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A study of a multi-systemic immune-mediated disease in the English Cocker Spaniel


Type

Thesis

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Authors

Coddou, Maria 

Abstract

Chronic pancreatitis (CP) is a common disease in the English Cocker Spaniel (ECS) and shows a distinctive clinical and histopathological appearance. It is characterised by duct destruction, interlobular fibrosis, dense periductular and perivenous lymphocytic aggregates, the presence of multi-organ manifestation, and increased numbers of IgG4+ plasma cells in the pancreas, and other affected organs. These features are also seen in human autoimmune pancreatitis (AIP) type 1, which is part of a multi-organ syndrome, recently recognised as IgG4-Related Disease (IgG4-RD). Human IgG4-RD may affect one or several organs, pancreatitis being the most common manifestation. It is often seen that serum IgG4 levels and IgG4+ plasma cell numbers are increased in the affected tissues.

The aims of this PhD were to further investigate CP in ECS dogs with a focus on its immunology and genetics to increase our understanding of its diagnosis and pathogenesis and its similarities and differences from human IgG4-RD. Thus, 104 ECS affected by CP and 44 age-matched ECS controls were recruited for this study. Clinical features of affected dogs were characterised and clinical similarities between CP in ECS and human IgG4-RD, including a high prevalence of multi-organ manifestation were seen. Affected ECS presented with a high prevalence of keratoconjunctivitis sicca, proteinuria, anal gland disease, suspected xerostomia, atopy and other immune-mediated diseases. A strong association between CP and ECS presenting blue roan coat colour was seen, suggesting a link between coat colour and immune-mediated conditions in this breed. Moreover, the development of an enzyme-linked immunosorbent assay (ELISA) capable of quantifying serum IgG4 was attempted without success. Therefore, serum IgG4 concentrations were assessed using a commercial ELISA kit. It was demonstrated that affected ECS had significantly higher IgG4 serum concentrations compared with controls. Cases presenting with clinical inflammatory manifestations in more than one organ had significantly higher concentrations of serum IgG4 than those with only pancreatic manifestation. Total serum IgG, IgE concentrations and IgG4/IgG ratios were also measured in cases and controls. No significant difference was observed regarding concentrations of total IgG and IgE in serum. Serum IgG4/IgG ratio was significantly higher in cases than controls. Finally, a genetic study trying to identify risk factors in affected dogs was performed. Potential genetic association previously found in a pilot study between CP in the ECS and the SNP rs852916308 located on chromosome 16, which overlies a region containing a group of T-cell receptor beta variable loci and the anionic trypsinogen gene, was rejected. The SNP rs852916308 was not polymorphic in ECS. Results found on the SNP rs22196038 located on chromosome 12, which is downstream of the branched-chain alpha-keto acid dehydrogenase BCKDHB gene, demonstrated some interesting potential genotype associations that need to be confirmed including a greater number of healthy ECS.

A greater understanding of the manifestation of the disease in ECS was obtained. Further studies are required to assess the efficacy of immunosuppressive therapy, and identify the pathogenesis and genetic basis of the disease. This will contribute to improve diagnosis and treatment resulting in the improvement of the quality of life in affected dogs.

Description

Date

2020-07-06

Advisors

Watson, Penny
Blacklaws, Barbara

Keywords

IgG4-related disease, Chronic pancreatitis, English cocker spaniel

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
This work was funded by the National Agency for Research and Development (ANID) / Scholarship Program / DOCTORADO BECAS CHILE