| 1. |
- Alaridah, Nader, et al.
(author)
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Impaired CXCR1-dependent oxidative defence in active tuberculosis patients.
- 2015
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In: Tuberculosis. - : Elsevier BV. - 1873-281X .- 1472-9792. ; 95:6, s. 744-750
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Journal article (peer-reviewed)abstract
- Much of the pronounced host inflammatory response that occurs in tuberculosis (TB) is related to failed immunity against the invading pathogen. The G-protein coupled receptors CXCR1 and CXCR2 are implicated in important signal transduction pathways in lung inflammatory responses. We investigated the expression and function of these receptors in a simple whole blood model from 24 patients with pulmonary TB and in subjects with latent TB infection (LTBI). Healthy controls were recruited from close contacts to the pulmonary index patients. We found that pulmonary TB patients had significantly increased CXCR1 expression on blood cells compared to LTBI subjects and controls (p < 0.001). In contrast, LTBI subjects had a significant increase in CXCR2 expression compared to pulmonary TB patients (p < 0.001) and controls (p < 0.01). Leukocyte function, measured as oxidative capacity, was decreased in pulmonary TB patients compared to LTBI and controls (p < 0.001) and correlated with the increased CXCR1 expression. Leukocyte recruitment, measured as the expression of microRNA-223 was increased in pulmonary TB patients compared to LTBI (p < 0.05). We found that variations in receptor expression are linked to disease progression and affect the immune response against Mycobacterium tuberculosis (Mtb).
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| 2. |
- Alaridah, Nader, et al.
(author)
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Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs
- 2017
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In: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 9, s. 318-329
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Journal article (peer-reviewed)abstract
- Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.
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| 3. |
- Beskow, Anna, et al.
(author)
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Susceptibility locus for epidermodysplasia verruciformis not linked to cervical cancer in situ
- 2001
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In: Hereditas. - : Springer Science and Business Media LLC. - 0018-0661 .- 1601-5223. ; 135:1, s. 61-63
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Journal article (peer-reviewed)abstract
- Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV), mainly HPV 16 and HPV 18. The aim of this study was to test if a locus previously mapped to a region on chromosome 17 qter in patients with epidermodysplasia verucciformis (EV) and psoriasis and considered to be responsible for an increased susceptibility to HPV 5, also is linked to increased HPV susceptibility in cervical cancer in situ. We also wanted to test whether HPV 16 positivity cluster in families with cervical cancer. DNA was extracted from formalin fixed biopsies of 224 affected from 77 families diagnosed with cervical cancer in situ. Two microsatellite markers (D17S939 and D17S802) containing the locus were genotyped and linkage analysis was performed. No linkage was found to any of the two markers, neither when considering all cancer cases as affected nor when only considering HPV 16 infected cancer cases as affected in the analysis. We conclude that the susceptibility locus for HPV 5 infections associated with EV and psoriasis does not seem to affect susceptibility to HPV 16, frequently detected in cervical cancer. Also, positivity for HPV 16 did not show a significant clustering in families.
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| 4. |
- Krais, Annette M, et al.
(author)
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Detection of the fungicide transformation product 4-hydroxychlorothalonil in serum of pregnant women from Sweden and Costa Rica
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In: Journal of Exposure Science & Environmental Epidemiology. - 1559-064X.
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Journal article (peer-reviewed)abstract
- BACKGROUND: 4-hydroxychlorothalonil (HCT, R182281), a transformation product of the fungicide chlorothalonil, was recently identified in human serum and breast milk. There are indications that HCT may be more toxic and environmentally persistent than chlorothalonil.OBJECTIVE: Our aim was to investigate serum concentrations of HCT in pregnant women in Sweden and Costa Rica.METHODS: We developed a quantitative analytical method for HCT using liquid chromatography tandem mass spectrometry. We measured HCT in 1808 serum samples from pregnant women from the general population in Sweden (1997-2015) and in 632 samples from 393 pregnant women from an agricultural population in Costa Rica (2010-2011). In Swedish samples, we assessed time trends and investigated seasonality. In the Costa Rican samples, we evaluated variability between and within women and explanatory variables of HCT concentrations.RESULTS: HCT was detected in all serum samples, and the limit of detection was 0.1 µg/L. The median HCT concentration in the Swedish samples was 4.1 µg/L (interquartile range [IQR] of 2.9 - 5.8 µg/L), and 3.9 times higher in the Costa Rican samples (median: 16.1 µg/L; IQR: 10.6 - 25.0 µg/L). We found clear seasonal variation with higher concentrations in the first half of each year among Swedish women. In the Costa Rican study, women working in agriculture and living near banana plantations had higher HCT concentrations, whilst higher parity and having a partner working in agriculture were associated with decreased HCT, and no clear seasonal pattern was observed.IMPACT STATEMENT: For the first time, this study quantifies human exposure to the fungicide chlorothalonil and/or its transformation product 4-hydroxychlorothalonil (HCT, R182281) and finds higher serum concentrations in women from a tropical agricultural setting as compared with women from the general population in Sweden.
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| 5. |
- Lam, Matti, et al.
(author)
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Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality
- 2019
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 383:1
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Journal article (peer-reviewed)abstract
- We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
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| 6. |
- Norén, Erika, et al.
(author)
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Urin- och serumhalter av organiska miljöföroreningar hos unga vuxna i skåne år 2000 – 2022 - Resultat från den sjätte delstudien 2022
- 2022
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Reports (other academic/artistic)abstract
- Allmänbefolkningen exponeras dagligen för ett flertal organiska miljöföroreningar via exempelvis livsmedel, produkter och andra material. Till dessa hör bl a bekämpningsmedel och perfluorerade ämnen (PFAS) i livsmedel, ftalater i plastmaterial och kosmetika, flamskyddsmedel i stoppade möbler och byggnadsmaterial samt polyaromatiska kolväten (PAH) från fordonsavgaser. Genom analys av exponeringsbiomarkörer för dessa ämnen i blod- eller urinprover ges ett mått på exponeringen hos individer, vilket gör det möjligt att uppskatta exponeringen i en definierad populationsgrupp. Genom upprepade provinsamlingar och analys är det möjligt att följa eventuella förändringar i exponeringen över tid.Sedan år 2000 har AMM rekryterat ungdomar/unga vuxna (ålder 16 – 21 år) i Skåne via mönstring till värnplikt och/eller gymnasieskolor. Dessa individer representerar en del av allmänbefolkningen utan yrkesrelaterad exponering och urinprov och blodprov har samlats in från samtliga studiedeltagare. År 2022 samlades prover in från 195 unga män och kvinnor på gymnasieskolor i Skåne. Proverna har analyserats i vårt laboratorium med LC-MS/MS med avseende på utvalda biomarkörer för exponering för sammanlagt ca 50 miljöföroreningar ur ovannämnda kategorier.Totalt 46 av 50 biomarkörer förekom i detekterbara koncentrationer i urin- eller serumprover, vilket tyder på en utbredd exponering men relativt låg exponering. Nedåtgående trender kunde observeras för flera av de ämnen där användningen begränsats eller fasats ut. Resultaten visade även på ökande trender för vissa ämnen som troligtvis ersatt utfasade kemikalier. Det är viktigt att fortsätta följa exponeringen över tid för att upptäcka om ämnen som inte är lika välstuderade, där eventuella hälsoeffekter är okända, tenderar att öka i populationen.
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| 7. |
- Tenland, Erik, et al.
(author)
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A novel derivative of the fungal antimicrobial peptide plectasin is active against Mycobacterium tuberculosis
- 2018
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In: Tuberculosis. - : Elsevier BV. - 1472-9792 .- 1873-281X. ; 113, s. 231-238
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Journal article (peer-reviewed)abstract
- Tuberculosis has been reaffirmed as the infectious disease causing most deaths in the world. Co-infection with HIV and the increase in multi-drug resistant Mycobacterium tuberculosis strains complicate treatment and increases mortality rates, making the development of new drugs an urgent priority. In this study we have identified a promising candidate by screening antimicrobial peptides for their capacity to inhibit mycobacterial growth. This non-toxic peptide, NZX, is capable of inhibiting both clinical strains of M. tuberculosis and an MDR strain at therapeutic concentrations. The therapeutic potential of NZX is further supported in vivo where NZX significantly lowered the bacterial load with only five days of treatment, comparable to rifampicin treatment over the same period. NZX possesses intracellular inhibitory capacity and co-localizes with intracellular bacteria in infected murine lungs. In conclusion, the data presented strongly supports the therapeutic potential of NZX in future anti-TB treatment.
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| 8. |
- Tenland, Erik, et al.
(author)
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Innate immune responses after airway epithelial stimulation with Mycobacterium bovis Bacille-Calmette Guérin
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
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Journal article (peer-reviewed)abstract
- Mycobacterium bovis bacilli Calmette-Guerin (BCG) is used as a benchmark to compare the immunogenicity of new vaccines against tuberculosis. This live vaccine is administered intradermal, but several new studies show that changing the route to mucosal immunisation represents an improved strategy. We analysed the immunomodulatory functions of BCG on human neutrophils and primary airway epithelial cells (AECs), as the early events of mucosal immune activation are unclear. Neutrophils and the primary epithelial cells were found to express the IL-17A receptor subunit IL-17RA, while the expression of IL-17RE was only observed on epithelial cells. BCG stimulation specifically reduced neutrophil IL-17RA and epithelial IL-17RE expression. BCG induced neutrophil extracellular traps (NETs), but did not have an effect on apoptosis as measured by transcription factor forkhead box O3 (FOXO3). BCG stimulation of AECs induced CXCL8 secretion and neutrophil endothelial passage towards infected epithelia. Infected epithelial cells and neutrophils were not found to be a source of IL-17 cytokines or the interstitial collagenase MMP-1. However, the addition of IFNγ or IL-17A to BCG stimulated primary epithelial cells increased epithelial IL-6 secretion, while the presence of IFNγ reduced neutrophil recruitment. Using our model of mucosal infection we revealed that BCG induces selective mucosal innate immune responses that could lead to induction of vaccine-mediated protection of the lung.
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