| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 103 === Fabry disease is an X-linked lysosomal storage disease results from mutations of α-galactosidase A (GLA). Surprisingly, 86% Fabry disease patients are IVS4 (IVS4+919G>A) mutation, also known as Fabry cardiac variant, in Taiwan. This mutation generates a rare alternative splicing form of GLA transcript that leads to the premature termination of GLA transcript. The clinical symptoms of patients include left ventricular hypertrophy, valvular involvement and cardiac fibrosis. Previous studies have suggested a strong link between hyper-activated immune response to the pathogenesis of cardiac fibrosis, therefore, we hypothesize that the immune system may be dysregulated and contribute to the cardiomyopathy in IVS4 patients.
To test our hypothesis, we collected and analyzed the immune cells from peripheral blood of IVS4 patients. We found the percentage of CD8 T cells was decreased in the peripheral blood and can be found together with macrophages in the cardiac tissue of IVS4 patients. We identified that the over-activated CD8 T cells may play an import role in development of the cardiomyopathy in IVS4 patients. In the plasma, we detected elevated levels of IL-1β in 20% of the IVS4 patients. Besides, our results indicated that monocytes express higher GLA than lymphocytes population, and noticed that the monocytes are vulnerable to lysotracker and Gb3 expression. Moreover, we showed that Gb3 stimulation is sufficient to induce the downregulation of MHCII, upregulation of CD1d, and production of IL-1β in monocytes. Together our results suggested that the immune system is disturbed in IVS4 patients.
These results may provide insights in understanding the molecular mechanisms of how disturbed glycolipid metabolism may affect immune cell functions. Furthermore, findings from this study may shed lights on development of novel treatment for Fabry disease patients.
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