Browsing by Subject "Autoimmune"

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  • Gershony, Liza C.; Belanger, Janelle M.; Short, Andrea D; Le, Myly; Hytönen, Marjo K.; Lohi, Hannes; Famula, Thomas R; Kennedy, Lorna J; Oberbauer, Anita M. (BioMed Central, 2019)
    Abstract Background Primary hypoadrenocorticism (Addison’s disease, AD) and symmetrical lupoid onychodystrophy (SLO) are two clinical conditions with an autoimmune etiology that occur in multiple dog breeds. In man, autoimmunity is associated with polymorphisms in immune-related genes that result in a reduced threshold for, or defective regulation of, T cell activation. The major histocompatibility complex (MHC) class II genes encode molecules that participate in these functions, and polymorphisms within these genes have been associated with autoimmune conditions in dogs and humans. Bearded collies have a relatively high prevalence of autoimmune diseases, particularly AD and SLO. Our study assessed the relationship between particular MHC (dog leukocyte antigen, DLA) class II haplotypes and the two autoimmune diseases most common in this breed. Moreover, five unrelated breeds at increased risk for AD were studied for comparative purposes and analyzed in the context of extant literature. Results A single DLA class II three-locus haplotype, determined by sequence-based typing, was associated with increased risk for AD (DLA-DRB1*009:01/DQA1*001:01/DQB1*008:02) in bearded collies. Comparative analysis with the five additional breeds showed limited allele sharing, with DQA1*001:01 and DQB1*002:01 being the only alleles observed in all breeds. A distinct three-locus risk haplotype (DLA-DRB1*001:01/DQA1*001:01/DQB1*002:01) was associated with AD in the West Highland white terrier and Leonberger. Two different risk haplotypes were associated with increased risk for SLO in the bearded collie (DLA-DRB1*018:01/DQA1*001:01/DQB1*002:01 and DLA-DRB1*018:01/DQA1*001:01/ DQB1*008:02). Conclusion Two-locus DQ haplotypes composed of DLA-DQA1*001:01 in association with DLA-DQB1*002:01 or DLA-DQB1*008:02 make up the four risk haplotypes identified in the present study and are also found in other risk haplotypes previously associated with diabetes mellitus and hypothyroidism across different dog breeds. Our findings build upon previously published data to suggest that this two-locus (DQ) model serves as a good indicator for susceptibility to multiple organ-specific autoimmune diseases in the canine population. However, it is also clear that additional loci are necessary for actual disease expression. Investigation of affected and unaffected dogs carrying these predisposing DQ haplotype signatures may allow for the identification of those additional genetic components that determine autoimmune disease expression and organ specificity.
  • Gershony, Liza C.; Belanger, Janelle M.; Hytonen, Marjo K.; Lohi, Hannes; Famula, Thomas R.; Oberbauer, Anita M. (2020)
    Background Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. Results Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. Conclusion Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
  • Gershony, Liza C.; Belanger, Janelle M.; Hytönen, Marjo K.; Lohi, Hannes; Famula, Thomas R; Oberbauer, Anita M. (BioMed Central, 2020)
    Abstract Background Primary hypoadrenocorticism (or Addison’s disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. Results Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. Conclusion Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
  • Pakozdy, A.; Patzl, M.; Zimmermann, L.; Jokinen, T. S.; Glantschnigg, U.; Kelemen, A.; Hasegawa, D. (2015)
    Leucine-rich glioma-inactivated (LGI) protein was first thought to have a suppressor effect in the formation of some cancers. Developments in physiology and medicine made it possible to characterize the function of the LGI protein family and its crucial role in different conditions more precisely. These proteins play an important role in synaptic transmission, and dysfunction may cause hyperexcitability. Genetic mutation of LGI1 was confirmed to be the cause of autosomal dominant lateral temporal lobe epilepsy in humans. The LGI2 mutation was identified in benign familial juvenile epilepsy in Lagotto Romagnolo (LR) dogs. Cats with familial spontaneous temporal lobe epilepsy have been reported, and the etiology might be associated with LGI protein family dysfunction. In addition, an autoimmune reaction against LGI1 was detected in humans and cats with limbic encephalitis. These advances prompted a review of LGI protein function and its role in different seizure disorders.