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The Journal of Neuroscience, December 12, 2007, 27(50):13730-13738; doi:10.1523/JNEUROSCI.3379-07.2007
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Neurobiology of Disease
Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease
Francesca Galbiati,1 Veronica Basso,5 Ludovico Cantuti,1 Maria Irene Givogri,1 Aurora Lopez-Rosas,1 Nicolas Perez,2 Chenthamarakshan Vasu,3 Hongmei Cao,4 Richard van Breemen,4 Anna Mondino,5 andErnesto R. Bongarzone1 Departments of 1Anatomy and Cell Biology, 2Microbiology and Immunology, and 3Surgery, College of Medicine, and 4Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612-7308, and 5Lymphocyte Activation Unit, San Raffaele Scientific Institute, Milan 20132, Italy
Correspondence should be addressed to either of the following: Dr. Anna Mondino, Lymphocyte Activation Unit, Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy, Email: mondino.anna{at}hsr.it; or Dr. Ernesto R. Bongarzone, Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, 808 South Wood Street, M/C 512, Chicago, IL 60612-7308, E-mail: Email: ebongarz{at}uic.edu
Lysosomal β-galactosylceramidase deficiency results in demyelination and inflammation in the nervous system causing the neurological Krabbe disease. In the Twitcher mouse model of this disease, we found that neurological symptoms parallel progressive and severe lymphopenia. Although lymphopoiesis is normal before disease onset, primary and secondary lymphoid organs progressively degenerate afterward. This occurs despite preserved erythropoiesis and leads to severe peripheral lymphopenia caused by reduced numbers of T cell precursors and mature lymphocytes. Hematopoietic cell replacement experiments support the existence of an epigenetic factor in mutant mice reconcilable with a progressive loss of autonomic axons that hampers thymic functionality. We propose that degeneration of autonomic nerves leads to the irreversible thymic atrophy and loss of immune-competence. Our study describes a new aspect of Krabbe disease, placing patients at risk of immune-related pathologies, and identifies a novel target for therapeutic interventions.
Key words: thymus; Krabbe disease; autonomic system; psychosine; T cells; inflammation; hematopoietic stem cells; axonal degeneration
Received July 26, 2007; revised Oct. 22, 2007; accepted Oct. 24, 2007.
Correspondence should be addressed to either of the following: Dr. Anna Mondino, Lymphocyte Activation Unit, Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy, Email: mondino.anna{at}hsr.it; or Dr. Ernesto R. Bongarzone, Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, 808 South Wood Street, M/C 512, Chicago, IL 60612-7308, E-mail: Email: ebongarz{at}uic.edu
This article has been cited by other articles:
A. B. White, M. I. Givogri, A. Lopez-Rosas, H. Cao, R. van Breemen, G. Thinakaran, and E. R. Bongarzone
Psychosine Accumulates in Membrane Microdomains in the Brain of Krabbe Patients, Disrupting the Raft Architecture
J. Neurosci., May 13, 2009; 29(19): 6068 - 6077.
[Abstract] [Full Text] [PDF]
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