?皮膚是我們抵抗感染的第一門戶,。當(dāng)人們感染一種罕見的威脅生命的自身免疫病（稱作尋常型天皰瘡）時候,，由于患者自身免疫系統(tǒng)攻擊控制皮膚細胞聚集的蛋白而導(dǎo)致他們?nèi)笔н@種保護,，最終進展為嚴(yán)重的大水皰和綻開的潰瘍使得其頂層與皮膚剝離，留下暴露的創(chuàng)傷口極容易導(dǎo)致嚴(yán)重的感染,。
??那些能抑止免疫系統(tǒng)藥物的發(fā)現(xiàn)是尋常型天皰瘡和其他自身免疫疾病的患者的福音,，可是這些藥物自身對患者也是致死性的，通常引起嚴(yán)重的副作用?，F(xiàn)在來自查佩爾希爾的北卡羅來納大學(xué)的研究人員已經(jīng)發(fā)現(xiàn)種更安全有效的方法治療尋常型天皰瘡患者,。研究人員在小鼠模型上使用一種化合物，且已經(jīng)明確這種化合物可以關(guān)閉激發(fā)皮膚損傷的信號而不遏制自身的免疫系統(tǒng),。
??該研究結(jié)果發(fā)表在今年8月份第22期《美國科學(xué)院院報》上,。此項目獲得了國立衛(wèi)生機構(gòu)的資助。來自北卡羅萊納大學(xué)醫(yī)學(xué)院皮膚與病理學(xué)系的副教授,，北卡羅萊納大學(xué) Lineberger 癌癥綜合研究中心的成員,，David S. Rubenstein博士認為：“即使我們不能阻止其免疫反應(yīng)，但如果熟知由它所引起損傷背后的機制,，我們就可以阻止這種損傷,。針對在細胞中發(fā)生的特發(fā)事件可以使我們能更安全有效地治療這類病人。”
??Rubenstein先前已經(jīng)發(fā)現(xiàn)P38的酶是導(dǎo)致PV患者自身抗體引起損傷機制的組份,。
??在PV的小鼠模型中,，研究人員通過注射能抑止p38酶的藥物來阻止起泡和發(fā)病的其他信號。試驗顯示抑止p38的藥物不能阻止自身抗體結(jié)合到皮膚細胞,。替代的是它能象發(fā)揮正常功能一樣可以阻止損傷皮膚,。這種藥物終止一系列的細胞信號事件，這些信號導(dǎo)致皮膚細胞間黏附能力的散失,。因此它能終止這種疾病而不影響其自身的免疫系統(tǒng),。
??Rubenstein認為：“現(xiàn)在有很多公司正在開發(fā)用于治療類風(fēng)濕關(guān)節(jié)炎以及銀屑病的p38抑止劑,，根據(jù)我們的研究結(jié)果建議那些藥物可能在治療pv病方面也有價值”。
??在該研究中用到的48只小鼠,，其中24只小鼠被注射高劑量自身抗體來導(dǎo)致類似與人PV的大皰疹,。另一組24只小鼠接受低劑量自身抗體導(dǎo)致不太嚴(yán)重的皰疹。每組一半的小鼠同時也接受p38抑止劑的治療,。
??在兩組接受p38抑止劑處理的小鼠中,，基本上沒有小鼠呈現(xiàn)PV的臨床前兆。例如在高劑量自身抗體處理組中,，其中12只沒有用p38抑止劑處理的有11只小鼠出現(xiàn)皰疹,，而另12只用p38 抑止劑處理的僅有一只出現(xiàn)皰疹。
英文原文：
Scientists stop autoimmune disease without shutting off immune system
Skin is our first line of defense against infection. But people with a rare, life-threatening autoimmune disease called pemphigus vulgaris lack that protection because their immune system attacks the proteins that hold skin cells together. They develop severe blisters and raw sores as the top layer of their skin falls apart, leaving them extremely vulnerable to infection.
The development of drugs that completely suppress the immune system offered a lifeline to patients with pemphigus vulgaris (PV) and other autoimmune disorders, but the drugs themselves can be lethal and often cause serious side effects.
Now, researchers at the University of North Carolina at Chapel Hill have found a safer, more effective way to treat PV patients. In mice, the researchers used a known compound to turn off the signals that trigger skin damage without suppressing the immune system. Similar drugs being developed for human use could offer a potential treatment for PV, the researchers said.
The results appear in the Aug. 22 issue of Proceedings of the National Academy of Sciences. The research was funded the National Institutes of Health.
"Even if we can't block the immune response, if we can understand the mechanisms behind the damage it causes, we can block that damage," said Dr. David S. Rubenstein, associate professor in the department of dermatology in the UNC School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center. "Targeting these specific events in the cell could enable us to more effectively and safely treat patients."
Rubenstein has previously shown an enzyme called p38 is part of the mechanism by which pemphigus vulgaris autoantibodies cause damage. Autoantibodies are immune-system cells that attack the body's own tissues.
In a mouse model of pemphigus vulgaris, the researchers prevented blistering and other signs of the disease by injecting a drug that inhibits the p38 enzyme. Tests showed that the p38 inhibitor drug didn't prevent autoantibodies from binding to the skin cells. Instead, it prevented them from damaging the skin as they normally do. The drug stopped a series of cell-signaling events that lead to the loss of adhesion or "stickiness" between skin cells. Thus, it stops the disease without affecting the immune system.
"There are a number of companies developing inhibitors of the p38 enzyme for treating rheumatoid arthritis and psoriasis," Rubenstein said. "Our study suggests that those same drugs might be valuable in treating pemphigus vulgaris."
Of the 48 mice used in the study, 24 received a high dose of autoantibody which causes gross blistering akin to human PV. The other group of 24 received a lower dose that would cause less severe blistering. Half of each group also received treatment with a p38 inhibitor.
In the two groups that received p38 inhibitor treatment, almost no mice showed clinical signs of pemphigus vulgaris. For instance, in the group that received the high dose of pemphigus vulgaris antibody, 11 out of 12 mice showed blistering, but of the 12 mice that received also received the p38 inhibitor, only one showed blistering.
