Overview of immune abnormalities in lysosomal storage disorders.

The critical relevance of the lysosomal compartment for normal cellular function can be proved by numbering the clinical phenotypes that arise in lysosomal storage disorders (LSDs), a group of around 70 different monogenic autosomal or X-linked syndromes, caused by specific lysosomal enzyme deficiencies: all LSDs are characterized by progressive accumulation of heterogeneous biologic materials in the lysosomes of various parts of the body such as viscera, skeleton, skin, heart, and central nervous system. At least a fraction of LSDs has been associated with mixed abnormalities involving the immune system, while some patients with LSDs may result more prone to autoimmune phenomena. A large production of proinflammatory cytokines has been observed in Gaucher and Fabry diseases, and wide different autoantibody production has been also reported in both. Many immune-mediated reactions are crucial to the pathogenesis of different inflammatory signs in mucopolysaccharidoses, and subverted heparan sulphate catabolism might dysregulate cellular homeostasis in the brain of these patients. Furthermore, an inappropriate activation of microglia is implicated in the neurodegenerative foci of Niemann-Pick disease, in which abnormal signalling pathways are activated by impaired sphingolipid metabolism. In addition, not the simple impaired catabolism of gangliosides per se, but also the production of anti-ganglioside autoantibodies contributes to the neurological disease of gangliosidoses. Even if the exact relationship between the modification of lysosomal activities and modulation of the immune system remains obscure, there is emerging evidence of different impaired immunity responses in a variety of LSDs: in this review we investigate and summarize the immune abnormalities and/or clinical data about immune system irregularities which have been described in a subset of LSDs.