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自闭症可能源自胎儿免疫缺陷

An Immune Disorder at the Root of Autism
自闭症可能源自胎儿免疫缺陷

IN recent years, scientists have made extraordinary advances in understanding the causes of autism, now estimated to afflict 1 in 88 children. But remarkably little of this understanding has percolated into popular awareness, which often remains fixated on vaccines.

据估计,在美国每88名儿童中就有一人经受着自闭症的折磨。近年来,科学家们已在自闭症起因的研究上取得了非凡的进步,然而真正能渗入公众意识的新认知却少之又少。人们仍旧把希望寄托于疫苗。

So here’s the short of it: At least a subset of autism — perhaps one-third, and very likely more — looks like a type of inflammatory disease. And it begins in the womb.

简单来说,至少有一部分自闭症(大约三分之一,极有可能更高)看起来像是一种炎症,且发源于母亲的子宫。
 

It starts with what scientists call immune dysregulation. Ideally, your immune system should operate like an enlightened action hero, meting out inflammation precisely, accurately and with deadly force when necessary, but then quickly returning to a Zen-like calm. Doing so requires an optimal balance of pro- and anti-inflammatory muscle.

这要从科学家所谓的免疫失调(immune dysregulation)说起。理想状态下,我们的免疫系统应该像个智勇双全的武打英雄,在必要时精准明确地抗击炎症,发出致命一击;然后迅速回零,静若佛陀。要练就此功,须有绝佳的促炎/抗炎平衡能力。

In autistic individuals, the immune system fails at this balancing act. Inflammatory signals dominate. Anti-inflammatory ones are inadequate. A state of chronic activation prevails. And the more skewed toward inflammation, the more acute the autistic symptoms.

但自闭症患者的免疫系统无法达到此平衡。炎症信号占据主导,抗炎信号则不足,患者长期处于一种慢性免疫活化的状态。平衡越偏向炎症,自闭症越严重。

Nowhere are the consequences of this dysregulation more evident than in the autistic brain. Spidery cells that help maintain neurons — called astroglia and microglia — are enlarged from chronic activation. Pro-inflammatory signaling molecules abound. Genes involved in inflammation are switched on.

再没有什么会比自闭症患者的大脑更能体现免疫失调的后果了:维持神经元的蛛形细胞(星形胶质细胞和小神经胶质细胞)因慢性免疫活化而增大、促炎信号分子充斥大脑、炎症相关基因被启动。

These findings are important for many reasons, but perhaps the most noteworthy is that they provide evidence of an abnormal, continuing biological process. That means that there is finally a therapeutic target for a disorder defined by behavioral criteria like social impairments, difficulty communicating and repetitive behaviors.

这些发现在很多方面都具重大意义,但也许最值得一提的是它们为持续的、异常的生物学过程提供了依据。也就是说,根据行为标准判定的诸如社交障碍、交流困难、重复性行为等行为异常,最终是有一个治疗靶点的。

But how to address it, and where to begin? That question has led scientists to the womb. A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.

那么如何治疗,从哪里下手呢?科学家将答案一路追至子宫。在丹麦,一项历时20年,基本上包含了全国新生儿的调查显示:若母亲在怀孕期间被感染,那么孩子患自闭症的风险会增高。如果在怀孕的前3个月因病毒感染(比如流感)而住院,儿童患自闭症的几率会增至3倍;若在4-6个月时遭到细菌感染(包括尿路感染),则几率增加4成。

The lesson here isn’t necessarily that viruses and bacteria directly damage the fetus. Rather, the mother’s attempt to repel invaders — her inflammatory response — seems at fault. Research by Paul Patterson, an expert in neuroimmunity at Caltech, demonstrates this important principle. Inflaming pregnant mice artificially — without a living infective agent — prompts behavioral problems in the young. In this model, autism results from collateral damage. It’s an unintended consequence of self-defense during pregnancy.

这里,我们并不是要说自闭症是由于病毒和细菌直接侵犯胎儿造成的。相反,胎儿的母亲排斥入侵微生物的行为——炎性反应——似乎才是罪魁祸首。加州理工学院(Caltech)的神经免疫学专家保罗·帕特森(Paul Patterson)证实了此观点。在无实际感染源的情况下,研究者用人工诱导方法使怀孕母鼠产生炎症,结果新生小鼠出现了行为障碍。此模型中,自闭症纯属间接伤害,是怀孕母鼠的自我保护机制不小心造成的。

Yet to blame infections for the autism epidemic is folly. First, in the broadest sense, the epidemiology doesn’t jibe. Leo Kanner first described infantile autism in 1943. Diagnoses have increased tenfold, although a careful assessment suggests that the true increase in incidences is less than half that. But in that same period, viral and bacterial infections have generally declined. By many measures, we’re more infection-free than ever before in human history.

不过,把自闭症流行的原因怪罪到感染的头上仍是不明智的。首先从大的方面来讲,二者的流行史并不一致。利奥·坎纳(Leo Kanner)于1943年首次描述了儿童自闭症。迄今为止被确诊的人数已增至10倍(仔细追究起来,实际上患者增加了不到5倍)。但与此同时,病毒和细菌感染大体呈减少趋势。从许多方面来看,人类都比从前受到的感染少多了。

Better clues to the causes of the autism phenomenon come from parallel “epidemics.” The prevalence of inflammatory diseases in general has increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children — at least double the prevalence of 1980 — and autoimmune disorders, which afflict 1 in 20.

观察与其同期流行的疾病能让我们更好地理解自闭症的诱因。过去60年里,炎症的发病率急剧增加。作为一个大类,炎症包括了哮喘(现在儿童患病率为10%,比1980年时至少翻了1倍)和自身免疫疾病(患病率为5%)。

Both are linked to autism, especially in the mother. One large Danish study, which included nearly 700,000 births over a decade, found that a mother’s rheumatoid arthritis, a degenerative disease of the joints, elevated a child’s risk of autism by 80 percent. Her celiac disease, an inflammatory disease prompted by proteins in wheat and other grains, increased it 350 percent. Genetic studies tell a similar tale. Gene variants associated with autoimmune disease — genes of the immune system — also increase the risk of autism, especially when they occur in the mother.

二者都与自闭症相关,特别是当母亲患有这些疾病时。在丹麦进行的另一项长达十几年,包含了70万名新生儿的研究发现,若孕妇患有类风湿性关节炎(rheumatoid arthritis,一种慢性全身性炎症,表现为关节的退行性病变),儿童患自闭症的风险将增加80%;若患有乳糜泻(celiac disease,由小麦、谷物中的蛋白质诱发的炎症),则风险提高350%。遗传学研究也得出了相同结论:与自身免疫病相关的免疫系统基因变异会增加儿童患自闭症的概率,特别是当变异发生在怀孕母亲的身上时。

In some cases, scientists even see a misguided immune response in action. Mothers of autistic children often have unique antibodies that bind to fetal brain proteins. A few years back, scientists at the MIND Institute, a research center for neurodevelopmental disorders at the University of California, Davis, injected these antibodies into pregnant macaques. (Control animals got antibodies from mothers of typical children.) Animals whose mothers received “autistic” antibodies displayed repetitive behavior. They had trouble socializing with others in the troop. In this model, autism results from an attack on the developing fetus.

在一些案例中,科学家们甚至发现了错误的免疫应答。自闭症患儿的母亲通常有一种独特的抗体结合在胎儿脑部的蛋白质上。前几年,加州大学戴维斯分校(University of California, Davis)神经发育障碍医学研究所(Medical Investigation of Neuro Developmental Disorders)的科学家们将这种抗体注射到怀孕猕猴体内(对照组动物注射的是正常儿童母亲体内的抗体)。获得“自闭症抗体”的猕猴产下的小猴出现了重复性行为,难以适应群体生活。此模型中,自闭症由发育中的胎儿遭受了伤害所致。

But there are still other paths to the disorder. A mother’s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child’s risk of autism.

能够造成行为异常的途径还有很多,比如在怀孕4-6个月期间被诊断出哮喘或过敏的母亲会增加孩子患自闭症的概率。

So does metabolic syndrome, a disorder associated with insulin resistance, obesity and, crucially, low-grade inflammation. The theme here is maternal immune dysregulation. Earlier this year, scientists presented direct evidence of this prenatal imbalance. Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed.

代谢综合征也一样,这是一种与胰岛素抵抗和肥胖相关的代谢紊乱——很重要的是——它亦属于慢性炎症。因此我们这里所说的关键点,就是孕妇的免疫系统失调。今年年初,科学家提供了孕期失衡的直接证据:从丹麦新生儿出生时收集的炎水中可以发现,后来出现自闭症症状的患儿,其出生时的羊水似有轻微炎症。

Debate swirls around the reality of the autism phenomenon, and rightly so. Diagnostic criteria have changed repeatedly, and awareness has increased. How much — if any — of the “autism epidemic” is real, how much artifact?

一直有争论不断围绕着自闭症现象的真实性与正确性。诊断标准一变再变,愈发引起公众的注意:究竟有多少 “流行性自闭症”是真的(如果确有其事的话),又有多少是臆造的?

YET when you consider that, as a whole, diseases of immune dysregulation have increased in the past 60 years — and that these disorders are linked to autism — the question seems a little moot. The better question is: Why are we so prone to inflammatory disorders? What has happened to the modern immune system?

如果我们宏观回望一下:60年来,免疫失调的患病率增加了,且都与自闭症有关。这样一看,上述疑问就显得无意义了。更好的问题其实是:我们为何如此容易出现炎性失调?我们现代化的免疫系统怎么了?

There’s a good evolutionary answer to that query, it turns out. Scientists have repeatedly observed that people living in environments that resemble our evolutionary past, full of microbes and parasites, don’t suffer from inflammatory diseases as frequently as we do.

进化给人们提供了合适的答案。科学家一再观察到,生活在堪比古代——充满了微生物和寄生虫的环境中的人们,很少患炎性疾病。

Generally speaking, autism also follows this pattern. It seems to be less prevalent in the developing world. Usually, epidemiologists fault lack of diagnosis for the apparent absence. A dearth of expertise in the disorder, the argument goes, gives a false impression of scarcity. Yet at least one Western doctor who specializes in autism has explicitly noted that, in a Cambodian population rife with parasites and acute infections, autism was nearly nonexistent.

自闭症大体上也符合此模式:发展中国家的发病率似乎要低一些。然而流行病专家总是认为低发病率是由于没诊断出来造成的。这些地区缺乏行为障碍方面的专家,加上争论不断,因而给人以病例不多的错误印象。但是,至少有一位西方国家的自闭症专家曾明确地告诉我们,在寄生虫和急性感染泛滥的柬埔寨,几乎没人患自闭症。

For autoimmune and allergic diseases linked to autism, meanwhile, the evidence is compelling. In environments that resemble the world of yore, the immune system is much less prone to diseases of dysregulation.

同时,与自闭症相关的自身免疫病和过敏性疾病具有更令人信服的证据。生活环境类似旧时的人们不易出现免疫系统失调的现象。

Generally, the scientists working on autism and inflammation aren’t aware of this — or if they are, they don’t let on. But Kevin Becker, a geneticist at the National Institutes of Health, has pointed out that asthma and autism follow similar epidemiological patterns. They’re both more common in urban areas than rural; firstborns seem to be at greater risk; they disproportionately afflict young boys.

一般来讲,专攻自闭症和炎症的科学家都注意不到这点,或者即使注意到了,也不愿意说。不过美国国家卫生研究所(National Institutes of Health)遗传学专家凯文·贝克尔(Kevin Becker)就提到过哮喘和自闭症有类似的流行病学模式:城市比农村病患多;第一胎生的孩子有更高的风险;小男孩中尤其常见。

In the context of allergic disease, the hygiene hypothesis — that we suffer from microbial deprivation — has long been invoked to explain these patterns. Dr. Becker argues that it should apply to autism as well. (Why the male bias? Male fetuses, it turns out, are more sensitive to Mom’s inflammation than females.)

说到过敏性疾病,卫生假说(hygiene hypothesis,幼年时因接触传染源、共生微生物和寄生物较少而抑制了免疫系统正常发展,增加了患过敏性疾病的可能)一直被用来解释其流行病学模式。贝克尔博士认为,它对于自闭症也同样适用。(为什么男性患者多?因为男胎比女胎对母亲的炎症更为敏感。)

More recently, William Parker at Duke University has chimed in. He’s not, by training, an autism expert. But his work focuses on the immune system and its role in biology and disease, so he’s particularly qualified to point out the following: the immune system we consider normal is actually an evolutionary aberration.

最近,杜克大学(Duke University)的威廉·帕克(William Parker)也参与到自闭症研究中来。尽管他不是专业培训出来的自闭症专家,但他致力于研究免疫系统及其在生物学和疾病方面的作用。因此他特别有资格提出以下观点:我们自认为正常的免疫系统事实上已误入进化的歧途。

Some years back, he began comparing wild sewer rats with clean lab rats. They were, in his words, “completely different organisms.” Wild rats tightly controlled inflammation. Not so the lab rats. Why? The wild rodents were rife with parasites. Parasites are famous for limiting inflammation.

几年前,他开始比较下水道里的野生大鼠和实验室大鼠。用他的话说,它们根本是“完全不同的物种”。野生大鼠可以很好的控制炎症,而实验室大鼠就不行。为什么?因为野生大鼠身上遍布寄生虫,寄生虫能抑制炎症是众所周知的。

Humans also evolved with plenty of parasites. Dr. Parker and many others think that we’re biologically dependent on the immune suppression provided by these hangers-on and that their removal has left us prone to inflammation. “We were willing to put up with hay fever, even some autoimmune disease,” he told me recently. “But autism? That’s it! You’ve got to stop this insanity.”

人类进化也始终有寄生虫的陪伴。帕克博士及很多专家都认为我们赖以存活的免疫抑制要靠这些食客们提供。除掉它们将使人类更易产生炎症。“我们甘愿忍受花粉症甚至一些自身免疫病带来的痛苦,”帕克最近对我说:“但是自闭症?不能再忍了!快停止这种愚蠢行径吧!”

What does stopping the insanity entail? Fix the maternal dysregulation, and you’ve most likely prevented autism. That’s the lesson from rodent experiments. In one, Swiss scientists created a lineage of mice with a genetically reinforced anti-inflammatory signal. Then the scientists inflamed the pregnant mice. The babies emerged fine — no behavioral problems. The take-away: Control inflammation during pregnancy, and it won’t interfere with fetal brain development.

怎么做才能“停止愚蠢行径”呢?解决了孕期失调的问题,你基本上就把自闭症扼杀在摇篮里了。这个结论是从啮齿类动物的实验中得来的。举个例子,瑞士的科学家培养出一种从基因上增强了抗炎信号的小鼠,然后对怀孕母鼠进行炎性刺激。结果,新生小鼠都是健康的,没有任何行为障碍。这里要告诉大家的是:怀孕期间必须控制炎症,而且这不会影响胎儿脑部发育。

For people, a drug that’s safe for use during pregnancy may help. A probiotic, many of which have anti-inflammatory properties, may also be of benefit. Not coincidentally, asthma researchers are arriving at similar conclusions; prevention of the lung disease will begin with the pregnant woman. Dr. Parker has more radical ideas: pre-emptive restoration of “domesticated” parasites in everybody — worms developed solely for the purpose of correcting the wayward, postmodern immune system.

于人类而言,对孕妇安全的药物可以有效控制孕期炎症。很多益生菌都具有抗炎能力,所以可能会对孕妇有益。绝非巧合,哮喘研究者也得出相似结论。今后防范肺部感染将从孕妇做起。帕克博士尚有更彻底的计策:预先在人体内重新注入“家养”寄生虫——专门为纠正我们偏离正轨的后现代免疫系统培养出的小虫子。

Practically speaking, this seems beyond improbable. And yet, a trial is under way at the Montefiore Medical Center and the Albert Einstein College of Medicine testing a medicalized parasite called Trichuris suis in autistic adults.

实际上,这并非不可能的任务,而且已经有实验正在进行中了。蒙蒂菲奥里医学中心(Montefiore Medical Center)和爱因斯坦医学院(Albert Einstein College of Medicine)的研究者正尝试用一种叫做猪鞭虫(Trichuris suis,源自猪的一种鞭虫)的医用寄生虫治疗成年自闭症患者。

First used medically to treat inflammatory bowel disease, the whipworm, which is native to pigs, has anecdotally shown benefit in autistic children.

先前,这种本来用于对付肠道炎症的鞭虫已令人惊喜地在自闭症儿童身上发挥了功效。

And really, if you spend enough time wading through the science, Dr. Parker’s idea — an ecosystem restoration project, essentially — not only fails to seem outrageous, but also seems inevitable.

假如你认认真真花时间研究这方面的科学进展,你会发现帕克博士的想法(简要说来就是生态系统复原计划)不仅不离谱,简直是大势所趋。

Since time immemorial, a very specific community of organisms — microbes, parasites, some viruses — has aggregated to form the human superorganism. Mounds of evidence suggest that our immune system anticipates these inputs and that, when they go missing, the organism comes unhinged.

自开天辟地之初,由微生物、寄生虫和一些细菌构成的特殊生物群落逐渐集合,最终形成人类这个超个体(superorganism)。无数证据证明我们的免疫系统期望这些个体的加入。当它们不在时,超个体就紊乱了。

Future doctors will need to correct the postmodern tendency toward immune dysregulation. Evolution has provided us with a road map: the original accretion pattern of the superorganism. Preventive medicine will need, by strange necessity, to emulate the patterns from deep in our past.

未来的医生一定要修正人类免疫系统愈发失调的后现代趋势。进化早就为我们设计好了路线图:像超个体最初形成那样进行不断添加。虽有些奇怪,但用预防性药物仿效最古老的模式终将是无可避免的了。
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