生物谷報(bào)道：自身免疫系統(tǒng)疾病如多發(fā)性硬化癥,，狼瘡和類風(fēng)濕性關(guān)節(jié)炎的反復(fù)發(fā)作長(zhǎng)期以來一直是困撓人們心中的謎團(tuán),。但是，來自斯坦福大學(xué)藥學(xué)院新的發(fā)現(xiàn)可以幫助科學(xué)家離解決這些問題更進(jìn)一步,，他們鑒別出了控制疾病復(fù)發(fā)的關(guān)鍵因子,。這項(xiàng)研究發(fā)表在12.3 日在網(wǎng)上提前公開的自然免疫學(xué)雜志上。用來作為決定什么時(shí)候疾病會(huì)復(fù)發(fā)的基礎(chǔ),，最終為預(yù)防疾病的復(fù)發(fā)提供治療方法,。
目前的這項(xiàng)研究開始于5年前：2001年發(fā)表于科學(xué)雜志上的一篇論文，Steinman,，資深作者,，醫(yī)學(xué)博士，神經(jīng)學(xué)教授發(fā)現(xiàn)一種叫做骨橋蛋白的蛋白質(zhì)廣泛地存在于多發(fā)性硬化癥病人的大腦組織中,，但是在正常的組織中卻沒有,，從那以后，另一組的研究也證實(shí)了在M.S 病人發(fā)作的期間與疾病發(fā)作之前相比 骨橋蛋白含量增高了,。
盡管已經(jīng)知道這種蛋白在骨生長(zhǎng)中扮演著重要的角色?，F(xiàn)在還不明白這種蛋白為什么會(huì)和多發(fā)性硬化癥有關(guān)，這樣的結(jié)果會(huì)出現(xiàn)在免疫系統(tǒng)攻擊保護(hù)神經(jīng)細(xì)胞髓鞘的時(shí)候,。為了探究這個(gè)問題,，Eun Mi Hur， PhD,，當(dāng)時(shí)還是Steinman's實(shí)驗(yàn)室畢業(yè)生，就開始用小鼠多發(fā)性硬化癥的模型（experimental autoimmune encephalomyletis or EAE）來研究骨橋蛋白是怎樣導(dǎo)致炎癥發(fā)生的,。她和Steinman在已經(jīng)有過癱瘓癥狀的小鼠注射骨橋蛋白,，這些小鼠的癥狀和M.S病人癥狀相似，發(fā)現(xiàn)這些小鼠的病癥復(fù)發(fā)了。觀察者們還發(fā)現(xiàn)復(fù)發(fā)往往會(huì)出現(xiàn)在大腦區(qū)域而不是在先前的區(qū)域,。比如說,，但注入骨橋蛋白之后，一些動(dòng)物先前的麻痹狀況會(huì)被視神經(jīng)炎掩蓋起來,。多發(fā)性硬化癥的特征是炎癥會(huì)不在不同的時(shí)間影響不同位置的神經(jīng)系統(tǒng),。
通過小鼠模型的研究和分子鑒定，Hur和Steinman證實(shí)了由免疫細(xì)胞和大腦產(chǎn)生的骨橋蛋白——加速了T細(xì)胞的存活 ,，這樣便對(duì)髓鞘進(jìn)行攻擊,， 通過增加 T細(xì)胞的數(shù)量，骨橋蛋白潛在的破壞性也增加了,。這些結(jié)果可能適用于許多其它的免疫系統(tǒng)疾病,，包括類風(fēng)濕性關(guān)節(jié)炎，1型糖尿病和狼瘡,。
骨橋蛋白是怎樣產(chǎn)生的,，他們?yōu)槭裁磿?huì)產(chǎn)生？盡管還不知道這個(gè)問題的答案,，但是這個(gè)發(fā)現(xiàn)令人著迷的具有實(shí)際意義的地方,。骨橋蛋白可以作為疾病復(fù)發(fā)前的標(biāo)志。而且,，如果這種蛋白能夠被阻斷,，那么就可以預(yù)防疾病的再次發(fā)生。進(jìn)一步的研究,，將決定是否能阻擾骨橋蛋白的作用,，產(chǎn)生一種新的治療方法來治療免疫系統(tǒng)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.
原文出處：
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
作者簡(jiǎn)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
