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- Aittoniemi, J, et al.
(author)
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Relation among mannose-binding lectin 2 genotype, β-cell autoantibodies, and risk for type 1 diabetes in Finnish children
- 2008
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In: Human Immunology. - : Elsevier BV. - 0198-8859 .- 1879-1166. ; 69:2, s. 108-111
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Journal article (peer-reviewed)abstract
- Mannose-binding lectin (MBL) is a key mediator of innate immunity, the insufficiency of which is caused by point mutations in the MBL2 gene. MBL insufficiency is associated with increased susceptibility to infections and certain autoimmune diseases, but its impact in the pathogenesis and risk of type 1 diabetes (T1D) is controversial. We investigated the significance of the MBL2 genotype on the risk of T1D in a Finnish study population comprising 470 diabetic children and 501 controls. Furthermore, the effect of MBL2 gene polymorphism on the emergence of β-cell autoantibodies in 289 unaffected children with human leukocyte antigen-conferred susceptibility to T1D was assessed. MBL genotype had no significant effect on the risk or onset age of T1D. However, children with the biallelic variant genotype reflecting total MBL deficiency tested positive more frequently for ≥3 autoantibodies compared with children with another genotype (odds ratio = 6.0, 95% confidence interval 1.3-28, p = 0.013). In conclusion, the MBL2 genotype did not affect susceptibility to T1D in children, and this finding does not support previous reports implicating a role of the MBL2 genotype as a factor predisposing to T1D. The association of the biallelic variant genotype with positivity for multiple autoantibodies suggests that intermolecular epitope spreading may be linked with impaired clearance of autoantigens as a result of MBL deficiency. © 2008 American Society for Histocompatibility and Immunogenetics.
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- Böttcher, Malin, et al.
(author)
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Reply [6]
- 2006
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 117:1
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Other publication (other academic/artistic)
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- Jevnikar, Z., et al.
(author)
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 577-590
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Journal article (peer-reviewed)abstract
- Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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- Lahdenperä, Anna, et al.
(author)
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Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes
- 2012
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In: Clinical and Experimental Immunology. - : John Wiley & Sons. - 0009-9104 .- 1365-2249. ; 167:2, s. 226-234
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Journal article (peer-reviewed)abstract
- Up-regulation of interleukin (IL)-17 in small intestinal mucosa has been reported in coeliac disease (CD) and in peripheral blood in type 1 diabetes (T1D). We explored mucosal IL-17 immunity in different stages of CD, including transglutaminase antibody (TGA)-positive children with potential CD, children with untreated and gluten-free diet-treated CD and in children with T1D. Immunohistochemistry was used for identification of IL-17 and forkhead box protein 3 (FoxP3)-positive cells and quantitative polymerase chain reaction (qPCR) for IL-17, FoxP3, retinoic acid-related orphan receptor (ROR)c and interferon (IFN)-γ transcripts. IL-1β, IL-6 and IL-17 were studied in supernatants from biopsy cultures. Expression of the apoptotic markers BAX and bcl-2 was evaluated in IL-17-stimulated CaCo-2 cells. The mucosal expression of IL-17 and FoxP3 transcripts were elevated in individuals with untreated CD when compared with the TGA-negative reference children, children with potential CD or gluten-free diet-treated children with CD (P andlt; 0·005 for all IL-17 comparisons and P andlt; 0·01 for all FoxP3 comparisons). The numbers of IL-17-positive cells were higher in lamina propria in children with CD than in children with T1D (P andlt; 0·05). In biopsy specimens from patients with untreated CD, enhanced spontaneous secretion of IL-1β, IL-6 and IL-17 was seen. Activation of anti-apoptotic bcl-2 in IL-17-treated CaCo-2 epithelial cells suggests that IL-17 might be involved in mucosal protection. Up-regulation of IL-17 could, however, serve as a biomarker for the development of villous atrophy and active CD.
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- McCrae, Cristopher, et al.
(author)
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Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells
- 2018
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In: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549. ; 59:6, s. 713-722
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Journal article (peer-reviewed)abstract
- Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-beta. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
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- Paronen, J, et al.
(author)
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Effect of maternal diet during lactation on development of bovine insulin-binding antibodies in children at risk for allergy
- 2000
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 106:2, s. 302-306
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Journal article (peer-reviewed)abstract
- Background: The role of exposure to dietary antigens through maternal milk is intriguing, because it may result either in immunization or in tolerance. Exposure to cow's milk proteins results in antibody formation against bovine insulin in infants at risk for type 1 diabetes. Objective: To study the appearance of IgG antibodies to bovine and human insulin in infants with an atopic family history whose mothers followed a cow's milk-free diet during the first 3 months of lactation. Methods: In a prospective cohort study on prevention of food allergies, 123 infants were exclusively breast-fed or received supplementafion with a hydrolyzed casein-based formula (Nutramigen) until the age of 6 months. The mothers either avoided cow's milk during the first 3 months of lactation (diet group) or had an unrestricted diet (nondiet group). The levels of IgG antibodies to bovine and human insulin were determined by enzyme immunoassay at 3, 6, 12, and 18 months and at 4 years. In addition, cord blood was obtained at birth and a maternal sample at delivery. Results: At 3 months, IgG antibodies to bovine insulin were low in both dietary groups (median levels 0.150 and 0.114 optical density units in the diet and nondiet groups). After exposure to dietary insulin, IgG antibodies to bovine insulin increased in both groups, reaching a peak at 12 months in the nondiet group and at 18 months in the diet group. At 18 months, IgG antibodies to bovine insulin were lower in infants in the nondiet group than in infants in the diet group (0.287 vs 0.500, P < .0001). At 4 years, the antibodies no longer differed between the groups. Conclusion: The exposure to cow's milk proteins through breast milk during the first 3 months of life resulted in decreased levels of antibodies to dietary bovine insulin at 18 months of age, suggesting a role for breast milk antigens in early tolerance induction.
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| 22. |
- Sjöwall, J, et al.
(author)
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Innate immune responses in Lyme borreliosis : enhanced tumour necrosis factor-alpha and interleukin-12 in asymptomatic individuals in response to live spirochetes
- 2005
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In: Clinical and Experimental Immunology. - Oxford : Blackwell Publishing. - 0009-9104 .- 1365-2249. ; 141:1, s. 89-98
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Journal article (peer-reviewed)abstract
- Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in DCs and IL-1 beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.
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