Ousman Shalina S, Tomooka Beren H, van Noort Johannes M, Wawrousek Eric F, O'Connor Kevin C, Hafler David A, Sobel Raymond A, Robinson William H, Steinman Lawrence
Department of Neurology and Neurological Sciences, Stanford University. Stanford, California 94305, USA.
Nature. 2007 Jul 26;448(7152):474-9. doi: 10.1038/nature05935. Epub 2007 Jun 13.
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.
αB-晶状体蛋白（CRYAB）是早期活跃的多发性硬化症病灶中最丰富的基因转录本，而在正常脑组织中则不存在此类转录本。这种晶状体蛋白具有抗凋亡和神经保护功能。CRYAB是来自多发性硬化症脑白质的CD4 + T细胞免疫的主要靶点。本文研究了这种免疫反应的病理生理学意义。我们证明，CRYAB是一种有效的负调节因子，在免疫系统和中枢神经系统（CNS）中对多种炎症途径起制动作用。与野生型对照相比，Cryab-/-小鼠在急性和进展期的实验性自身免疫性脑脊髓炎（EAE）表现更严重，T细胞和巨噬细胞分泌的Th1和Th17细胞因子水平更高，中枢神经系统炎症更强烈。此外，Cryab-/-星形胶质细胞显示出更多的裂解型半胱天冬酶-3和更多的TUNEL染色，表明Cryab具有抗凋亡功能。在多发性硬化症患者的脑脊液和患有EAE的小鼠血清中检测到抗CRYAB抗体。给予重组CRYAB可改善EAE。因此，在多发性硬化症中，针对炎症负调节因子CRYAB的免疫反应会加剧炎症和脱髓鞘。给予CRYAB本身可对抗这种情况以治疗正在进行的疾病。
