| 1. |
- Tengvall, Katarina, et al.
(författare)
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Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:5, s. e1003475-
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Tidskriftsartikel (refereegranskat)abstract
- Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.
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| 2. |
- Ardesjö-Lundgren, Brita, et al.
(författare)
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Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs
- 2017
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Ingår i: Veterinary dermatology (Print). - : Wiley. - 0959-4493 .- 1365-3164. ; 28:4, s. 377-e88
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCanine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome‐wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin‐2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.ObjectivesThe main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD‐affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.Animals/MethodsSkin biopsies were collected from nine CAD‐affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.ResultsWe observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding‐partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.ConclusionPlakophilin‐2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.
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| 3. |
- Fall, Tove, 1979-, et al.
(författare)
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Diabetes Mellitus in Elkhounds Is Associated with Diestrus and Pregnancy
- 2010
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Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 24:6, s. 1322-1328
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Tidskriftsartikel (refereegranskat)abstract
- Background: Female Elkhounds are shown to be at increased risk for diabetes mellitus, and occurrence of diabetes during pregnancy has been described in several cases. Hypothesis: Onset of diabetes mellitus in Elkhounds is associated with diestrus. Animals: Sixty-three Elkhounds with diabetes mellitus and 26 healthy controls. Methods: Medical records from 63 Elkhounds with diabetes were reviewed and owners were contacted for follow-up information. Blood samples from the day of diagnosis were available for 26 dogs. Glucose, fructosamine, C-peptide, growth hormone (GH), insulin-like growth factor-1, progesterone, and glutamate decarboxylase isoform 65-autoantibodies were analyzed and compared with 26 healthy dogs. Logistic models were used to evaluate the association of clinical variables with the probability of diabetes and with permanent diabetes mellitus after ovariohysterectomy (OHE). Results: All dogs in the study were intact females and 7 dogs (11%) were pregnant at diagnosis. The 1st clinical signs of diabetes mellitus occurred at a median of 30 days (interquartile range [IQR], 3-45) after estrus, and diagnosis was made at a median of 46 days (IQR, 27-62) after estrus. Diabetes was associated with higher concentrations of GH and lower concentrations of progesterone compared with controls matched for time after estrus. Forty-six percent of dogs that underwent OHE recovered from diabetes with a lower probability of remission in dogs with higher glucose concentrations (odds ratio [OR], 1.2; P = .03) at diagnosis and longer time (weeks) from diagnosis to surgery (OR, 1.5; P = .05). Conclusions: Diabetes mellitus in Elkhounds develops mainly during diestrus and pregnancy. Immediate OHE improves the prognosis for remission of diabetes.
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| 4. |
- Chankeaw, Wiruntita, et al.
(författare)
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Elevated non-esterified fatty acids impair survival and promote lipid accumulation and pro-inflammatory cytokine production in bovine endometrial epithelial cells
- 2018
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Ingår i: Reproduction, Fertility and Development. - 1031-3613 .- 1448-5990. ; 30, s. 1770-1784
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Tidskriftsartikel (refereegranskat)abstract
- Elevated non-esterified fatty acids (NEFAs) are associated with negative effects on bovine theca, granulosa and oviductal cells but the effects of NEFAs on bovine endometrial epithelial cells (bEECs) are not as well documented. The objective of this study was to define the effects of NEFAs on bEECs. Postprimary bEECs were treated with 150, 300 or 500 mu M of either palmitic acid (PA), stearic acid (SA) or oleic acid (OA) or a mixture of NEFAs (150 mu M of each FA) or 0.5% final concentration of vehicle ethanol (control). Viability and proliferation of bEECs exposed to 150 mu M of each NEFA or a mixture of NEFAs were unaffected. Increased lipid accumulation was found in all treated groups (P < 0.01). In cells exposed to 500 mu M of each NEFA and 300 mu M PA decreased cell viability (P < 0.001), proliferation (P < 0.05) and increased apoptosis (P < 0.05) were observed. Treatment with 500 mu M OA, PA and SA had the strongest effects on cell viability, proliferation and apoptosis (P < 0.05). Treatment with PA and OA increased interleukin-6 (IL-6) concentrations (P < 0.05), whereas only the highest concentration of PA, OA and SA stimulated IL-8 production (P < 0.05). These results suggest that high concentrations of NEFAs may impair endometrial function with more or less pronounced effects depending on the type of NEFA and time of exposure.
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| 5. |
- Laskowski, Denise, et al.
(författare)
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Insulin during in vitro oocyte maturation has an impact on development, mitochondria, and cytoskeleton in bovine day 8 blastocysts
- 2017
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Ingår i: Theriogenology. - : Elsevier BV. - 0093-691X .- 1879-3231. ; 101, s. 15-25
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Tidskriftsartikel (refereegranskat)abstract
- Insulin is a key metabolic hormone that controls energy homeostasis in the body, including playing a specific role in regulating reproductive functions. Conditions associated with hyperinsulinemia can lower developmental rates in bovine in vitro embryo production and are linked to decreased fertility in humans, as in cases of obesity or type 2 diabetes. Embryo quality is important for fertility outcome and it can be assessed by choosing scoring standards for various characteristics, such as developmental stage, quality grade, cell number, mitochondrial pattern or actin cytoskeleton structure. Changes in the embryo's gene expression can reflect environmental impacts during maturation and may explain morphological differences. Together with morphological evaluation, this could enable better assessment and possibly prediction of the developmental potential of the embryo. The aim of this study was to use a bovine model to identify potential gene signatures of insulin-induced changes in the embryo by combining gene expression data and confocal microscopy evaluation. Bovine embryos were derived from oocytes matured in two different insulin concentrations (10 mu g mL(-1) and 0.1 mu g mL(-1)), then stained to distinguish f-Actin, DNA and active mitochondria. The total cell number of the embryo, quality of the actin cytoskeleton and mitochondrial distribution were assessed and compared to an insulin-free control group. A microarray-based transcriptome analysis was used to investigate key genes involved in cell structure, mitochondrial function and cell division. Our results indicate that insulin supplementation during oocyte maturation leads to lower blastocyst rates and a different phenotype, characterised by an increased cell number and different actin and mitochondrial distribution patterns. These changes were reflected by an up-regulation of genes involved in cell division (MAP2K2; DHCR7), cell structure (LMNA; VIM; TUBB2B; TUBB3; TUBB4B) and mitochondrial activation (ATP5D; CYP11A1; NDUFB7; NDUFB10; NDUFS8). Taken together, we hypothesise that the increased proliferation in the insulin-treated groups might impair the developmental potential of the embryos by inducing metabolic stress on the molecular level, which could be detrimental for the survival of the embryo. (C) 2017 Elsevier Inc. All rights reserved.
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| 6. |
- Guo, Yongzhi, et al.
(författare)
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159 changes in protein expression profiles in bovine endometrial epithelial cells (bEEC) following E coli lipopolysaccharide challenge
- 2014
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Ingår i: Reproduction, Fertility and Development. - 1031-3613 .- 1448-5990. ; 27, s. 170-170
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- E. coli is one of the most frequent bacteria involved in uterine diseases. Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria involved in the pathogenic processes leading to postpartum metritis and endometritis in cattle. It also causes inflammation of the endometrium. Increase of cell proliferation by LPS is part of the inflammatory process and has been reported in human epithelial and immune cells (Martin et al. 2000 J. Immunol. 165, 139-147) and from bovine endometrial epithelial cells (bEEC) (Guo et al. 2014 Reprod. Fertil. Dev. 26, 165-166). The aim of this study was to investigate possible changes in protein expression in relation with the proliferative response of bEEC after challenge with E. coli-LPS. In vitro culture of bEEC was performed from 3 cows. On passage 5, bEEC from each individual were exposed to 0, 8, and 16µgmL-1 LPS for 72h. At time 0 and 72h later, attached cells were counted and for each time and LPS dosage, cells were frozen for proteomic analyses. The variation of cells number over time was analysed by ANOVA (SAS 9.1, proc GLM; SAS Institute, Inc., Cary, NC, USA). All samples were analysed (every sample run in triplicate) by 2-D gel electrophoresis coupled to matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF)/time-of-flight (TOF) mass spectrometry (MS) and shotgun nLC-MS/MS analysis. As reported before, a significant increase in cell number was observed for cells treated with 8µgmL-1 LPS (P≤0.001), whereas changes in cell number were highly variable and nonsignificant for 16µgmL-1 LPS. From each sample, ~800 proteins were visualised. Results from 2-D gel coupled to MALDI-TOF/TOF were very reproducible (same responses between individual cows) and revealed changes in protein profiles very much related (from P<0.05 to P<0.01) to proliferative phenotypes for seven proteins. From shotgun analysis, 27 proteins were found significantly differentially expressed (P<0.05 to P<0.01) following exposure to LPS (21 up-regulated and 6 down-regulated). Among the 21 found as up-regulated, 20 were differentially expressed both for the 8 and 16µgmL-1 LPS, whereas 5 out of 6 were down-regulated for both dosages. Differentially expressed proteins were associated to cell proliferation, apoptosis, oxidative stress, regulation of histones, allergy, and general cell metabolism pathways. Candidate proteins need to be confirmed from larger series of individuals and relevant pathways further studied.
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| 7. |
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| 8. |
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| 9. |
- Wilbe, Maria, et al.
(författare)
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Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease
- 2015
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAM-TOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.
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| 10. |
- Ahlgren, Kerstin, M., et al.
(författare)
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Type I Interferon signature in Nova Scotia duck tolling retriever dogs with steroid responsive meningitis-arteritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Dogs of the breed Nova Scotia duck tolling retriever (NSDTR) are prone to develop a disease complex in some aspects resembling human systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells (PBMCs) from human SLE patients have an increased mRNA expression type I interferon (IFN) regulated genes. However, it is unknown whether diseased dogs also display the typical type I IFN signature. Methods: To test canine sera for their capacity to induce type I IFN response Mardin-Darby canine kidney (MDCK) cells were cultured with sera from healthy dogs (n=25), immune-mediated rheumatic disease (IMRD) dogs with anti-nuclear antibodies (ANA+) (n=30) or dogs with steroid responsive meningitis-arteritis (SRMA) (n=25). mRNA expression of the genes MX1, IFIT1 and CXCL10 was measured by quantitative Real Time PCR. Results: A highly significant (p=0.0009) increase in mRNA expression of the type I IFN responsive gene MX1 was detected in cells stimulated by sera from dogs with SRMA, but not from IMRD ANA+ dogs. Expression of IFIT1 was twice as high in cells stimulated by sera from dogs with SRMA compared to both healthy dogs and ANA+ dogs. The mean expression of CXCL10 was nearly ten times higher in cells stimulated by sera from SRMA dogs than by ANA+ dogs and four times higher compared to cells stimulated by control dogs. Conclusion: Presence of type I IFN in sera from diseased NSDTR dogs was found in this study. This implies that this canine model can be used for identification of pathways of importance for autoimmune disorders in humans and for testing of novel therapeutic approaches. Our results can also be a step on the way towards personalized drugs in these dogs.
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