| 1. |
- Andersson, Anders, et al.
(författare)
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Interleukin-16-producing NK cells and T-cells in the blood of tobacco smokers with and without COPD
- 2016
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Ingår i: International Journal of Chronic Obstructive Pulmonary Disease. - : Informa UK Limited. - 1178-2005. ; 11, s. 2245-2258
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term exposure to tobacco smoke causes local inflammation in the airways that involves not only innate immune cells, including NK cells, but also adaptive immune cells such as cytotoxic (CD8(+)) and helper (CD4(+)) T-cells. We have previously demonstrated that long-term tobacco smoking increases extracellular concentration of the CD4(+)-recruiting cytokine interleukin (IL)-16 locally in the airways. Here, we hypothesized that tobacco smoking alters IL-16 biology at the systemic level and that this effect involves oxygen free radicals (OFR). Methods: We quantified extracellular IL-16 protein (ELISA) and intracellular IL-16 in NK cells, T-cells, B-cells, and monocytes (flow cytometry) in blood samples from long-term tobacco smokers with and without chronic obstructive pulmonary disease (COPD) and in never-smokers. NK cells from healthy blood donors were stimulated with water-soluble tobacco smoke components (cigarette smoke extract) with or without an OFR scavenger (glutathione) in vitro and followed by quantification of IL-16 protein. Results: The extracellular concentrations of IL-16 protein in blood did not display any substantial differences between groups. Notably, intracellular IL-16 protein was detected in all types of blood leukocytes. All long-term smokers displayed a decrease in this IL-16 among NK cells, irrespective of COPD status. Further, both NK and CD4(+) T-cell concentrations displayed a negative correlation with pack-years. Moreover, cigarette smoke extract caused release of IL-16 protein from NK cells in vitro, and this was not affected by glutathione, in contrast to the decrease in intracellular IL-16, which was prevented by this drug. Conclusion: Long-term exposure to tobacco smoke does not markedly alter extracellular concentrations of IL-16 protein in blood. However, it does decrease the intracellular IL-16 concentrations in blood NK cells, the latter effect involving OFR. Thus, long-term tobacco smoking exerts an impact at the systemic level that involves NK cells; innate immune cells that are critical for host defense against viruses and tumors-conditions that are over-represented among smokers.
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| 2. |
- Andersson, Karin, 1972, et al.
(författare)
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Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis.
- 2017
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Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1863:3, s. 663-673
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.
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| 3. |
- Johansson, Kristina, et al.
(författare)
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Bone marrow type 2 innate lymphoid cells: a local source of interleukin-5 in interleukin-33-driven eosinophilia
- 2018
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Ingår i: Immunology. - : Wiley. - 0019-2805. ; 153:2, s. 268-278
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Tidskriftsartikel (refereegranskat)abstract
- T helper type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2s) and eosinophil progenitors have previously been described to produce interleukin-5 (IL-5) in the airways upon allergen provocation or by direct administration of IL-33. Eosinophilic airway inflammation is known to be associated with IL-5-dependent eosinophil development in the bone marrow, however, the source of IL-5 remains unclear. T helper cells, ILC2s and CD34(+) progenitors have been proposed to be involved in this process, therefore, we investigated whether these cells are taking part in eosinophilopoiesis by producing IL-5 locally in the bone marrow in IL-33-driven inflammation. Airway exposure with IL-33 led to eosinophil infiltration in airways and elevated eotaxin-2/CCL24. Importantly, IL-5 production as well as expression of the IL-33 receptor increased in ILC2s in the bone marrow under this treatment. A small but significant induction of IL-5 was also found in CD34(+) progenitors but not in T helper cells. Similar results were obtained by in vitro stimulation with IL-33 where ILC2s rapidly produced large amounts of IL-5, which coincided with the induction of eosinophil hematopoiesis. IL-33-mediated eosinophil production was indeed dependent on IL-5 as both airway and bone marrow eosinophils decreased in mice treated with anti-IL-5 in combination with IL-33. Interestingly, the responsiveness of ILC2s to IL-33 as well as IL-33-induced eotaxin-2/CCL24 were independent of the levels of IL-5. In summary, we demonstrate for the first time that IL-33 acts directly on bone marrow ILC2s, making them an early source of IL-5 and part of a process that is central in IL-33-driven eosinophilia.
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| 4. |
- Johansson, Kristina, et al.
(författare)
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MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation
- 2017
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 139:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic airway inflammation is triggered by allergen exposure through several steps including release of IL-33, which promotes cytokine (IL-5, IL-13) production by type 2 innate lymphoid cells (ILC2s). MicroRNA (miR)-155 has recently been described to regulate adaptive responses in allergic inflammation. However, the role of miR-155 in the regulation of ILC2s remains unexplored. Objective: We sought to elucidate the contribution of miR-155 in ILC2 expansion using experimental murine models of allergic airway inflammation. Methods: To determine the role of miR-155 in the regulation of ILC2s in allergic airway inflammation, miR-155 deficient (miR-155-/-) and wild-type (WT) mice were subjected to acute or chronic allergen-induced inflammation or treated with recombinant IL-33. Results: miR-155 was 10-fold upregulated in WT-derived ILC2s in response to IL-33. Furthermore, miR-155-/- mice demonstrated impaired lung IL-33 levels in response to allergen challenge and the number of ILC2s was significantly reduced in allergen-challenged miR-155-/- mice compared with WT mice. Exogenous IL-33 treatment revealed that miR-155 is needed for IL-33-induced ILC2 expansion and eosinophilic airway inflammation. Indeed, ILC2s from IL-33-challenged miR-155-/- lungs exhibited impaired proliferation, GATA-3 expression, and IL-13 production as compared with IL-33-challenged WT ILC2s. Conclusions: Our findings for the first time demonstrate that ILC2s and IL-33 signaling are regulated by miR-155 in allergic airway inflammation.
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| 5. |
- Malmhäll, Carina, 1959, et al.
(författare)
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Altered miR-155 Expression in Allergic Asthmatic Airways
- 2017
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 85:4, s. 300-307
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Tidskriftsartikel (refereegranskat)abstract
- We and others have previously identified microRNAs (miRNAs) with pathological roles in animal models of asthma, where miR-146a and miR-155 have been described to play important roles in inflammatory responses. To date, few studies have investigated miRNA expression in human asthmatics. In the current study, significantly lower levels of miR-155 were detected in cell-free sputum from allergic asthmatics compared to healthy controls. Induced sputum isolated from allergic asthmatics in and out of pollen season revealed that miR-155 expression, but not miR-146a, is reduced in lymphocytes in season compared to post-season. In contrast, miR-155 was found to increase, whereas miR-146a decreased in PBMCs and cell-free PBMC culture media upon T cell receptor stimulation via alpha CD3/CD28 in both allergic asthmatics and healthy controls. Our findings suggest that miR-155 is differentially expressed ex vivo in airways of allergic asthmatics compared to healthy controls, which may have implications in the local immune response in allergic asthma.
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| 6. |
- Nwaru, Bright I, 1978, et al.
(författare)
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Cohort profile: the West Sweden Asthma Study (WSAS): a multidisciplinary population-based longitudinal study of asthma, allergy and respiratory conditions in adults
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- The West Sweden Asthma Study (WSAS) is a population-representative longitudinal study established to: (1) generate data on prevalence trends, incidence and remission of asthma, allergy and respiratory conditions, (2) elucidate on the risk and prognostic factors associated with these diseases, (3) characterise clinically relevant phenotypes of these diseases and (4) catalyse relevant mechanistic, genomic, genetic and translational investigations.WSAS comprised of randomly selected individuals aged 16 to 75 years who are followed up longitudinally. The first stage involved a questionnaire survey (>42000 participants) and was undertaken in 2008 and 2016. A random sample (about 8000) of participants in the initial survey undergoes extensive clinical investigations every 8 to 10 years (first investigations in 2009 to 2012, second wave currently ongoing). Measurements undertaken at the clinical investigations involve structured interviews, self-completed questionnaire on personality traits, physical measurements and extensive biological samples.Some of our key findings have shown a 54% increase in the use of asthma medications between the 1990s and 2000s, primarily driven by a five-fold increase in the use of inhaled corticosteroids. About 36% of asthmatics expressed at least one sign of severe asthma indicator, with differential lung performance, inflammation and allergic sensitisation among asthmatics with different signs of severe asthma. Multi-symptom asthmatics were at greater risk of having indicators of severe asthma. In all adults, being raised on a farm was associated with a decreased risk of allergic sensitisation, rhinitis and eczema, but not asthma. However, among adolescents (ie, those 16 to 20 years of age), being raised on a farm decreased the risk of asthma. Personality traits were associated with both beliefs of asthma medication and adherence to treatment.Follow-up of the cohort is being undertaken every 8 to 10 years. The repeated clinical examinations will take place in 2019 to 2022. The cohort data are currently being linked to routine Swedish healthcare registers for a continuous follow-up. Mechanistic, genomic, genetic and translational investigations are ongoing.
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| 7. |
- Ramos-Ramírez, Patricia, et al.
(författare)
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Weight Gain Alters Adiponectin Receptor 1 Expression on Adipose Tissue-Resident Helios plus Regulatory T Cells
- 2016
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 83:4, s. 244-254
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue produces multiple mediators that modulate the immune response. Adiponectin is an adipocyte-derived cytokine that exhibits metabolic and anti-inflammatory effects. Adiponectin acts through binding to adiponectin receptor 1 and 2 (AdipoR1/AdipoR2). AdipoR1 is ubiquitously expressed, whereas AdipoR2 is restricted to skeletal muscle and liver. AdipoR1 expression has been reported on a small percentage of T cells; nevertheless, it is still unknown whether Foxp3(+) regulatory T cells (Tregs) express AdipoR1. Recently, it has been shown that Tregs accumulate in adipose tissue and that they play a potential role in modulating adipose tissue inflammation. Our aim was to evaluate AdipoR1 expression in adipose tissue-resident Tregs and to evaluate the effect of weight gain on this expression. Male C57BL/6 mice were fed with a high-fat diet for 14weeks (to develop overweight) or 21weeks (to develop obesity). Mice on a standard diet were used as age-matched controls. Helios expression was evaluated as a marker to discriminate thymic-derived from peripherally induced Tregs. The majority of Tregs in both adipose tissue and the spleen expressed Helios. Adipose tissue Tregs expressed higher levels of AdipoR1 than Tregs in the spleen. AdipoR1 expression on adipose tissue Helios(+) Tregs was negatively correlated with epididymal fat. Overall, we show that AdipoR1 is expressed on adipose tissue-resident Tregs, mainly Helios(+) Tregs, and that this expression is dependent on weight and fat accumulation. Because both adiponectin and Tregs play roles in anti-inflammatory mechanisms, our data propose a new mechanism through which weight gain might alter immunoregulation.
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| 8. |
- Samitas, Konstantinos, 1977, et al.
(författare)
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Precursor B Cells Increase in the Lung during Airway Allergic Inflammation: A Role for B Cell-Activating Factor
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Background B cells, key cells in allergic inflammation, differentiate in the bone marrow and their precursors include pro-B, pre-B and immature B cells. Eosinophil progenitor cells increase in the lung after allergen exposure. However, the existence and possible role of B cell precursors in the lung during allergic inflammation remains elusive. A BALB/c mouse model of allergic airway inflammation was utilized to perform phenotypic and quantification analyses of pro-B and pre-B cells in the lung by flow cytometry. B cell maturation factors IL-7 and B cell-activating factor (BAFF) and their receptors (CD127 and BAFFR, BCMA, TACI, respectively) were also evaluated in the lung and serum. The effect of anti-BAFF treatment was investigated both in vivo (i.p. administration of BAFF-R-Ig fusion protein) and in vitro (colony forming cell assay). Finally, BAFF levels were examined in the bronchoalveolar lavage (BAL) of asthmatic patients and healthy controls. Precursor pro and pre-B cells increase in the lung after allergen exposure, proliferate in the lung tissue in vivo, express markers of chemotaxis (CCR10 and CXCR4) and co-stimulation (CD40, CD86) and are resistant to apoptosis (Bax). Precursor B cells express receptors for BAFF at baseline, while after allergen challenge both their ligand BAFF and the BCMA receptor expression increases in B cell precursors. Blocking BAFFR in the lung in vivo decreases eosinophils and proliferating precursor B cells. Blocking BAFFR in bone marrow cultures in vitro reduces pre-B colony formation units. BAFF is increased in the BAL of severe asthmatics. Our data support the concept of a BAFF-mediated role for B cell precursors in allergic airway inflammation.
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| 9. |
- Wasén, Caroline, et al.
(författare)
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Smoking activates cytotoxic CD8(+) T cells and causes survivin release in rheumatoid arthritis
- 2017
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 78, s. 101-110
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Tidskriftsartikel (refereegranskat)abstract
- CD8(+) T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8(+) T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8(+) T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8(+) T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8(+) T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1(-)IL-7R(+) CD8(+) T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA. (C) 2016 The Authors. Published by Elsevier Ltd.
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| 10. |
- Wasén, Caroline, et al.
(författare)
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Smoking Is Associated With Low Levels of Soluble PD-L1 in Rheumatoid Arthritis
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression. Aim: To investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1). Method: Serum levels of sPD-L1 were measured in 246 RA patients and in 168 healthy subjects. The analysis was done with respect to inflammation, smoking, treatments, and autoantibody status. The effect of therapeutic TNF-inhibiting antibodies (TNFi) on sPD-L1 was studied in 16 RA patients at their first infliximab infusion. The expression of Fc gamma-receptor (Fc gamma R) subclass IIB and IIIA was analyzed with quantitative polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) from 12 RA patients and 15 healthy controls, and in healthy PBMC exposed to IgG containing antibodies to cyclic citrullinated peptides (aCCP). Results: The negative association between smoking and sPD-L1 in RA patients was established by multiple logistic regression (OR = 0.52, p = 0.038). Other covariates in the regression model were serum levels of IL-1 beta representing inflammation (OR = 1.6, p = 0.0076) and aCCP positivity (OR = 1.9, p = 0.047). First infliximab infusion repressed sPD-L1 (p = 0.023) in patients, and low levels of sPD-L1 were found in patients with early RA treated with TNFi (p = 0.018). Treatment with TNFi was associated with higher sPD-L1 in patients with long disease duration (p = 0.041) and restored levels in smokers. In vitro exposure to aCCP+ IgG suppressed sPD-L1 (p = 0.036), but aCCP+ patients with long disease duration had higher sPD-L1 (p = 0.016). High ratio of the inhibitory Fc gamma R subclass IIB over the stimulatory IIIA resulted in low sPD-L1 release (p = 0.029). Smoking was associated with a higher Fc gamma R IIB/IIIA ratio (p = 0.00062) and lower levels of sPD-L1 (p = 0.013). Conclusion: In RA, serum sPD-L1 was related to systemic inflammation and aCCP positivity. Smoking altered the expression of Fc gamma Rs and limited sPD-L1 in RA patients, permitting inappropriate T cell responses. Differential regulation of sPD-L1 during the early and late RA may indicate transposition from acute to chronic inflammation.
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| 11. |
- Weidner, Julie, 1983, et al.
(författare)
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microRNAs in asthma pathogenesis - from mouse to man
- 2019
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Ingår i: Journal of Translational Genetics and Genomics. - : OAE Publishing Inc.. - 2578-5281. ; 3:2
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Forskningsöversikt (refereegranskat)abstract
- Asthma is a heterogenic disease affecting over 300 million people of all ages and socioeconomic status worldwide. The disease is characterized by chronic airway inflammation, reversible airflow obstruction, wheeze, cough and shortness of breath. Although asthma has been traditionally described by phenotypes such as immune cell type or allergy, it is clear that a variety of subtypes have emerged, adding further complexity to the disease. microRNAs are small, non-coding RNAs that act as regulatory molecules, binding to one or several target mRNAs, often resulting in translational silencing. In recent years, microRNAs have been the subject of many studies in order to better understand the mechanisms driving asthma development as well as discovery of potential biomarkers for asthma. In this review, we focus on the emerging role of microRNAs in asthma, from animal models to human cohorts.
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