Banki K, Colombo E, Sia F, Halladay D, Mattson D H, Tatum A H, Massa P T, Phillips P E, Perl A
Department of Pathology, State University of New York College of Medicine, Syracuse 13210.
J Exp Med. 1994 Nov 1;180(5):1649-63. doi: 10.1084/jem.180.5.1649.
Although the etiology of multiple sclerosis (MS) is unknown, there is compelling evidence that its pathogenesis is mediated through the immune system. Molecular mimicry, i.e., crossreactivity between self-antigens and viral proteins, has been implicated in the initiation of autoimmunity and MS. Based on homology to human T cell lymphotropic virus type I (HTLV-I) a novel human retrotransposon was cloned and found to constitute an integral part of the coding sequence of the human transaldolase gene (TAL-H). TAL-H is a key enzyme of the nonoxidative pentose phosphate pathway (PPP) providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid biosynthesis. Another fundamental function of the PPP is to maintain glutathione at a reduced state and, consequently, to protect sulfhydryl groups and cellular integrity from oxygen radicals. Immunohistochemical analyses of human brain sections and primary murine brain cell cultures demonstrated that TAL is expressed selectively in oligodendrocytes at high levels, possibly linked to production of large amounts of lipids as a major component of myelin, and to the protection of the vast network of myelin sheaths from oxygen radicals. High-affinity autoantibodies to recombinant TAL-H were detected in serum (25/87) and cerebrospinal fluid (15/20) of patients with MS. By contrast, TAL-H antibodies were absent in 145 normal individuals and patients with other autoimmune and neurological diseases. In addition, recombinant TAL-H stimulated proliferation and caused aggregate formation of peripheral blood lymphocytes from patients with MS. Remarkable amino acid sequence homologies were noted between TAL-H and core proteins of human retroviruses. Presence of crossreactive antigenic epitopes between recombinant TAL-H and HTLV-I/human immunodeficiency virus type 1 (HIV-1) gas proteins was demonstrated by Western blot analysis. The results suggest that molecular mimicry between viral core proteins and TAL-H may play a role in breaking immunological tolerance and leading to a selective destruction of oligodendrocytes in MS.
尽管多发性硬化症（MS）的病因尚不清楚，但有确凿证据表明其发病机制是由免疫系统介导的。分子模拟，即自身抗原与病毒蛋白之间的交叉反应，被认为与自身免疫和MS的起始有关。基于与人类I型嗜T细胞病毒（HTLV-I）的同源性，克隆了一种新型人类逆转录转座子，并发现它构成了人类转醛醇酶基因（TAL-H）编码序列的一个组成部分。TAL-H是非氧化戊糖磷酸途径（PPP）的关键酶，为核酸合成提供5-磷酸核糖，为脂质生物合成提供NADPH。PPP的另一个基本功能是将谷胱甘肽维持在还原状态，从而保护巯基和细胞完整性免受氧自由基的侵害。对人脑切片和原代小鼠脑细胞培养物的免疫组织化学分析表明，TAL在少突胶质细胞中高水平选择性表达，这可能与作为髓磷脂主要成分的大量脂质的产生有关，也与保护庞大的髓鞘网络免受氧自由基的侵害有关。在MS患者的血清（25/87）和脑脊液（15/20）中检测到针对重组TAL-H的高亲和力自身抗体。相比之下，145名正常个体以及患有其他自身免疫性和神经疾病的患者中不存在TAL-H抗体。此外，重组TAL-H刺激了MS患者外周血淋巴细胞的增殖并导致聚集形成。在TAL-H与人逆转录病毒的核心蛋白之间发现了显著的氨基酸序列同源性。通过蛋白质印迹分析证明了重组TAL-H与HTLV-I/人类免疫缺陷病毒1型（HIV-1）糖蛋白之间存在交叉反应性抗原表位。结果表明，病毒核心蛋白与TAL-H之间的分子模拟可能在打破免疫耐受并导致MS中少突胶质细胞的选择性破坏中起作用。
