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- Andersson, Cecilia K, et al.
(författare)
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Distal respiratory tract viral infections in young children trigger a marked increase in alveolar mast cells
- 2018
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Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood. Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection. Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0-78) MCs per mm2) compared to controls (0.63 (0-4) MCs per mm2, p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34+ tryptase+ progenitors (controls: 0% (0-1%); LRTIs: 0.9% (0-3%) CD34+ MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07-0.3); LRTIs: 0.3 (0.02-2) VCAM-1 per mm2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3-0.5); HDM: 0.6 (0.4-0.9); H1N1: 1.4 (0.4-2.0); HDM+H1N1: 2.2 (1.2-4.4) MCs per mm2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2-4.4); day 57: 4.6 (1.6-15) MCs per mm2 (p=0.01)) but not when infected with H1N1 alone. Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development.
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| 4. |
- Jovic, Sandra, et al.
(författare)
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Expression of MIG/CXCL9 in Cystic Fibrosis and Modulation of Its Activities by Elastase of Pseudomonas aeruginosa.
- 2014
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 6:6, s. 846-859
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Tidskriftsartikel (refereegranskat)abstract
- In cystic fibrosis (CF), colonization of the airways with Pseudomonas aeruginosa is associated with disease deterioration. The mechanism behind the disease progression is not fully understood. The present work shows that the antibacterial chemokine MIG/CXCL9 is present in the airways and in sputum of CF patients. MIG/CXCL9 showed high bactericidal activity against. P. aeruginosa, including some strains from the airways of CF patients. Full-length MIG/CXCL9 was detected in sputum from healthy controls and CF patients colonized with P. aeruginosa. However, degraded MIG/CXCL9 was only found in CF sputum. In vitro, elastase of P. aeruginosa cleaved off a fragment of similar size and two additional fragments from MIG/CXCL9. The fragments showed less bactericidal activity against P. aeruginosa compared with the full-length protein. The fragments did not activate the MIG/CXCL9 receptor CXCR3 (expressed e.g. by NK cells, mast cells, and activated T cells) but instead displayed noncompetitive inhibition. In vitro, a decrease in CXCR3-bearing cells was found within and in the proximity of the bronchial epithelium of CF lung tissue compared with controls. Taken together, both bactericidal and cell-recruiting activities of MIG/CXCL9 are corrupted by P. aeruginosa through release of elastase, and this may contribute to impaired airway host defense in CF. © 2014 S. Karger AG, Basel.
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| 6. |
- Jovic, Sandra, et al.
(författare)
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The neutrophil-recruiting chemokine GCP-2/CXCL6 is expressed in cystic fibrosis airways and retains its functional properties after binding to extracellular DNA.
- 2016
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 9:1, s. 112-123
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Tidskriftsartikel (refereegranskat)abstract
- Infections in cystic fibrosis (CF), often involving Pseudomonas aeruginosa, result from a dysregulated airway immunity where one hallmark is the accumulation of necrotic and apoptotic immune cells, in particular neutrophils. In addition, neutrophils actively release DNA, forming neutrophil extracellular traps (NETs) that contain antimicrobial proteins. Altogether, free DNA in complex with actin accumulates in the airway lumen, resulting in highly viscous sputum that provides an anionic matrix, binding cationic antimicrobial proteins. In this study, granulocyte chemotactic protein 2 (GCP-2)/CXCL6, a neutrophil-activating chemokine with bactericidal properties, was detected in the airway epithelium of CF patients and was also present in azurophilic and specific granules of neutrophils. Elastase of neutrophils, but not of P. aeruginosa, completely degraded CXCL6 (chemokine (C-X-C motif) ligand 6). In addition, CXCL6 colocalized with extracellular DNA in both CF sputa and in in vitro-formed NETs. In vitro, CXCL6 bound DNA with a KD of 2,500 nM. Interestingly, both the bactericidal and the receptor-activating properties of CXCL6 (against neutrophils) remained largely unaffected in the presence of DNA. However, the chemotactic properties of CXCL6 were reduced by the presence of DNA. Taken together, CXCL6 is expressed in CF, retaining its functional properties even after binding to the anionic scaffold that extracellular DNA provides in CF.Mucosal Immunology advance online publication, 20 May 2015; doi:10.1038/mi.2015.43.
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| 7. |
- Mandrika, Ilona, et al.
(författare)
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Proteochemometric modelling of antibody-antigen interactions using SPOT synthesised peptide arrays
- 2007
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 20:6, s. 301-307
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Tidskriftsartikel (refereegranskat)abstract
- Proteochemometrics is a technology for the study of molecular recognition based on chemometric techniques. Here we applied it to analyse the amino acids and amino acid physico-chemical properties that are involved in antibodies' recognition of peptide antigens. To this end, we used a study system comprised by a diverse single chain antibody library derived from the murine mAb anti-p24 (HIV-1) antibody CB4-1, evaluated on peptide arrays manufactured by SPOT synthesis. The binding pattern obtained was correlated to physico-chemical descriptors (z-scales) of antibodies and peptides amino acids using partial least-squares projections to latent structures. Cross terms derived from antibody and antigen descriptors were included, which substantially improved the proteochemometric model. The final model was statistically highly satisfactory with a correlation coefficient R(2) = 0.73 and predictive ability Q(2) = 0.68. The physico-chemical properties of each interacting amino acid residue of both the peptides and the antibodies being essential for the antigen-antibody recognition could be retrieved from the model. The study shows for the first time the feasibility of using proteochemometrics to analyse the molecular recognition of antigens by antibodies.
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| 8. |
- Mori, Michiko, et al.
(författare)
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Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease
- 2013
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:6, s. 521-531
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Tidskriftsartikel (refereegranskat)abstract
- Rationale The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. Objectives To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. Methods Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. Results Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)+ dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin+ dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. Conclusions Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.
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| 9. |
- Shikhagaie, Medya Mara, et al.
(författare)
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Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 18:7, s. 1761-1773
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Tidskriftsartikel (refereegranskat)abstract
- Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s. NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.
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