CONICET | Buscador de Institutos y Recursos Humanos

Lysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwantedmaterials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substratesstimulates the activation of pathogenic cascades, including immunological processes, and particularly the activationof inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activatedbecause the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process.Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression ofimmune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating fromdendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine(lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thustriggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increasedrelease of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to theover-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heartinvolvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages,suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may beassociated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases inpro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activationof chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy mustbe started early, before this process becomes irreversible.