ReviewOverview of immune abnormalities in lysosomal storage disorders
Section snippets
Introduction: the lysosomal storage disorders
Lysosomal storage disorders (LSDs) are a group of rare genetic syndromes resulting from abnormal build-up of undegraded materials which accumulate in the lysosomes of different cells of the human body, as a result of total or partial functional loss of specific lysosomal enzymes or co-factors implicated in the degradation of those materials [1]: more specifically the upstream precursors accumulate, and LSD clinical presentation reflects the amount of residual enzymatic activity, ranging from
An evolving pathophysiology among autoimmune, autoinflammatory and autophagy responses
The molecular clarification of LSDs has provided a better understanding of their pathogenesis and treatment opportunities, but also shown that many inflammatory manifestations might derive by autoimmunity and also self-produced inflammation. The connection between LSDs and autoimmune processes is not clear, though we know that autoimmune diseases encompass a wide spectrum of clinical signs as a reflection of their complex pathophysiology starting in the loss of self-tolerance and involving
The proinflammatory scenery of Gaucher disease
Gaucher disease is the most prevalent LSD and is caused by two disease-causing alleles in the GBA1 gene, leading to decreased activity of the lysosomal enzyme β-glucocerebrosidase, which leads to the accumulation of its substrate, glucosylceramide, in macrophages [21]. The consequence of this deficiency is attributed to the accumulation of glucosylceramides in the monocyte/macrophage lineage, inducing their transformation into Gaucher cells, enlarged cells with eccentric nuclei and cytoplasm
Immune abnormalities in Fabry disease
Fabry disease (OMIM 301500) is an X-linked disorder in which mutations of the GLA gene cause the deficiency of the lysosomal enzyme α-galactosidase A, with progressive multi-site build-up of the neutral glycosphingolipid globotriaosylceramide (Gb3), and is the second most common among all LSDs [33]. The phenotype associated with Fabry disease may vary depending on factors like genotype, gender, or still yet unknown genetic modifiers, and includes early stroke, cardiomyopathy, end-stage renal
Upregulation of immunity-related genes in mucopolysaccharidosis
Mucopolysaccharidoses (MPS) are caused by progressive storage of undegraded glycosaminoglycans, also named mucopolysaccharides, large linear unbranched polysaccharides consisting of repeated disaccharide units, which contain amino sugars and uronic acids. There are five identified mucopolysaccharides: dermatan sulphate, heparan sulphate, keratan sulphate, chondroitin sulphate, and hyaluronic acid, major components of the extracellular matrix, where they bind and retain water molecules and fill
Inappropriate microglial activation in Niemann-Pick disease
Sphingolipids are ubiquitous membrane molecules present in every cell, but mostly represented in the central nervous system: their metabolism is a complex network of interdependent events, which are tightly connected with the intracellular traffic of these lipids. Disorders deriving from dysfunction in sphingolipid metabolism are associated with abnormal lipid distribution in brain cells and progressive neurodegeneration, caused by the deficient activity of the enzyme acid sphingomyelinase,
Anti-ganglioside autoantibodies in gangliosidosis
Gangliosidoses are progressive neurodegenerative diseases caused by lysosomal enzyme deficiencies and subsequent lysosomal accumulation of undegraded gangliosides in the neurons: these ubiquitous molecules are expressed in all vertebrates and are characterized by sialic acid-containing glycolipids, formed by the ceramide, which is the hydrophobic portion, and oligosaccharide chains, which are the remaining hydrophilic counterpart [67]. These complex lipids are mostly localized within plasma
Conclusive remarks
LSDs affect people of whatever age, displaying a progressively inexorable course from childhood and throughout adulthood. Before introducing enzyme replacement therapy, treatment for these diseases was essentially palliative and aimed at alleviating specific symptoms, without targeting the underlying pathological condition, and the only therapies that could potentially alter the natural course of LSDs were hematopoietic stem cell transplantation in Gaucher disease and renal transplantation in
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