| 1. |
- Frankowiack, Marcel
(författare)
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Canine disease models for IgA deficiency
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Selective IgA deficiency (IgAD) is the most common primary immunodeficiency disorder in Caucasians and is defined as serum IgA concentrations below or equal to 0.07 g/l, with normal serum concentrations of IgM and IgG, in individuals 4 years of age or older. The prevalence of IgAD is approximately 1:600 in the general population and recent results have shown that patients with IgAD have significantly poorer physical health and an increased risk of early death. The domestic dog is more than just a companion and working animal. The almost 400 distinct modern dog breeds represent great phenotypical diversity and there are more than 350 naturally occurring genetic diseases in dogs which clinically resemble the corresponding human diseases. As a result of domestication, the dog’s genome is characterised by long haplotype blocks and linkage disequilibrium (LD) making the dog an appealing model for genetic studies of human diseases. Low serum IgA concentrations in dogs have been reported to clinically resemble human IgAD. However, even though the literature on IgA concentrations in dogs is extensive, the normal range of serum IgA as well as a generally accepted cut-off value for IgAD deficiency has not yet been established. We performed an extensive screen of serum IgA concentrations in more than 1,500 dogs from 22 breeds. Dog breed-specific differences in the prevalence of IgAD indicate the involvement of genetic factors in the development of the disease. Furthermore, certain dog breeds were found to stand out as high-risk breeds. Genome-wide association studies (GWAS) in selected high-risk breeds show that IgAD is associated with genes involved in B cell development and haematopoiesis. Additionally, serum IgA concentrations were found to play an important role in the aetiology of canine atopic dermatitis (CAD), an autoimmune disease in dogs. Molecular identity allowed the quantification of IgA in serum samples from Canadian and Scandinavian wolves with the same antibodies as those used in dogs. Interestingly, wolves from Scandinavia show significantly lower IgA concentrations as compared to Canadian wolves. Due to its size, the Scandinavian wolf population is prone to inbreeding and therefore, it is known to suffer from a decrease in genetic variation. Further analyses are needed to investigate whether Scandinavian wolves and dogs with a high-risk profile for IgAD share certain genetic factors
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| 2. |
- Frankowiack, Marcel, et al.
(författare)
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IgA deficiency in wolves
- 2013
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Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X .- 1879-0089. ; 40:2, s. 180-184
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Tidskriftsartikel (refereegranskat)abstract
- Low mean concentrations of serum immunoglobulin A (IgA) and an increased frequency of overt IgA deficiency (IgAD) in certain dog breeds raises the question whether it is a breeding-enriched phenomenon or a legacy from the dog's ancestor, the gray wolf (Canis lupus). The IgA concentration in 99 serum samples from 58 free-ranging and 13 captive Scandinavian wolves, was therefore measured by capture ELISA. The concentrations were markedly lower in the wolf serum samples than in the dog controls. Potential differences in the IgA molecule between dogs and wolves were addressed by sequencing the wolf IgA heavy chain constant region encoding gene (IGHA). Complete amino acid sequence homology was found. Detection of wolf and dog IgA was ascertained by showing identity using double immunodiffusion. We suggest that the vast majority of wolves, the ancestor of the dog, are IgA deficient.
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| 3. |
- Frankowiack, Marcel, et al.
(författare)
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IgA deficiency in wolves from Canada and Scandinavia
- 2015
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Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X .- 1879-0089. ; 50:1, s. 26-28
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in both humans and selected breeds of domestic dogs. In both species, IgAD is associated with recurrent infections and immune mediated diseases. Previous results imply that IgAD is also common in the wild ancestor of domestic dogs, the gray wolf. Here, we report that serum IgA concentrations are significantly different in Scandinavian and Canadian wolves (p =3.252e-15) with an increased prevalence for IgAD in Scandinavian wolves (60%), which is as high as those found in high-risk dog breeds.
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| 4. |
- Olsson, Mia, et al.
(författare)
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Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.
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| 5. |
- Olsson, Mia, et al.
(författare)
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The dog as a genetic model for immunoglobulin A (IgA) deficiency : Identification of several breeds with low serum IgA concentrations
- 2014
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 60:3-4, s. 255-259
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.
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| 6. |
- 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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