conclusion: The results are promising for the continued development of mesoporous silica materials for therapeutic applications.
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| 24. |
- Kupferschmidt, Natalia, et al.
(author)
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Mesoporous silica particles potentiate antigen specific T cell responses
- 2014
-
In: Nanomedicine. - : Future Medicine Ltd. - 1743-5889 .- 1748-6963. ; 9:12, s. 1835-1846
-
Journal article (peer-reviewed)abstract
- Aim: To study the adjuvant effect of mesoporous silica particles and their capability of modifying an already existing allergic Th2-like immune response. Materials & methods: The adjuvant effect of Santa Barbara Amorphous-15 (SBA-15) mesoporous silica particles was studied in an antigen-specific ovalbumin (OVA) system in vitro and in vivo. The capacity of the OVA-loaded SBA-15 particles (SBA-15-OVA) to modify an existing immune response was assessed in a murine allergy model. Results: SBA-15-OVA induced significantly stronger OVA-specific splenocyte proliferation compared with OVA alone. Significantly higher IFN-γ production was observed in ex vivo OVA-stimulated splenocytes from SBA-15-OVA-immunized mice compared with mice injected with only SBA-15 or OVA. Treatment of OVA-sensitized mice with SBA-15-OVA modified the immune response with significantly lower serum levels of OVA-specific IgE and higher IgG levels compared with the alum-OVA-treated group. Conclusion: The results are promising for the continued development of mesoporous silica materials for therapeutic applications. Original submitted 18 January 2013; Revised submitted 30 August 2013
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| 25. |
- Larsson, Marie
(author)
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Dendritic cells from human blood : Antigen handling and expression of adhesion molecules
- 1996
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Doctoral thesis (other academic/artistic)abstract
- Dendritic cells are a system of professional antigen-presenting cells that initiate the immune responses. Dendritic cells are widely distributed in the body, both in nonlymphoid tissues, lymphoid tissues and fluids of the body. Dendritic cells arise from the bone marrow and can be classified into interstitial dendritic cells in nonlymphoid tissues, interdigitating dendritic cells in secondary lymphoid tissue, dendritic cells in blnod and veiled cells in lymphatics. They can exhibit differences in each of these compartments that relate to maturation state and microenvironment.Dendritic cells process and present antigens efficiently in situ and stimulate responses from naive and memory T cells in the paracortical area of secondary lymphoid organs. Properties contributing to the dendritic cells' specialized function are the efficiency in clustering T cells and giving the right signals needed to activate naive and resting T cells. The present work was focused on elucidating some key properties of DC biology. The results show that mature human blood dendritic cells express sialyl Lewis x (CD15s), sialyl Lewis a, CD44 and CD77. Adhesion of mature blnod dendritic cells to activated endothelium (human umbilical cord endothelial cells) involves Eselectin. Immature blnod (cytokine-driven) dendritic cells use FcyRII for uptake of IgG immune complexes. Annexin V is involved in antigen trafficking in the endocytotic pathway of soluble proteins in mature blood dendritic cells. Immature blood dendritic cells (cytokine-driven) have the capacity to handle uptake of both soluble and microbial antigens, via fluid-phase pinocytosis, receptor-mediatedendocytosis and phagocytosis. No productive infection of influenza virus and no exogenous ll..-2 is demanded when dendritic cells are used as antigen-presenting cells. Dendritic cells induce cytotoxic T cells even with attenuated influenza A virus.
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