Investigations of a novel lymphoproliferative disease in British shorthair kittens : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand
In 2009, three sibling British shorthair (BSH) kittens presented with lymphoproliferative disease (LPD) causing massive enlargement of multiple lymph nodes, a presentation that suggested an inherited predisposition to the disease. While aspects of the disease presentation suggested a diagnosis of lymphoma, other features were inconsistent with lymphoid neoplasia. In particular, the consistently young age of affected kittens, the pattern of disease affecting multiple littermates, and the presence of such marked generalised lymphadenopathy, were all atypical for feline lymphoma. This unusual constellation of clinical and pathologic features in affected BSH kittens had not been previously reported in cats but had several similarities to the human disease autoimmune lymphoproliferative syndrome (ALPS), a rare inherited disorder causing persistent LPD, increased numbers of CD3+/CD4-/CD8- double negative T-cells (DNT cells) and variable manifestations of autoimmunity. The majority of human ALPS patients have inherited Fas gene mutations causing defective T-cell apoptosis, although in some patients the cause of disease is still unknown.
The thesis further describes and investigates this novel LPD in BSH kittens. The results of breeding trials, pedigree information and reviews of historical records support an inherited basis for the disease, most likely with either a simple autosomal recessive or modified autosomal dominant mode of inheritance. The typical clinical presentation is the development of a massive multicentric lymphadenopathy, splenomegaly and probable haemolytic anaemia in previously healthy kittens between 5 to 7 weeks of age. Microscopic pathology and immunophenotypic studies are suggestive of multicentric T-cell lymphoma affecting the lymph nodes, spleen, and sometimes other organs, but clonality assays confirm a non-clonal and likely non-neoplastic T-cell LPD. Where tested, the proliferating T-cells show a DNT cell immunophenotype and reduced apoptosis on in situ methods. Qualitative Fas gene abnormalities were not identified in affected kittens using reverse-transcriptase polymerase chain reaction techniques.
The studies described in the thesis therefore confirm a novel and likely non-neoplastic T-cell LPD in BSH kittens with a probable inherited basis. Results support defective T-cell apoptosis as a possible factor in disease development, although causative genetic abnormalities have not yet been identified. The disease in kittens has several similarities to ALPS in people, although the apparent absence of Fas gene abnormalities in affected kittens may limit the use of the feline disease as a disease model for ALPS.