来自Dana-Farber癌症研究机构的研究人员解答了人类生理学上最为古老的问题，人体的免疫系统为什么只攻击外来微生物，却对小肠中寄居的庞大的微生物群视而不见？
根据这篇发表于2月号Nature Immunology的报告中，Shannon Turley领导的研究小组发现淋巴结细胞指导免疫细胞不去理会健康的组织。这项发现对于自体免疫疾病如第一型糖尿病、多发性硬化症的治疗提供新的思路。
免疫系统判断健康组织和外来物质的依据很简单，就是经由识别细胞表面一种称为抗原的细胞表面蛋白。多年来，科学家们一直困惑不解的是，与细菌或其它微生物频繁接触的组织，是否也有着同样的策略。在小肠中存在着一些帮助消化的细菌，如此规模庞大的细菌足以引发一次强烈的免疫系统反应，但是究竟是什么机制，让T细胞总是对小肠视而不见，使得这个重要器官免受攻击。
在这篇新的研究中，研究人员发现，树突细胞并非唯一教导T细胞忍受小肠组织的唯一细胞。除了树突细胞之外，附近淋巴结中的基质细胞也会传播这种耐受信号。尽管淋巴结细胞并不如树突细胞般，是专职的抗原递呈细胞，但淋巴结基质细胞也行使着同样的职责，将正常细胞的抗原呈现给免疫系统。
英文原文：
Why doesn't the immune system attack the small intestine?
Shannon Turley, PhD
Answering one of the oldest questions in human physiology, researchers at Dana-Farber Cancer Institute have discovered why the body's immune system — perpetually on guard against foreign microbes like bacteria — doesn't attack tissues in the small intestine that harbor millions of bacteria cells.
In a study in the February issue of Nature Immunology, and which is currently available on the journal's Web site as an advanced online publication, investigators led by Shannon Turley, PhD, of Dana-Farber identify an unlikely group of peacemakers: lymph node cells that instruct key immune system cells to leave healthy tissue alone. The finding, which illuminates a previously unknown corner of the human immune system, may lead to new forms of treatment for autoimmune diseases such as Type 1 diabetes and multiple sclerosis.
"We've discovered that cells not generally thought of as part of the immune system actually play an important role in protecting the intestine from immune system attack," says Turley. "Because the cells are found in lymph nodes throughout the body, they may offer a way of suppressing a variety of autoimmune diseases," which result from immune system assault on healthy tissue.
The immune system distinguishes between normal and foreign agents by small proteins, called antigens, on the cell surface. In parts of the body, such as the pancreas, that are sheltered from the outside environment, cells known as dendritic cells display the antigens of their normal neighbors in a way that puts the immune system "at ease." By reading those antigens without being on alert, the immune system's T cells learn that such cells are off-limits to attack.
For years, scientists have wondered whether the same mechanism is at work in tissues that come in regular contact with bacteria and other microbial organisms. The small intestine, for example, which absorbs essential nutrients from food and drink and protects the body from invasive microbes, is literally teeming with bacteria, which help break down waste. The presence of so many bacteria is a potential trigger for an immune system response. Why do T cells almost always ignore the small intestine, leaving this vital tissue unharmed?
"It's obvious that T cells must be able to ignore — or become 'tolerized' to — normal intestinal tissue," states Turley, who is also an assistant professor of pathology at Harvard Medical School. "But it has been unclear how dendritic cells, which are extremely sensitive to microbial agents such as bacteria, teach T cells to resist attacking healthy intestinal cells."
In the new study, Turley and her colleagues found that, in fact, dendritic cells aren't essential in creating tolerance in T cells. Instead, and unexpectedly, tolerance is produced by "stromal" cells from nearby lymph nodes. Although they aren't classified as "professional antigen-presenters," as dendritic cells are, the stromal cells serve the same purpose: exhibiting normal-cell antigens to the immune system.
"Our study points to a previously unknown mechanism of immune system tolerance," Turley explains. "When you think of the conditions in the small intestine, with so many millions of bacteria cells and so much opportunity for dendritic cells to stimulate an immune attack, it's remarkable that intestinal tissue is so rarely the target of an immune attack. Our findings demonstrate that the immune system has features that remain to be discovered."
The study was funded by the Claudia Adams Barr Program for Innovative Cancer Research at Dana-Farber, the National Institute of Diabetes and Digestive Kidney Diseases, and the Institut de la Recherche Agronomique.
The lead author of the study is Je-Wook Lee, PhD, of Dana-Farber. Co-authors are Mathieu Epardaud, PhD, Jing Sun, MD, PhD, Jessica Becker, Alexander Cheng, and Ai-ris Yonekura, of Dana-Farber, and Joan Heath, PhD, of the Ludwig Institute for Cancer Research, Victoria, Australia.
