Breed risk, immunophenotypes and genomic studies of canine atopic dermatitis

Abstract

BREED RISK, IMMUNOPHENOTYPES AND GENOMIC STUDIES OF CANINE ATOPIC DERMATITIS Canine atopic dermatitis (AD) is a complex genetically-linked immunological hypersensitivity which has similar clinical signs and pathological features to human AD, and involves immune dysregulation and skin barrier impairment. This thesis examines genetic factors underpinning canine AD and focuses on breed prevalence and evaluation of changes in the blood. Sixteen breeds with increased relative risk (≥1.5) were identified and gender predisposition in two dog breeds was revealed. One clade of dog breeds is highly represented amongst AD patients worldwide, and with increased RR in Australia. A 19 cytokine/chemokine multiplex bio-assay measured significantly elevated CXCL8, IL-7 and IL-15 concentrations, and reduced Stem-cell factor (SCF) in plasma of canine AD patients (n=27) compared to controls (n=11). Microarray gene expression data from leukocytes of atopic dogs (n=6) and controls (n=6) revealed 603 differentially expressed (DE) genes. Amongst these, candidate immune-related genes were highlighted, including the most under-represented gene, IL-7 receptor alpha subunit (IL7R). Quantitative real time PCR confirmed reduced gene expression for genes of the IL-7/IL7R pathway. A significant enrichment cluster consisting of immune-related pathways was identified, including T-cell receptor and B-cell receptor pathways. Expression analysis of miRNA from leukocytes of AD dogs identified15 with differential patterns of expression. The miRNA cfa-miR-31 had low levels in atopic dogs, suggesting a potential immune impairment dysregulation. Integrating the data gathered in the array studies reported in this thesis together with the genetic structure of dog breeds provides a powerful model to enable better characterisation of Australian dog breed susceptibility to canine AD and breed-related phenotypes. The IL-7/IL7R pathway may play a key role in the immune response in canine AD, may provide biomarkers to assist with diagnoses, and is a potential target for therapeutic agents