1.
Greiff, Lennart, et al.
(författare)
Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
1997
Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391
Tidskriftsartikel (refereegranskat) abstract
Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
2.
Liu, Yawei, et al.
(författare)
Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE.
2006
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 12:5, s. 518-525
Tidskriftsartikel (refereegranskat) abstract
Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1–TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+TGF-beta1+CTLA-4+FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.
3.
Heyman, Lovisa
(författare)
Berries in Prevention of Metabolic Disease – focus on obesity, diabetes and gut microbiota
2015
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The increasing prevalence of obesity is a worldwide health problem closely linked to diet and lifestyle factors. Obesity is associated with increased risk of several metabolic disorders including insulin resistance, nonalcoholic fatty liver disease and type 2 diabetes. Hence, there is a great need to identify dietary strategies for the prevention of obesity and related diseases. This thesis investigates the potential of different berries to mediate beneficial health effects in a mouse model of diet-induced obesity and prediabetes. We found that supplementation with lingonberries, blackcurrants and bilberries reduced body weight gain, insulin resistance, low-grade inflammation and hepatic lipid accumulation in C57BL/6J mice fed a high-fat diet. Supplementation with raspberries, crowberries, blackberries or prunes had no or small effects, whereas açai berries promoted development of obesity and fatty liver compared to the control group receiving high-fat diet without berries. Global hepatic gene expression analysis revealed that the phenotype in the lingonberry and bilberry groups was coupled to an anti-inflammatory effect, including downregulation of acute-phase proteins and inflammatory mediators. Mice receiving açai displayed an upregulation of steatosis markers and genes related to lipid synthesis, in line with the exacerbation of high-fat-induced fatty liver in these mice. The HELP-tagging assay was used to identify differentially methylated CpG sites in the lingonberry group compared to the high-fat control group. Lingonberries induced genome-wide and specific alterations of DNA methylation, however the significance of these findings remains to be established. Furthermore, different batches of lingonberries were found to have different capacity to prevent obesity. However lingonberries prevented low-grade inflammation, metabolic endotoxemia and modified the gut microbiota of high-fat fed mice, including increasing the Firmicutes/Bacteroidetes ratio. These findings were independent of effects on body weight gain and achieved regardless of the source of berries. The capacity of lingonberries to counteract negative outcomes of an unhealthy diet should be further evaluated in humans, including assessment of anti-inflammation and microbiota modulation. The generated knowledge about berries and their effects on metabolism may be useful in designing future dietary strategies aimed at preventing metabolic disease.
4.
Persson, Carl, et al.
(författare)
Unbalanced research
2001
Ingår i: Trends in Pharmacological Sciences. - 0165-6147. ; 22:10, s. 538-541
Tidskriftsartikel (refereegranskat)
5.
Eklund, Erik, et al.
(författare)
Proteoglycan production in disomic and trisomy 7-carrying human synovial cells.
2002
Ingår i: Matrix Biology. - 1569-1802. ; 21:4, s. 325-335
Tidskriftsartikel (refereegranskat) abstract
To gain further insight into the synthesis and structure of the synovial matrix of joints, we have established cell cultures from synovial specimens and elaborated their production of hyaluronan and proteoglycans. The cultures secreted mainly the small proteoglycan decorin, but also considerable amounts of the related biglycan and the large proteoglycan versican. Only minor amounts of heparan sulfate proteoglycans were found. All cultures also had a high production of hyaluronan, which highlights the important role for normal joint function of these cells. In joint diseases, a common feature is the presence of an extra chromosome 7 (trisomy 7) in the synovial cells. To study the possible consequences of trisomy 7 on the synovial cell function, we extended our study to cultures that had been sub-cloned to contain high amounts of trisomy 7-carrying cells. These cell cultures had approximately four times more versican than their disomic counterparts in the cell culture medium, indicating that versican may be a mediator in the processes of joint destructive disorders. To find an explanation for this increase in versican, we investigated the expression/secretion of PDGF-AA and IL-6, cytokines with their genes located to chromosome 7. Indeed, both these cytokines were increased in the cultures with high frequencies of trisomy 7. We then added the two cytokines to cell cultures of disomic synovial cells, but only cells treated with IL-6 displayed an increased amount of versican. Thus, we suggest that the increased amount of versican in cultures of trisomy 7-carrying cells relates to an autocrine loop involving an increased IL-6 production.
6.
Andersson, C, et al.
(författare)
The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
2011
Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
Tidskriftsartikel (refereegranskat) abstract
Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
7.
Brorsson, Caroline, et al.
(författare)
Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes
2011
Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:2, s. 107-114
Tidskriftsartikel (refereegranskat) abstract
We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.
8.
Kjellerås, Jennifer, et al.
(författare)
Improved efficacy by using the pTnT-rhtTG plasmid for the detection of celiac disease specific tissue transglutaminase autoantibodies in radioligand binding assays
2011
Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa Healthcare. - 0036-5513 .- 1502-7686. ; 71:8, s. 701-704
Tidskriftsartikel (refereegranskat) abstract
Background: Tissue transglutaminase (tTG) autoantibodies are serological markers for celiac disease. The aim was to study the efficacy of the pTnT-rhtTG plasmid and subsequent diagnostic accuracy of tTG autoantibodies for childhood celiac disease using radioligand binding assays.Methods: Coupled in vitro transcription and translation of tTG were performed by pTnT-rhtTG as well as by the pGEMt Easy-rhtTG vectors using the TNT SP6 Coupled Reticulocyte Lysate System in the presence of [(35)S] methionine. Sera from 190 celiac disease children and 74 controls were measured for tTG autoantibodies in two separate radioligand binding assays using anti-human IgA agarose and protein A sepharose beads for the detection of IgA-tTG and IgG-tTG, respectively.Results: Median incorporation of [(35)S] methionine into the pTnT-rhtTG was 26% compared to 16% for the pGEMt Easy-rhtTG plasmid (p = 0.0016). Using pTnT-rhtTG (as compared to pGEMt Easy-rhtTG), sensitivities were IgA-tTG = 96.3% (95.7%) and IgG-tTG = 95.8% (97.3%) and specificities were IgA-tTG = 91.9% (90.5%) and IgG-tTG = 94.6% (98.4%). According to receiver operator characteristics for the pTnT (pGEMt Easy) assays, area under the curves were IgA-tTG = 98.4% (98.4%) and IgG-tTG = 97.7% (97.2%), respectively.Conclusion: The pTnT-rhtTG plasmid increased the efficacy of tTG antigen usage without reducing the diagnostic accuracy of IgA-tTG and IgG-tTG for childhood celiac disease. The pTnT-rhtTG plasmid is therefore recommended over the pGEMt Easy-rhtTG for the assessment of IgA-tTG and IgG-tTG using radioligand binding assays.
9.
Shulman, L M, et al.
(författare)
Antibodies to islet cell autoantigens, rotaviruses and/or enteroviruses in cord blood and healthy mothers in relation to the 2010-2011 winter viral seasons in Israel : a pilot study
2014
Ingår i: Diabetic Medicine. - : Wiley-Blackwell. - 0742-3071 .- 1464-5491. ; 31:6, s. 681-685
Tidskriftsartikel (refereegranskat) abstract
AimsTo determine whether antivirus and/or islet cell antibodies can be detected in healthy pregnant mothers without diabetes and/or their offspring at birth in two winter viral seasons.MethodsMaternal and cord blood sera from 107 healthy pregnant women were tested for islet cell autoantibodies using radioligand binding assays and for anti-rotavirus and anti-CoxB3 antibody using an enzyme-linked immunosorbent assay.ResultsGlutamic acid decarboxylase (GAD)65 autoantibodies and rotavirus antibodies, present in both maternal and cord blood sera, correlated with an odds ratio of 6.89 (95% CI: 1.01-46.78). For five, 22 and 17 pregnancies, antibodies to GAD65, rotavirus and CoxB3, respectively, were detected in cord blood only and not in the corresponding maternal serum. In 10 pregnancies, rotavirus antibody titres in the cord blood exceeded those in the corresponding maternal serum by 2.5-5-fold. Increased antibody titres after the 20(th) week of gestation suggested CoxB3 infection in one of the 20 pregnancies and rotavirus in another.ConclusionThe concurrent presence of GAD65 antibodies in cord blood and their mothers may indicate autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. Cord blood antibody titres that exceed those of the corresponding maternal sample by >2.5-fold, or antibody-positive cord blood samples with antibody-negative maternal samples, may imply an active in utero immune response by the fetus. What's new? It has been hypothesized that viral infections initiate islet cell autoimmunity. Previous research suggests an association of viral infection in utero and islet autoimmunity. We found a significant correlation between glutamic acid decarboxylase 65 autoantibodies and anti-rotavirus in healthy mothers at delivery and in cord blood. The presence of antibodies in cord blood with antibody-negative mothers suggests an independent fetal immune response. Our findings support the hypothesis that viral infections during pregnancy damage fetal islet cells, triggering islet autoimmunity.
10.
Skärstrand, H, et al.
(författare)
Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy
2013
Ingår i: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 27:6, s. 609-617
Tidskriftsartikel (refereegranskat) abstract
Aims: The neurotransmitter Neuropeptide Y (NPY) was previously reported as a minor autoantigen in newly diagnosed type 1 diabetes (T1D) patients. The single nucleotide polymorphism at rs16139 (T1128C, L7P) in the NPY gene was associated with an increased risk for the development of type 2 diabetes (T2D). We aimed to develop a radiobinding assay for NPY-L (Leucine) and NPY-P (Proline) autoantibodies (A) to study the levels and the association with other islet autoantibodies and neuropathy. Methods: Autoantibodies against NPY-L, NPY-P, ZnT8, GAD65 and IA-2 were studied in T1D (n = 48) and T2D (n = 26) patients with duration up to 42 and 31 years. A subgroup of T1D (n = 32) patients re-examined, 5-8 years after first visit, was tested for peripheral (Z-score) and autonomic neuropathy (E/I ratio). Results: NPY-LA and NPY-PA were detected in 23% and 19% in T1D (p<0.001), and 12% and 23% in T2D patients (p<0.001) compared to 2.5% controls (n = 398). The levels of NPYA declined during follow-up in the T1D patients (p < 0.001). The neuropathy was not related to the NPYA or the other islet autoantibodies. Conclusions: Regardless of the absence of an association between NPYA and neuropathy, NPY may contribute to the pathogenesis of T1D and T2D as a minor autoantigen.
