Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination.
alphaB-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.
Ousman
Shalina S
SS
Department of Neurology and Neurological Sciences, Stanford University. Stanford, California 94305, USA.
Tomooka
Beren H
BH
van Noort
Johannes M
JM
Wawrousek
Eric F
EF
O'Connor
Kevin C
KC
Hafler
David A
DA
Sobel
Raymond A
RA
Robinson
William H
WH
Steinman
Lawrence
L
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
D016328:NF-kappa B; D018696:Neuroprotective Agents; D038203:alpha-Crystallin B Chain; D053148:Caspase 3