| 1. |
- Wilbe, Maria, et al.
(författare)
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Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 250-254
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Tidskriftsartikel (refereegranskat)abstract
- The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.
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| 2. |
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| 3. |
- Ahlgren, Kerstin. M, et al.
(författare)
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Diabetes mellitus in dog - : No evidence for a type-1-like phenotype
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims/hypothesis Diabetes mellitus (DM) is one of the most common endocrine disorders in dogs, and is commonly proposed to be of autoimmune origin. Although the clinical symptoms of human type 1 diabetes (T1D) and canine DM are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported. Methods Sera from 121 diabetic dogs representing 38 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs from 40 breeds. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immunoprecipitation. Results None of the canine sera analyzed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Conclusions/interpretations Based on sera from 121 diabetic dogs from 38 different breeds were tested for humoral autoreactivity using four different assays, contrary to previous observations, we find no support for an autoimmune aetiology in canine diabetes.
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| 4. |
- Ahlgren, Kerstin M, et al.
(författare)
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Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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| 5. |
- 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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| 6. |
- Bergman, Daniel, et al.
(författare)
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Characterization of canine anti-mouse antibodies highlights that multiple strategies are needed to combat immunoassay interference
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Immunoassays are widely used for detection and quantification of analytes in biological samples, but are vulnerable to analytical errors caused by interfering sample substances. Of particular interest are endogenous anti-animal antibodies that may bind to the immunoassay antibodies and cause erroneous test results. This phenomenon is a hazard to patient safety in both human and veterinary medicine. Here, we demonstrate that anti-mouse antibodies in dogs bind selectively to different regions of the murine IgG molecule, cross-react with IgG from different species, and consist of all major antibody classes present in canine serum (IgA, IgG and IgM). The antibody characteristics varied among individuals and their prevalence differed between two dog breeds. The selective binding to different IgG regions suggests that the antibodies might not originate from immunization through exposure to mice or other species. These findings show that canine anti-mouse antibodies are highly heterogeneous in nature and therefore require a combination of strategies to be counteracted.
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| 7. |
- Bergman, Daniel, et al.
(författare)
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Investigation of interference from canine anti-mouse antibodies in hormone immunoassays
- 2019
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Ingår i: Veterinary clinical pathology. - : Wiley. - 0275-6382 .- 1939-165X. ; 48:S1, s. 59-69
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Canine anti-mouse antibodies are a potential source of immunoassay interference, but erroneous immunoassay results are not always easily identifiable. Anti-Müllerian hormone (AMH) is a marker for the presence of gonads in dogs, but elevated AMH concentrations in neutered dogs could also be caused by antibody interference. For other assays, a discrepant result obtained after antibody precipitation might indicate antibody interference.OBJECTIVES: We aimed to evaluate if canine anti-mouse antibodies are a source of erroneous results in the AMH assay and if antibody precipitation with polyethylene glycol (PEG) is a useful tool for detecting antibody interference in a variety of immunoassays used in the veterinary clinical laboratory.METHODS: Twenty-nine positive and 25 negative samples for anti-mouse antibodies were analyzed for AMH, canine total thyroxine (TT4), canine thyroid-stimulating hormone (TSH) and progesterone before and after treatment with PEG. Results that differed by more than four SDs from the intra-assay coefficients of variation were considered discrepant. Elevated AMH concentrations in neutered dogs with anti-mouse antibodies and no visible gonads present were considered evidence of interference.RESULTS: Evidence of antibody interference was found in two samples analyzed for AMH. The presence of anti-mouse antibodies did not lead to a higher proportion of discrepant results after PEG treatment for any of the immunoassays. The overall incidence of discrepant results for healthy controls was very high (73%).CONCLUSIONS: Canine anti-mouse antibodies are a source of erroneous AMH results. Antibody precipitation with PEG is not a useful tool for detecting interference caused by such antibodies.
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| 8. |
- Bergman, Daniel, et al.
(författare)
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Pre-existing canine anti-IgG antibodies: implications for immunotherapy, immunogenicity testing and immunoassay analysis
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- One of the most enigmatic features of humoral immunity is the prevalent presence of circulating autoantibodies against IgG. These autoantibodies consist of several subsets, including rheumatoid factors, anti-Fab/anti-F(ab′)2-autoantibodies, and anti-idiotypic antibodies. Anti-IgG autoantibodies can impair the safety and efficacy of therapeutic antibodies and interfere with immunogenicity tests in clinical trials. They can also cross-react with allospecific IgG, presenting as heterophilic antibodies that interfere with diagnostic immunoassays. Owing to these factors, recent years have seen a resurgent interest in anti-IgG autoantibodies, but their underlying clinical significance, as well as biological roles and origins, remain opaque. Increased knowledge about canine anti-IgG autoantibodies could facilitate the development of canine immunotherapies and help in understanding and counteracting immunoassay interference. This study investigated the clinical significance and interconnection of heterophilic antibodies, anti-Fab, and anti-F(ab′)2-autoantibodies in dogs. We performed a 2-year prospective follow-up of dogs with heterophilic antibodies and analyzed serum for anti-Fab and anti-F(ab′)2-autoantibodies. Canine heterophilic antibodies can persist for at least 2 years in serum. A widespread occurrence of anti-Fab and anti-F(ab′)2-autoantibodies was found, with reactivity to cryptic epitopes in the IgG hinge region and sporadic cross-reactivity with mouse IgG. Canine anti-Fab and anti-F(ab′)2-autoantibodies are thus potential sources of clinical immunogenicity and immunoassay interference.
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| 9. |
- Bergman, Daniel, et al.
(författare)
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Prevalence of interfering antibodies in dogs and cats evaluated using a species-independent assay.
- 2018
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Ingår i: Veterinary clinical pathology. - : Wiley. - 0275-6382 .- 1939-165X. ; 47:2, s. 205-212
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Interfering antibodies in human serum and plasma are known to react with mammalian antibodies in immunoassays and cause false-positive test results. Although this phenomenon was recently shown in companion animals, knowledge regarding immunoassay interference in veterinary medicine is very limited.OBJECTIVES: The aims of this study were to set up a species-independent immunoassay procedure to detect interference in serum samples, to screen for interference in a cross-section of canine and feline patient samples from an animal hospital, and to determine if the detected interference could be neutralized using an immunoassay based on nonmammalian reagents.METHODS: A 2-site sandwich-type interference assay was set up using commercially available mouse reagents. A total of 369 serum samples from 320 dogs and 263 samples from 218 cats were analyzed using the interference assay. Multiple samples were submitted from 36 dogs and 39 cats. Nineteen samples identified as interference-positive were analyzed in an assay using chicken antibodies.RESULTS: Interference was detected in samples from 28 dogs (9%) and 10 cats (5%) screened with the interference assay. Except for 1 cat, consistent results were obtained for all 75 dogs and cats that submitted more than 1 sample. The interference was eliminated when analyzed in the chicken-based assay (P < .001).CONCLUSIONS: Substances with reactivity toward mouse IgG can be detected in serum samples from dog and cat patients using a 2-site interference assay. The detected substances are most likely interfering antibodies, possibly originating from immunization with other mammalian species.
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