Autonomic denervation of lymphoid organs leads to epigenetic immune atrophy in a mouse model of Krabbe disease.
Lysosomal beta-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.
Galbiati
Francesca
F
Department of Anatomy, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612-7308, USA.
Basso
Veronica
V
Cantuti
Ludovico
L
Givogri
Maria Irene
MI
Lopez-Rosas
Aurora
A
Perez
Nicolas
N
Vasu
Chenthamarakshan
C
Cao
Hongmei
H
van Breemen
Richard
R
Mondino
Anna
A
Bongarzone
Ernesto R
ER
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001369:Axons / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005698:Galactosylceramidase / Q000172:deficiency / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000473:pathology; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D011609:Psychosine / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D013950:Thymus Gland / Q000294:innervation* / Q000473:pathology
D011609:Psychosine; D005698:Galactosylceramidase