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Immune system irregularities in lysosomal storage disorders

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Abstract

Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation of disease-specific biological materials such as proteolipids or metabolic intermediates within the lysosome. The lysosomal compartment’s central importance to normal cellular function can be appreciated by examining the various pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies have revealed that several LSDs also have irregularities in the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and α-mannosidosis are examples of a subset of LSD patients that are predisposed towards immune suppression. In contrast, GM2 gangliosidosis, globoid cell leukodystrophy, Niemann-Pick disease type C1 and juvenile neuronal ceroid lipofuscinosis are LSDs that are predisposed towards immune system hyperactivity. Antigen presentation and processing by dedicated antigen presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are among the many crucial immune system functions in which the lysosome plays a central role. Although the relationship between the modification of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is emerging evidence for early neuroimmune responses in a variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment’s role in the immune system with clinical data on immune system irregularities in a subset of LSDs.

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Acknowledgments

This study was supported by in part by National Institutes of Health grants NS044310 and NIEHS Toxicology Training Grant T32 ES07026-27.

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Authors and Affiliations

  1. Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 645, Rochester, NY, 14642, USA

    Julian A. Castaneda & David A. Pearce

  2. Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA

    David A. Pearce

  3. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA

    David A. Pearce

  4. Pediatric Storage Disorders Laboratory, Department of Neuroscience and Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, James Black Centre, 125 Coldharbour Lane, SE5 9NU, London, UK

    Ming J. Lim & Jonathan D. Cooper

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  1. Julian A. Castaneda
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Correspondence to David A. Pearce.

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Castaneda, J.A., Lim, M.J., Cooper, J.D. et al. Immune system irregularities in lysosomal storage disorders. Acta Neuropathol 115, 159–174 (2008). https://doi.org/10.1007/s00401-007-0296-4

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  • DOI: https://doi.org/10.1007/s00401-007-0296-4

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