Vartanian T, Li Y, Zhao M, Stefansson K
Department of Neurology, Beth Israel Hospital, Boston, Massachusetts, USA.
Mol Med. 1995 Nov;1(7):732-43.
The histopathology of multiple sclerosis (MS) is characterized by a loss of myelin and oligodendrocytes, relative preservation of axons, and a modest inflammatory response. The reasons for this selective oligodendrocyte death and demyelination are unknown.
In light of the T lymphocyte and macrophage infiltrates in MS lesions and the numerous cytokines these cells secrete, the direct influence of cytokines on survival of cultured oligodendrocytes and sensory neurons was investigated. Expression of cytokines in vivo was determined by immunolabeling cryostat sections of snap-frozen tissue containing chronic active lesions from four different patients. The samples were also analyzed for the presence of apoptotic nuclei by in situ labeling of 3'-OH ends of degraded nuclear DNA.
The results showed: (i) interferon-gamma (IFN gamma) to be a potent inducer of apoptosis among oligodendrocytes in vitro and that this effect can be reversed by leukemia inhibitory factor (LIF); (ii) IFN gamma has a minimal effect on the survival of cultured neurons; (iii) IFN gamma at the margins of active MS plaques but not in unaffected white matter; (iv) evidence for apoptosis of oligodendrocytes at the advancing margins of chronic active MS plaques.
Injury to a substantial number of oligodendrocytes in MS is the results of programmed cell death rather than necrotic cell death mechanisms. We postulate that IFN gamma plays a role in the pathogenesis of MS by activating apoptosis in oligodendrocytes.
多发性硬化症（MS）的组织病理学特征为髓鞘和少突胶质细胞缺失、轴突相对保留以及适度的炎症反应。这种选择性少突胶质细胞死亡和脱髓鞘的原因尚不清楚。
鉴于MS病灶中有T淋巴细胞和巨噬细胞浸润以及这些细胞分泌的多种细胞因子，研究了细胞因子对培养的少突胶质细胞和感觉神经元存活的直接影响。通过对来自四名不同患者的含有慢性活动性病灶的速冻组织的低温恒温器切片进行免疫标记，确定体内细胞因子的表达。还通过对降解的核DNA的3'-OH末端进行原位标记，分析样品中凋亡细胞核的存在情况。
结果显示：（i）γ干扰素（IFNγ）在体外是少突胶质细胞凋亡的有效诱导剂，这种作用可被白血病抑制因子（LIF）逆转；（ii）IFNγ对培养的神经元存活影响极小；（iii）IFNγ存在于活动性MS斑块边缘而非未受影响的白质中；（iv）在慢性活动性MS斑块进展边缘存在少突胶质细胞凋亡的证据。
MS中大量少突胶质细胞的损伤是程序性细胞死亡而非坏死性细胞死亡机制的结果。我们推测IFNγ通过激活少突胶质细胞凋亡在MS发病机制中起作用。
