Elsevier

Immunology Letters

Volume 188, August 2017, Pages 79-85
Immunology Letters

Review
Overview of immune abnormalities in lysosomal storage disorders

https://doi.org/10.1016/j.imlet.2017.07.004Get rights and content

Highlights

  • Lysosomal storage disorders (LSDs) are inherited diseases caused by mutations affecting genes that encode lysosomal enzymes implicated in the degradation of a wide range of structural components of different organs: a host of studies have indicated that several LSDs conceal irregularities in the immune system.

  • Chronic stimulation of different immune pathways is a hallmark of both Gaucher and Fabry disease, while an interplay of metabolic and inflammatory reactions can be shown in mucopolysaccharidoses and Niemann-Pick patients, differently by the clear autoimmune phenomena observed in gangliosidoses.

  • New insights regarding the pathophysiology of LSDs will open new therapeutic strategies for a more personalized treatment of these diseases.

Abstract

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.

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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