生物谷报道：自身免疫系统疾病如多发性硬化症，狼疮和类风湿性关节炎的反复发作长期以来一直是困挠人们心中的谜团。但是，来自斯坦福大学药学院新的发现可以帮助科学家离解决这些问题更进一步，他们鉴别出了控制疾病复发的关键因子。这项研究发表在12.3 日在网上提前公开的自然免疫学杂志上。用来作为决定什么时候疾病会复发的基础，最终为预防疾病的复发提供治疗方法。
目前的这项研究开始于5年前：2001年发表于科学杂志上的一篇论文，Steinman，资深作者，医学博士，神经学教授发现一种叫做骨桥蛋白的蛋白质广泛地存在于多发性硬化症病人的大脑组织中，但是在正常的组织中却没有，从那以后，另一组的研究也证实了在M.S 病人发作的期间与疾病发作之前相比 骨桥蛋白含量增高了。
尽管已经知道这种蛋白在骨生长中扮演着重要的角色。现在还不明白这种蛋白为什么会和多发性硬化症有关，这样的结果会出现在免疫系统攻击保护神经细胞髓鞘的时候。为了探究这个问题，Eun Mi Hur， PhD，当时还是Steinman's实验室毕业生，就开始用小鼠多发性硬化症的模型（experimental autoimmune encephalomyletis or EAE）来研究骨桥蛋白是怎样导致炎症发生的。她和Steinman在已经有过瘫痪症状的小鼠注射骨桥蛋白，这些小鼠的症状和M.S病人症状相似，发现这些小鼠的病症复发了。观察者们还发现复发往往会出现在大脑区域而不是在先前的区域。比如说，但注入骨桥蛋白之后，一些动物先前的麻痹状况会被视神经炎掩盖起来。多发性硬化症的特征是炎症会不在不同的时间影响不同位置的神经系统。
通过小鼠模型的研究和分子鉴定，Hur和Steinman证实了由免疫细胞和大脑产生的骨桥蛋白——加速了T细胞的存活 ，这样便对髓鞘进行攻击， 通过增加 T细胞的数量，骨桥蛋白潜在的破坏性也增加了。这些结果可能适用于许多其它的免疫系统疾病，包括类风湿性关节炎，1型糖尿病和狼疮。
骨桥蛋白是怎样产生的，他们为什么会产生？尽管还不知道这个问题的答案，但是这个发现令人着迷的具有实际意义的地方。骨桥蛋白可以作为疾病复发前的标志。而且，如果这种蛋白能够被阻断，那么就可以预防疾病的再次发生。进一步的研究，将决定是否能阻扰骨桥蛋白的作用，产生一种新的治疗方法来治疗免疫系统疾病。
Figure 1. Opn induces worsening autoimmune relapses and severe progression of autoimmune demyelinating disease.
(a) Clinical scores of EAE induced by immunization of Opn-wild-type mice (Opn-WT; n = 10) and Opn-knockout mice4 (Opn-KO; n = 14) with MOG peptide; half of the Opn-knockout mice (n = 7) were given rOPN daily for 32 d after the initial peak of the clinical disease, initiated during the first remission of each mouse. (b) Clinical scores of female SJL/J mice immunized with the peptide of proteolipid protein and then treated with PBS (n = 9 mice) or with rOPN (n = 9 mice) as described in a. Upward arrows (a,b), first day of rOpn treatment. (c) Clinical scores of MOG-specific TCR–transgenic mice23 given primary immunization with MOG peptide without pertussis toxin and then treated with PBS (n = 6 mice) or with rOPN (n = 6 mice) daily beginning on the day of primary immunization; mice were immunized with MOG peptide plus pertussis toxin 25 d after primary immunization. (d) Hematoxylin-and-eosin staining of optic nerve tissue sections isolated from MOG-specific TCR–transgenic mice with optic neuritis and EAE. Naive, no MOG immunization. Original magnification, 200. (e) TUNEL staining of brain and spinal cord tissue from Opn-knockout and Opn-wild-type mice immunized with MOG peptide to induce EAE, obtained on day 17 after immunization. Arrows indicate TUNEL-positive (brown) nuclei of infiltrating lymphocytes stained with 3,3'-diaminobenzidine. Scale bars, 25 m. Data represent mean clinical score (+ s.e.m.) of three experiments (a–c) and images are of representative tissues from three (d) or two (e) experiments.
原文出处：
Nature Immunology - 8, 74 - 83 (2006)
Published online: 3 December 2006; | doi:10.1038/ni1415
Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells pp74 - 83
Eun Mi Hur, Sawsan Youssef, M Edward Haws, Susan Y Zhang, Raymond A Sobel & Lawrence Steinman
Published online: 03 December 2006 | doi:10.1038/ni1415
Abstract | Full text | PDF (506K) | Supplementary Information
See also: News and Views by Stromnes & Goverman
作者简介：
Lawrence Steinman
Academic Appointments
Professor Neurology & Neurological Sciences
Professor Pediatrics
Professor (By courtesy) Genetics
Professional Education
Degree Awarding Institution Field of Study Year of Graduation
MD Harvard University Neurochemistry 1973
Research Interests
Our laboratory is dedicated to understanding the pathogenesis of autoimmune diseases, particularly multiple sclerosis. We have developed several new therapies for autoimmunity, including some in Phase 2 clinical trials, as well as one approved drug, natalizumab. We have developed microarray technology for detecting autoantibodies to myelin proteins and lipids. We employ a diverse range of molecular and celluar approaches to trying to understand multiple sclerosis.
Publications
· Kanter JL, Narayana S, Ho PP, Catz I, Warren KG, Sobel RA, Steinman L, Robinson WH "Lipid microarrays identify key mediators of autoimmune brain inflammation." Nat Med 2006; 12: 1: 138-143 More
· Dunn SE, Youssef S, Goldstein MJ, Prod'homme T, Weber MS, Zamvil SS, Steinman L "Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin." J Exp Med 2006; 203: 2: 401-12 More
· Langer-Gould A, Steinman L "What went wrong in the natalizumab trials?" Lancet 2006; 367: 9512: 708-10 More
· Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L "Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells." Nat Immunol 2006; More
· Steinman L, "Case history: Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab." Nat Rev Drug Discov 2005; 4: 6: 510-8 More
