Novel insights into Addison's disease in dogs

Abstract

Addison’s disease is a dangerous hormone deficiency found in humans and dogs. Studies in humans support a complex autoimmune etiology, however evidence in studies in dogs is sparse. The work summarized in this dissertation was conducted to evaluate contributions from each of the three main types of risk factors of a complex autoimmune disease to developing AD in dogs; immunological, genetic, and environmental risk factors. Firstly, the immunological study tested the hypothesis that similar to humans with AD, dogs with AD have anti-adrenocortical autoantibodies. Several different immunoassays were performed to screen IgGs from three dog breeds predisposed to AD (Standard Poodles, Portuguese Water Dogs, and English Cocker Spaniels) for autoantibodies to adrenal antigens. Two different, mostly non-overlapping positive results were found in Western blots; IgGs from dogs with AD often had antibodies to a 42kDa band or to a 75kDa band. However, inconsistent replicability made it difficult to form definitive conclusions. Results from other immunoassays were also either inconclusive or negative. Secondly, the genetic study tested the hypothesis that certain MHC Class II genes and/or haplotypes are associated with AD in dogs from a breed with elevated risk of developing AD, Standard Poodles. Sanger sequencing of exon 2 of MHC class II haplotypes allowed for the identification of two sex-specific associations. Thirdly, an online survey study was used to compare the frequencies of certain environmental exposures and lifestyle factors between dogs with and without AD in a study cohort consisting of dogs from two high risk breeds, Standard Poodles and Portuguese Water Dogs. The variable with the highest effect size associated with AD was spay (odds ratio 2.5, 95% CI [1.4-3.5]) and neutering (odds ratio 6.0, 95% CI [2.6-13.9]). A lack of consistent positive results in the immunology study can be interpreted several different ways; 1) technical issues prevented autoantibodies from being detected, 2) AD in dogs from the breeds in this study is not immune-mediated, or 3) AD is primarily T-cell mediated and there are no autoantibodies. Results from the genetic and survey study suggest that sex hormones play a role in influencing susceptibility to AD in dogs. However, these results are correlational and future studies are needed to determine whether these associations can be explained by molecular mechanisms.