Title
Protective and therapeutic role for αB-crystallin in autoimmune demyelination
Author
Ousman, S.S.
Tomooka, B.H.
van Noort, J.M.
Wawrousek, E.F.
O'Conner, K.
Hafler, D.A.
Sobel, R.A.
Robinson, W.H.
Steinman, L.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
αB-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue. This crystallin has anti-apoptotic and neuroprotective functions. CRYAB is the major target of CD4+ T-cell immunity to the myelin sheath from multiple sclerosis brain. The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab-/- mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab-/- astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease. ©2007 Nature Publishing Group.
Subject
Biomedical Research
caspase 3
cytokine
gamma interferon
interleukin 12p40
interleukin 17
interleukin 2
recombinant alphab crystallin
recombinant protein
tumor necrosis factor
antibody
brain
gene
immune response
immune system
nervous system disorder
rodent
allergic encephalomyelitis
animal cell
animal experiment
animal model
animal tissue
apoptosis
article
astrocyte
central nervous system
cerebrospinal fluid
controlled study
cytokine release
demyelination
female
gene function
human
immune response
immune system
macrophage
mouse
multiple sclerosis
myelin sheath
nick end labeling
nonhuman
priority journal
T lymphocyte
Th1 cell
wild type
alpha-Crystallin B Chain
Animals
Apoptosis
Astrocytes
Caspase 3
Encephalomyelitis, Autoimmune, Experimental
Humans
Inflammation
Macrophages
MAP Kinase Signaling System
Mice
Multiple Sclerosis
Myelin Sheath
Neuroglia
Neuroprotective Agents
NF-kappa B
T-Lymphocytes, Helper-Inducer
Mus
To reference this document use:
http://resolver.tudelft.nl/uuid:ef5dbbfd-93b9-4cbe-9f15-25e844b050b8
DOI
https://doi.org/10.1038/nature05935
TNO identifier
240092
ISSN
0028-0836
Source
Nature, 448 (7152), 474-479
Document type
article