| 1. |
- Fransén, Karin, 1973-, et al.
(författare)
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CRP levels are significantly associated with CRP genotype and estrogen use in The Lifestyle, Biomarker and Atherosclerosis (LBA) study
- 2022
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Ingår i: BMC Cardiovascular Disorders. - : BioMed Central. - 1471-2261 .- 1471-2261. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The C‑reactive protein (CRP) is an important biomarker for atherosclerosis and single nucleotide poly‑morphisms (SNPs) in the CRP locus have been associated with altered CRP levels and associated with risk for cardio‑vascular disease. However, the association between genetic variations in the CRP gene, estrogen use and CRP levels orearly signs of atherosclerosis in young healthy individuals is not fully characterized. We aimed to evaluate the influ‑ence of five genetic variants on both plasma CRP levels and carotid intima‑media thickness (cIMT) values, includingaspects on estrogen containing contraceptive use in females.Methods: Genotyping was performed with TaqMan real time PCR and compared with high sensitivity CRP serumlevels in 780 Swedish young, self‑reported healthy individuals. Haplotypes of the SNPs were estimated with the PHASEv 2.1. The cIMT was measured by 12 MHz ultrasound. The contraceptive use was self‑reported.Results: Strong associations between CRP and genotype were observed for rs3091244, rs1800947, rs1130864, andrs1205 in women (all p < 0.001). In men, only rs1800947 was associated with CRP (p = 0.029). The independent effectof genotypes on CRP remained significant also after adjustment for established risk factors. Female carriers of the H1/ATGTG haplotype had higher CRP than non‑carriers. This was specifically pronounced in the estrogen‑using group(p < 0.001), and they had also higher cIMT (p = 0.002) than non‑carriers but with a small cIMT difference between thehaplotype groups (0.02 mm). In parallel, a significant correlation between CRP and cIMT in the estrogen using groupwas observed (r = 0.194; p = 0.026).Conclusions: Estrogen use, genotypes and haplotypes in the CRP locus are significantly associated with CRP levels.Based on an observed interaction effect between sex/estrogen use and the H1/ATGTG haplotype on CRP, and amarginally thicker cIMT in the estrogen using group, our data suggest that both genotypes and estrogen usage couldbe involved in arterial wall structural differences. The causality between CRP levels and cIMT remains unclear, and theobserved difference in cIMT is not clinically relevant in the present state. Future larger and longitudinal studies mayshed further light on the role of more long‑term estrogen use and early atherosclerosis.
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| 2. |
- Heikkila, K., et al.
(författare)
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Job strain and the risk of severe asthma exacerbations : a meta-analysis of individual-participant data from 100 000 European men and women
- 2014
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 69:6, s. 775-783
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMany patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. MethodsWe analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. ResultsDuring a median follow-up of 10years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). ConclusionsOur findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.
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| 3. |
- Bengnér, Johannes, et al.
(författare)
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Serum amyloid A – A prime candidate for identification of neonatal sepsis
- 2021
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Ingår i: Clinical Immunology. - : Elsevier. - 1521-6616 .- 1521-7035. ; 229:108787
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal sepsis is common, lethal, and hard to diagnose. In combination with clinical findings and blood culture, biomarkers are crucial to make the correct diagnose. A Swedish national inquiry indicated that neonatologists were not quite satisfied with the available biomarkers. We assessed the kinetics of 15 biomarkers simultaneously: ferritin, fibrinogen, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ, interleukin (IL)-1β, −6, −8, −10, macrophage inflammatory protein (MIP)-1β, procalcitonin, resistin, serum amyloid A (SAA), tumor necrosis factor (TNF)-α, tissue plasminogen activator-3 and visfatin. The goal was to observe how quickly they rise in response to infection, and for how long they remain elevated. From a neonatal intensive care unit, newborns ≥28 weeks gestational age were recruited. Sixty-eight newborns were recruited to the study group (SG), and fifty-one to the control group (CG). The study group subjects were divided into three subgroups depending on clinical findings: confirmed sepsis (CSG), suspected sepsis (SSG) and no sepsis. CSG and SSG were also merged into an entire sepsis group (ESG) for sub-analysis. Blood samples were collected at three time-points; 0 h, 12–24 h and 48–72 h, in order to mimic a “clinical setting”. At 0 h, visfatin was elevated in SSG compared to CG; G-CSF, IFN-γ, IL-1β, −8 and − 10 were elevated in SSG and ESG compared to CG, whereas IL-6 and SAA were elevated in all groups compared to CG. At 12–24 h, IL-8 was elevated in ESG compared to CG, visfatin was elevated in ESG and SSG compared to CG, and SAA was elevated in all three groups compared to CG. At 48–72 h, fibrinogen was elevated in ESG compared to CG, IFN-γ and IL-1β were elevated in SSG and ESG compared to CG, whereas IL-8 and SAA were elevated in all three groups compared to CG. A function of time-formula is introduced as a tool for theoretical prediction of biomarker levels at any time-point. We conclude that SAA has the most favorable kinetics regarding diagnosing neonatal sepsis, of the biomarkers studied. It is also readily available methodologically, making it a prime candidate for clinical use.
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| 4. |
- Jonson, Carl-Oscar, et al.
(författare)
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Regulatory T-cell associated activity in Photopheresis-induced Immune tolerance in Recent Onset Type 1 Diabetes Children
- 2008
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 153:2, s. 174-181
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Tidskriftsartikel (refereegranskat)abstract
- Extracorporeal photochemotherapy (ECP) has demonstrated immunological effects. The proposed cytotoxic lymphocyte antigen 4 (CTLA-4) involvement, together with forkhead box P3 (FoxP3) and transforming growth factor (TGF)-β are associated with regulatory T cell activity. The aim of the study was to evaluate the regulatory T cell-associated effect of ECP in recent onset type 1 diabetic (T1D) children. Children (n = 20) with T1D received photopheresis 8-methoxypsoralen + ECP or placebo + shampheresis. Peripheral blood mononuclear cells (PBMC) collected pretreatment (day 1) and post-treatment (day 90) were stimulated with phytohaemagglutinin (PHA) and T1D-associated glutamic acid decarboxylase 65 (GAD65) peptide a.a. 247–279. CTLA-4, sCTLA-4, FoxP3 and TGF-β mRNA transcription was quantified. Photopheresis-treated individuals' relative mRNA expression was generally maintained during the course of the study. Placebo individuals increased in spontaneous CTLA-4 mRNA (P < 0·05) but decreased in expression after stimulation with GAD65-peptide (P < 0·05) and PHA (P < 0·05). Spontaneous TGF-β (P < 0·05) increased whereas PHA- (P < 0·01) and GAD65-peptide (P < 0·01)-induced TGF-β expression decreased in the placebo group, whereas it was maintained in the treated group. Without intervention, expression of CTLA-4 and TGF-β, stimulated with PHA and GAD65 peptide, decreased with time, with a parallel reduction of GAD65-peptide and PHA-stimulated TGF-β expression. These parameters were counteracted by ECP. In conclusion, our results indicate that ECP maintains regulatory T cell-associated activity in recent-onset T1D.
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| 5. |
- Ross, Owen A., et al.
(författare)
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Mitochondrial DNA damage in lymphocytes : a role in immunosenescence?
- 2002
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Ingår i: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 37:2-3, s. 329-340
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Tidskriftsartikel (refereegranskat)abstract
- An age-related increase of DNA damage/mutation has been previously reported in human lymphocytes. The high copy number and mutation rate make the mtDNA genome an ideal candidate for assessing damage and to act as a potential biomarker of ageing. In the present study, two assays were developed to evaluate the level of mtDNA4977 and the accumulation of point mutations with age. A competitive polymerase chain reaction (PCR) methodology incorporating three primers was used to detect and quantify the levels of mtDNA4977 and a novel heteroduplex reference strand conformational analysis (RSCA) technique was used to analyse the accumulation of point mutations. The assays were applied to an in vitro model of T cell ageing and ex vivo DNA samples from an elderly cohort of subjects and a younger control group. The mtDNA4977 was detected in all the DNA samples examined but only a very low concentration was observed and no age-related increase or accumulation was observed. No accumulation of point mutations was identified using RSCA within the T cell clones as they were aged or the ex vivo lymphocytes from the elderly cohort. A higher level of variation was observed within the ex vivo DNA samples, verifying the high resolution of RSCA and its ability to identify different mtDNA species, although no correlation with age was observed. The low level of mtDNA damage observed with respect to the ex vivo lymphocyte DNA samples within this study may be due in part to the high turnover of blood cells/mtDNA, which may inhibit the accumulation of genetically abnormal mtDNA that may play a role in immunosenescence. A similar explanation may also apply to the in vitro model of T cell ageing if the vast majority of the cells are replicating rather than entering senescence.
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| 6. |
- Fryk, Emanuel, et al.
(författare)
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Galectin-1 correlates with inflammatory markers and T regulatory cells in children with type 1 diabetes and/or celiac disease
- 2024
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press. - 1365-2249 .- 0009-9104. ; 215:3, s. 240-250
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) and celiac disease (CeD) are common autoimmune diseases in children where the pathophysiology is not fully characterized. The autoimmune process involves a complex scenario of both inflammatory and regulatory features. Galectin-1 (GAL-1) has a wide range of biological activities e.g. interaction with immune cells. We examined the relationship between GAL-1 and soluble immune markers and T-cell subsets in a cohort of children with T1D and/or CeD relative to healthy children. GAL-1, together with several soluble immune markers [e.g. interleukins (IL)], tumor necrosis factor (TNF), acute phase proteins, and matrix metalloproteinases (MMP) were measured in sera from children with T1D and/or CeD by fluorochrome (Luminex) technique using children without these diseases as a reference. Subgroups of T cells, including T-regulatory (Treg) cells, were analysed by flow cytometry. Association between GAL-1, pro-inflammatory markers, and Treg cells differed depending on which illness combination was present. In children with both T1D and CeD, GAL-1 correlated positively with pro-inflammatory markers (IL-1 beta, IL-6, and TNF-alpha). Composite scores increased the strength of correlation between GAL-1 and pro-inflammatory markers, Th1-associated interferon (IFN)-gamma, and T1D-associated visfatin. Contrary, in children diagnosed with exclusively T1D, GAL-1 was positively correlated to CD25hi and CD25hiCD101+ Treg cells. For children with only CeD, no association between GAL-1 and other immune markers was observed. In conclusion, the association observed between GAL-1, soluble immune markers, and Treg cells may indicate a role for GAL-1 in the pathophysiology of T1D and, to some extent, also in CeD. Type 1 diabetes (T1D) and celiac disease (CeD) are common autoimmune diseases in children where pathophysiology is not fully characterized. The autoimmune process involves a complex scenario of both inflammatory and regulatory features. Galectin-1 (GAL-1) has a wide range of biological activities e.g. interaction with immune cells and the association observed between GAL-1, soluble immune markers, and T regulatory (Treg) cells may indicate a role for GAL-1 in the pathophysiology of children with T1D and, to some extent, also in children with CeD. Graphical Abstract
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| 7. |
- Tompa, Andrea, 1969, et al.
(författare)
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Shift in the B cell subsets between children with type 1 diabetes and/or celiac disease
- 2024
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press. - 1365-2249 .- 0009-9104. ; 216:1, s. 36-44
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Tidskriftsartikel (refereegranskat)abstract
- Our purpose was to characterize the pattern of B cell subsets in children with a combined diagnosis of type 1 diabetes (T1D) and celiac disease (C) since children with single or double diagnosis of these autoimmune diseases may differ in peripheral B cell subset phenotype patterns. B cells were analyzed with flow cytometry for the expression of differentiation/maturation markers to identify transitional, naive, and memory B cells. Transitional (CD24(hi)CD38(hi)CD19(+)) and memory Bregs (mBregs; CD24(hi)CD27(+)CD19(+), CD1d(+)CD27(+)CD19(+), and CD5(+)CD1d(+)CD19(+)) were classified as B cells with regulatory capacity. Children with a combined diagnosis of T1D and C showed a pattern of diminished peripheral B cell subsets. The B cells compartment in children with combined diagnosis had higher percentages of memory B subsets and Bregs, including activated subsets, compared to children with either T1D or C. Children with combined diagnosis had a lower percentage of naive B cells (CD27(-)CD19(+); IgD(+)CD19(+)) and an increased percentage of memory B cells (CD27(+)CD19(+); IgD(-)CD19(+)). A similar alteration was seen among the CD39(+) expressing naive and memory B cells. Memory Bregs (CD1d(+)CD27(+)CD19(+)) were more frequent, contrary to the lower percentage of CD5(+) transitional Bregs in children with a combined diagnosis. In children with either T1D or C, the peripheral B cell compartment was dominated by naive cells. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C. This is an immunological challenge of impact on the pathophysiology of these autoimmune diseases. A larger compartment of naive B and Breg subsets, including activated subsets, and smaller compartment of the memory B and Breg subsets are seen in children with isolated type 1 diabetes (T1D) or celiac disease (C). In children with the combined diagnosis, a shifting of the naive B subset compartment toward a more mature/differentiated B cell compartment was observed, indicating another type of disturbance of the B cell mediated immune regulation compared to what is present in the context of only one isolated autoimmune disease. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C.
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| 8. |
- Åkesson, Karin, et al.
(författare)
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Low expression of CD39(+)/CD45RA(+) on regulatory T cells (T-reg) cells in type 1 diabetic children in contrast to high expression of CD101(+)/CD129(+) on T-reg cells in children with coeliac disease
- 2015
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Ingår i: Clinical and Experimental Immunology. - : Wiley: 12 months. - 0009-9104 .- 1365-2249. ; 180:1, s. 70-82
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (T-reg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th:CD4(+) or Tc:CD8(+)); naive (CD27(+)CD28(+)CD45RA(+)CCR7(+)), central memory (CD27(+)CD28(+)CD45RA(-)CCR7(+)), effector memory (early differentiated; CD27(+)CD28(+)CD45RA(-)CCR7(-) and late differentiated; CD27(-)CD28(-)CD45RA(-)CCR7(-)), terminally differentiated effector cells (TEMRA; CD27(-)CD28(-)CD45RA(+)CCR7(-)) and T-reg (CD4(+)CD25(+)FOXP3(+)CD127(-)) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4(+) cells (Pless than005), but lower percentages of both early and late effector memory CD8(+) cells (Pless than005) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (Pless than005) and also a lower percentage of CD39(+) and CD45RA(+) within the T-reg population (CD4(+)CD25(+)FOXP3(+)CD127(-)) (Pless than005). Children with exclusively coeliac disease had a higher MFI of CD101 (Pless than001), as well as a higher percentage of CD129(+) (Pless than005), in the CD4(+)CD25(hi) lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4(+) cells compared to CD8(+) cells. T1D children show signs of low CD39(+)/CD45RA(+) T-reg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101(+)/CD129(+) T-reg cells that may indicate suppressor activity.
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| 9. |
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| 10. |
- Tompa, Andrea, et al.
(författare)
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Suppressed immune profile in children with type 1 diabetes in combination with celiac disease
- 2019
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Konferensbidrag (refereegranskat)abstract
- Introduction: Cytokines, chemokines, acute phase proteins (APP), adipocytokines and matrix metalloproteinases (MMP) are involved in different pathophysiological processes of inflammatory character. The role of the different immune markers and the peripheral immunoregulatory milieu in children diagnosed with type 1 diabetes (T1D) in combination with celiac disease (CD) is not fully understood and is not well studied. The purpose of the present study was therefore to acquire more knowledge and to gain deeper understanding on peripheral immunoregulatory milieu in children with T1D and/or CD.Methods: The study included children diagnosed with T1D in combination with CD (n=18), children with T1D (n=27) or CD (n=16), and reference children (n=42).Blood samples were collected, and serum stored in -80°C until analysis, avoiding multiple freeze-thaw cycles. The inflammatory cyto/chemokines (IL-1β, -5, -6, -8, -9, -10, -13, -15, -17A, -22, -25, -33, IFN-γ, TNF-α, G-CSF, MCP-1, MIP-1α, MIP-1β), diabetes related immune markers (visfatin, resistin), APP (procalcitonin (PTC), ferritin, tissue protein activator, fibrinogen, serum amyloid A) and matrix metalloproteinases (MMP-1, -2, -3) were analyzed with Luminex technique using Bio-Plex assays. Hierarchical cluster analysis was used to identify similarities/differences in immune profiles between children with double diagnosis and children with single diagnosis and reference children. Mann-Whitney U test was used for comparison of the different diagnosis groups within the clusters and whole cohort, respectively.Results: The largest cluster included 75% of the participants and the diagnose distribution in the cluster were very similar to the distribution in the whole study cohort. The remaining 25% were divided in two smaller clusters representing 15.5% and 6.5% respectively. The major finding of this study showed that children with double diagnosis had (1) lower serum levels of IL-22, MCP-1, PCT, visfatin and MMP-2 compared to children with T1D; and (2) lower serum levels of the APC associated chemokine MIP-1α compared to reference children, observed in the main cluster. Most of these observations were also seen in the whole cohort. Conclusion: Our observations indicate decreased serum levels of IL-22, MIP-1α, MCP-1, PCT, visfatin and MMP-2 in children diagnosed with T1D in combination with CD. These results indicate a suppressed immune profile including Th17 cytokines, chemokines, acute phase proteins, diabetes-related and matrix metalloproteinase immune markers. Functional studies of the involved immune cells (CD4+ Treg, CD8+ Treg, NK-cells and dendritic cells) could contribute to elucidate the heterogeneous immunological processes in children with more than one autoimmune disease.
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