THYMIC ALTERATIONS IN FELINE GM1 GANGLIOSIDOSIS

GM1 gangliosidosis is an inherited metabolic disease characterized by progressive neurological deterioration with premature death seen in ch ildren and numerous animals, including cats. We have observed that thy muses from affected cats greater than seven months of age (GM1 mutant cats) show marked thymic reduction compared to age-matched normal cats . The studies reported here were done to describe alterations in the t hymus prior to (less then 90 days of age) and during the development o f mild (90 to 210 days of age) to severe (greater than 210 days of age ) progressive neurologic disease and to explore the pathogenesis of th e thymic abnormality. Although histologic examination of the thymus fr om GM1 affected cats less than 210 days of age showed no significant d ifferences from age-matched control cats, thymuses from GM1 mutant cat s greater than 210 days of age were significantly reduced in size (app roximately 3-fold), Histologic sections of lymph nodes, adrenal glands , and spleens from GM1 gangliosidosis-affected cats showed no signific ant differences. Flow cytometric analyses showed a marked decrease in the percentage of immature CD4(+)CD8(+) thymocytes (p<0.001) and signi ficantly increased CD4(-)CD8(+) cells (p<0.01) in GM1 mutant cats grea ter than 210 days of age when compared to normal age matched cats. Co- labelling with CD4, CD8, and CD5 indicated an increase in the percenta ge of GM1 mutant cat thymocytes at this age which were CD5(high), sugg esting the presence of more mature cells. Cytometric analyses of subpo pulations of peripheral lymphocytes indicated an increase in CD4(-)CD8 (+) cells (p<0.05) with concurrent decreases in CD4(+)CD8(-) and CD4(- )CD8(-) cells (which were not significant). Similar analyses of thymoc yte and lymphocyte subpopulations from cats <210 days of age showed no significant differences between GM1 mutant and normal cells. GM1 muta nt cats at all ages had increased surface binding of Cholera toxin B o n thymocytes, indicating increased surface GM1 ganglioside expression. Increases were highly significant in GM1 mutant cats greater than 210 days of age. In situ labelling for apoptosis was increased in GM1 mut ant cats between 90 to 200 days of age when thymic masses were within normal limits. In GM1 mutant cats over 200 days of age, decreased labe lling was observed when thymic mass was reduced and the CD4(+)CD8(+) s ubpopulation, known to be very susceptible to apoptosis, was significa ntly decreased. These data describe premature thymic involution in fel ine GM1 gangliosidosis and suggest that increased surface GM1 ganglios ides alters thymocyte development in these cats. (C) 1998 Elsevier Sci ence B.V. All rights reserved.