Abstract
Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes. This is caused by deficiencies in lysosomal enzymes involved in degradation of these molecules. Dependent on disease, progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure, and in others, to cognitive decline, which is still a challenge for current therapies. The worsening of neuropathology, observed in patients following recovery from flu-like infections, suggests that inflammation is highly implicated in disease progression. This review provides an overview of the pathological features associated with the mucopolysaccharidoses and summarises current knowledge regarding the inflammatory responses observed in the central nervous system and periphery. We propose a model whereby progressive accumulation of glycosaminoglycans elicits an innate immune response, initiated by the Toll-like receptor 4 pathway, but also precipitated by secondary storage components. Its activation induces cells of the immune system to release pro-inflammatory cytokines, such as TNF-α and IL-1, which induce progression through chronic neuroinflammation. While TNF-α is mostly associated with bone and joint disease in mucopolysaccharidoses, increasing evidence implicates IL-1 as a main effector of innate immunity in the central nervous system. The (NOD)-like receptor protein 3 inflammasome is therefore implicated in chronic neuroinflammation and should be investigated further to identify novel anti-inflammatory treatments.
Highlights
Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, 3721 Stopford Building, Oxford Road, Manchester M13 9PT, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, The Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Abstract: Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes
As they were able to detect non-reducing end (NRE) GAGs in plasma and urine of patients, this suggests that these GAG fragments have already been partially degraded to their current state in the lysosome, and trafficked by an unknown mechanism to the plasma and urine, where they have the potential to interact with toll-like receptors (TLR), important for innate immunity
We propose that the progressive accumulation of abnormal GAGs triggers an inflammatory response in MPSs, which is initiated by TLR4 activation (Figure 2)
Summary
The mucopolysaccharidoses (MPSs) are a rare heterogeneous group of lysosomal storage disorders (LSDs) (4.5:100,000 live births) [1] which result from the defective catabolism of mucopolysaccharides, termed glycosaminoglycans (GAGs) [2] This is caused by mutations in the genes encoding the lysosomal enzymes responsible for the degradation of GAGs [3], leading to lysosomal and extracellular accumulation of partly degraded GAG molecules. The MPSs caused by incomplete HS degradation usually result in cognitive decline in patients, including abnormal behaviour and neuro-inflammation [6,7] In this regard, the Royal Manchester Children’s Hospital, as well as other clinicians looking after similar patients, have anecdotally reported a more severe cognitive decline in MPS patients following recovery from a flu-like infection, suggesting the implication of inflammation in disease progression. We have been interested in unveiling the link between the altered GAG catabolism and the inflammatory response, and only are we able to shed further light on the immunological perspective of disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
