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Protective and therapeutic role for αB-crystallin in autoimmune demyelination

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Author: Ousman, S.S. · Tomooka, B.H. · Noort, J.M. van · Wawrousek, E.F. · O'Conner, K. · Hafler, D.A. · Sobel, R.A. · Robinson, W.H. · Steinman, L.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Nature, 7152, 448, 474-479
Identifier: 240092
doi: doi:10.1038/nature05935
Keywords: 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

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.