最新研究：导致免疫系统胡乱攻击的嫌疑犯！！

文章来源：Science Daily

翻译：觅健社区

转载请注明来源“觅健”社区

日期：2015.7.6

来源：美国天普大学健康系统

摘要：红斑狼疮，多发性硬化症，和1型糖尿病都是免疫系统攻击自身的疾病。但是为什么免疫系统会攻击自身至今都是个未解之谜。如今，研究发现细菌群落作为生物膜，在自身免疫性疾病的系统性红斑狼疮的发展中扮演着重要的角色——一项发现对一些自身免疫性疾病提供了重要的线索。

正文：

红斑狼疮，多发性硬化症，和1型糖尿病都是免疫系统本该攻击外来入侵物质，但却攻击自身的疾病。但是为什么免疫系统会误导攻击对象至今是个谜。

现在，天普大学医学院（TUSM）的研究发现，细菌群落作为生物膜，在自身免疫性疾病的系统性红斑狼疮的发展中扮演着重要的角色——一项发现对一些自身免疫性疾病提供了重要的线索。

一支由天普大学医学院（TUSM）的科研型医学博士Cagla Tükel和临床型医学博士Stefania Gallucci带领的研究小组，研究了内脏中的细菌生物膜是怎样驱使有红斑狼疮倾向的老鼠开始红斑狼疮的。这项成果发表在最新的《免疫》杂志上。Tükel博士是天普大学医学院微生物学与免疫学的助理教授，Gallucci博士是天普大学医学院微生物学与免疫学的副主任兼副教授。这两位都是自身免疫中心的成员。

“本次工作强调了把感染视为引发红斑狼疮的重要性，”Gallucci博士说，“生物膜与免疫系统是如何相互作用的，目前得知甚少，是由于大部分的研究只着眼于生物膜是如何保护细菌的，以及生物膜是如何使细菌耐受如抗生素之类的抗菌剂的，但是几乎没人研究过哪种生物膜对免疫系统有响应。”

生物膜是一种密集的细菌社区，能分泌出蛋白质和其他物质。这些物质组成一种基体，这种基体能保护细菌免受抗菌剂、免疫系统和其它的侵害。生物膜出现在我们的内脏中，置身于细菌群中帮助我们消化。同时，他们可作为牙菌斑而存在，也可出现在尿路感染中。他们也可以出现在静脉插管这样的人造表面上。而红斑狼疮是生物膜蛋白质沉淀，也称为淀粉体。常见的肠道细菌大肠杆菌，常常对伴随着食物中毒的严重的肠胃不适有响应，鼠伤寒沙门氏菌中，由于淀粉体呈现出弯弯曲曲的纤维状，而被称为弯曲。

也有部分的生物膜是细菌分泌的DNA。这个研究小组发现了，当弯曲淀粉体和DNA相遇，它们在生物膜上组成超级稳定的结构。当研究人员试图把DNA从这个稳定的结构中分离出来时，用尽了所有的酶对其作用，甚至用了化学试剂，弯曲淀粉体始终不让DNA从中脱离。弯曲淀粉体-DNA复合体加速了生物膜的创建，研究人员了解到。研究者还发现，正是这种弯曲淀粉体-DNA复合体使得免疫体统出现故障的。

总所周知，感染和红斑狼疮的斑的出现密切相关——红斑狼疮出现斑说明红斑狼疮已经恶化。确实，由于感染而导致的狼疮患者死亡率有20%~55%。接近23%的红斑狼疮患者因为感染出现并发症才住院治疗的。更进一步来说，沙门氏菌对红斑狼疮患者更具侵害性，可能会导致潜在的致命并发症。

这项新的研究表明了，沙门氏菌和大肠杆菌的生物膜中弯曲淀粉体-DNA的复合体不仅引发炎症，还会使得红斑狼疮的抗体变得具有自攻击性。

为了证明免疫响应中生物膜的作用，研究人员想要知道免疫系统的哨兵，树突细胞，是如何形成生物膜的。树突细胞把“卷须状物”送往生物膜，并吃下部分卷须状物来向其他细胞示意。然后，它们产出大量的前炎性细胞活素。这种前炎性细胞活素会刺激免疫系统采取行动。前炎性细胞活素中的1型干扰素，就与红斑狼疮有关。

“当我发现树突细胞在生物膜上表现的如此活跃的时候，我非常兴奋，”Gallucci说道。当树突细胞暴露在弯曲淀粉体-DNA的复合体中时，细胞因子释放的水平，实际上超过了先前已知最猛烈的的响应——脂多糖的响应。

为了测试实验室条件下免疫响应是否足以诱导自身免疫以及红斑狼疮的自攻击性，研究人员用有自身免疫病的小老鼠进行试验。正如许多其他疾病情况一样，红斑狼疮具有遗传倾向，在环境刺激下出现。研究者想知道弯曲淀粉体-DNA的复合体是否会成为那种引发红斑狼疮的环境刺激。他们把易感染的小老鼠注射弯曲淀粉体-DNA的复合体，两周后，研究者发现了会攻击自身的抗体。自身抗体，以双链DNA为目标，是红斑狼疮的一个诊断特点。响应非常迅速。在老鼠身上通常要5个月左右会发展成为自身抗体抗体。

另一组小老鼠没有自发的发展成红斑狼疮，但有自身免疫遗传倾向也会与弯曲淀粉体-DNA的复合体反应，释放自身抗体。第三组则是没有任何自身免疫病倾向的正常小老鼠，在注射两周后，也发展出了自身抗体，但是自身抗体的含量比有红斑狼疮倾向的老鼠的水平要低。

所有的小老鼠都出现了自身抗体，无论弯曲淀粉体-DNA的复合体是来自沙门氏菌还是健康消化系统中的大肠杆菌。实际上，肠道中三分之四的细菌家族都含有弯曲基因：拟杆菌，变形菌门，和厚壁菌门，对易得病的病人提供了患病突破口。“这是如何发生的，我认为，这将会使我们下一个研究方向，”Gallucci博士说道。研究小组已经在时刻关注着小老鼠们，什么可以阻止肠道中的弯曲淀粉体-DNA的复合体的形成。更为深入的是，研究小组正在和风湿病学家，Roberto Caricchio博士，狼疮诊所的主任，寻求合作，来研究是否病患们会出现弯曲淀粉体-DNA的复合体。

“下一步是探索这种复合体刺激自身免疫的机理，”Tükel博士说道，“肠道中的益菌在通过肠屏障时会出现问题，他们会出现在不该出现的地方。因此，除了感染菌，肠漏症也会引发许多问题。我们现在渐渐明白我们肠道中的细菌是如何触发复合体，导致人类患病，比如红斑狼疮。因此，了解细菌群落和它们与免疫系统的相互作用至关重要。”

这项研究可能可以对有淀粉体参与的疾病提供线索，Tükel说。比如，大脑中的淀粉样蛋白斑是阿尔茨海默病的信号。2型糖尿病和帕金森氏病也有特性的淀粉体。“现在，我们只能推测，”她说，“一些报告显示出抗生素治疗可能可以改变阿尔茨海默病的进程。抗生素，在一些场合，能减缓智力下降，这表示，细菌感染或一种细菌成分可能会助长其发展成为疾病。这可能是个关联，但眼下，这些都只是猜测。”

了解生物膜是如何诱发自身免疫，最终影响病患的治疗方案，Gallucci博士说道，“所以，了解生物膜如何影响斑的形成可能会引发一场医疗变革。现在，都是用免疫抑制药物。也许你想做些别的什么，像是对潜在感染的治疗。”

参考文献：

1.Paul M. Gallo, Glenn J. Rapsinski, R. Paul Wilson, Gertrude O. Oppong, Uma Sriram, Mark Goulian, Bettina Buttaro, Roberto Caricchio, Stefania Gallucci, Cagla Tükel. Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity. Immunity, 2015; 42 (6): 1171 DOI: 10.1016/j.immuni.2015.06.002

原文：

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Bacterial biofilms may play a role in lupus, research finds

Date:

July 6, 2015

Source:

Temple University Health System

Summary:

Lupus, multiple sclerosis, and type-1 diabetes are among more than a score of diseases in which the immune system attacks the body. But why the immune system begins its misdirected assault has remained a mystery. Now, researchers have shown that bacterial communities known as biofilm play a role in the development of the autoimmune disease systemic lupus erythematosus -- a discovery that may provide important clues about several autoimmune ailments.

 

FULL STORY:

 

Lupus, multiple sclerosis, and type-1 diabetes are among more than a score of diseases in which the immune system attacks the body it was designed to defend. But just why the immune system begins its misdirected assault has remained a mystery.

 

Now, researchers at Temple University School of Medicine (TUSM) have shown that bacterial communities known as biofilm play a role in the development of the autoimmune disease systemic lupus erythematosus -- a discovery that may provide important clues about several autoimmune ailments.

 

A team led by TUSM researchers Çagla Tükel, PhD, and Stefania Gallucci, MD, show how bacterial biofilms found in the gut can provoke the onset of lupus in lupus-prone mice. The research is published in the current issue of the journal Immunity. Dr. Tükel is an Assistant Professor of Microbiology and Immunology at TUSM, and Dr. Gallucci is Associate Chair, Microbiology and Immunology, as well as an Associate Professor in Microbiology and Immunology at TUSM. Both are members of the Temple Autoimmunity Center.

 

"This work stresses the importance of considering infections as a possible trigger for lupus," Dr. Gallucci said. "Very little was known about how biofilms interact with the immune system because most of the research has been looking at how biofilms protect bacteria, how they make bacteria resistant to antimicrobials such as antibiotics, but almost nothing was known about what biofilms do to the immune response," she said.

 

Biofilm is a densely packed bacterial community that excretes proteins and other substances. Those substances form a matrix that protects the bacteria from antimicrobials, the immune system, and other stressors. Biofilms can occur in our guts, among the bacteria that help us digest. They exist as dental plaque, or arise in urinary tract infections. They also can find a home on human-made surfaces such as intravenous catheters. Central to the lupus story is a biofilm protein deposit called an amyloid. In the common gut bacteria E. coli, as well as the bacteria often responsible for severe gastrointestinal distress that accompanies food poisoning, Salmonella Typhimurium, amyloids are called curli because of their curly fiber-like appearance.

 

Also part of the biofilm is DNA excreted by bacteria. The Temple team discovered that when curli amyloids and DNA meet, they form remarkably durable bonds in the biofilm. When the researchers attempted to separate the DNA from these bonds using a variety of enzymes as well as chemicals, the curli wouldn't let go. Curli-DNA complexes speed up the creation of the biofilm, the researchers learned. And the Temple researchers found it is also in this composite of curli-plus-DNA that autoimmune trouble appears to arise.

 

It's long been known that infection is associated with lupus flares -- a flare in lupus is when symptoms worsen. Indeed, infections play a role in between 20 percent and 55 percent of lupus patient mortality. Up to 23 percent of hospitalizations in lupus patients are due to infectious disease complications. Further, the bacteria Salmonella are more aggressive in lupus patients, with the ability to create potentially lethal complications.

 

The new research shows that the complexes formed from curli amyloid and DNA in the biofilms of both Salmonella and E. coli give rise to not only inflammation, but the self-attacking antibodies of lupus.

 

To demonstrate the role of biofilms in immune response, the researchers wanted to see how the sentinels of the immune system, called dendritic cells, reacted to a biofilm. The dendritic cells sent "tendrils" into the biofilm and ate up part of it to signal other molecules. Further, they produced large amounts of chemicals called proinflammatory cytokines. These cytokines are important in inciting the immune system to act. Among the cytokines was Type-1 interferon, known to be associated with lupus.

 

"I was super excited when I saw how activated the dendritic cells were on the biofilm " Dr. Gallucci said. The levels of cytokines released when dendritic cells were exposed to curli-DNA complexes actually exceeded the most robust response known previously -- the response to lipopolysaccharide (LPS).

 

To test if the immune response seen in the laboratory would be enough to induce autoimmunity and the attack on self that occurs in lupus, the researchers used mice that are prone to develop autoimmune disease. As is the case with many diseases, lupus is the result of a genetic propensity that lies dormant in the absence of an environmental trigger. The researchers wanted to see if the curli-DNA complexes could provide that trigger. They injected susceptible mice with the amyloid-DNA composites or a placebo. Within two weeks, the researchers found the kind of antibodies that attack "self," known as autoantibodies. The autoantibodies, which target double-stranded DNA, are a diagnostic hallmark of lupus. The response was remarkably fast. It normally takes mice four to five months to develop autoantibodies.

 

Another strain of mice that do not develop lupus spontaneously but are genetically predisposed to autoimmunity also reacted to the curli-DNA composites with rapid production of autoantibodies. A third strain of mice with no propensity for any autoimmune disease, developed autoantibodies within two weeks of injection, but at lower levels than in the mice with a propensity toward lupus.

 

All mice developed the autoantibodies whether the curli-DNA composites came from Salmonella or from the kind of E. coli that's found in a healthy digestive system. In fact, three of the four bacterial families that contain curli genes are found in the gut: Bacteroidetes, Proteobacteria, and Firmicutes, suggesting a possible source of vulnerability in susceptible patients. "How that happens, I think that will be the next level of our project," Dr. Gallucci said. The research team is already looking at mouse models to see what may lead to the escape of curli-DNA complexes from the gut. Further, the team is collaborating with rheumatologist Dr. Roberto Caricchio, Director of the Temple Lupus Clinic, to see if the patients show signs of exposure to the curli-DNA complexes.

 

"The next step is to explore the mechanism of how these composites are stimulating autoimmunity," Dr. Tükel said. "The beneficial bacteria found in our guts can cause problems when they cross the intestinal barrier and reach to places they shouldn't be. Thus, besides infectious bacteria, a leaky gut could cause many problems. We are now starting to understand how the bacteria in our gut may trigger complex human diseases including lupus. So it's critical for us to understand the biology of the bacterial communities and their interactions with the immune system."

 

The research may offer clues to diseases involving amyloids, Dr. Tükel said. For instance, amyloid plaques in the brain are a signature of Alzheimer's disease. Type-2 diabetes and Parkinson's disease also feature amyloids. "Right now, we can only speculate," she said. "Some reports suggested that antibiotic treatment may be changing the course of Alzheimer's disease. Antibiotics are thought, in some cases, to slow the mental decline suggesting that bacterial infections, or a bacterial component, may be contributing to the disease. That could be a link, but for the moment, it's only speculation."

 

Understanding how biofilms trigger autoimmunity may ultimately lead to changes in patient treatment, Dr. Gallucci said. "So understanding how the biofilms affect flares could lead to a different treatment approach. Now, they give immune suppressive drugs. Maybe you want to do something else, like treat the underlying infection."

 

Journal Reference:

1.Paul M. Gallo, Glenn J. Rapsinski, R. Paul Wilson, Gertrude O. Oppong, Uma Sriram, Mark Goulian, Bettina Buttaro, Roberto Caricchio, Stefania Gallucci, Çagla Tükel. Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity. Immunity, 2015; 42 (6): 1171 DOI: 10.1016/j.immuni.2015.06.002