Podcasts 科学播客 | 「戒烟多年也无用？吸烟对免疫系统挥之不去的影响」

Nick Petrić Howe

We all know that smoking is bad for us, but now new research has revealed that it also has long lasting effects on our immune system even years after quitting.

众所周知吸烟对我们有害，但最新研究揭示，即使戒烟多年后，它对我们的免疫系统仍然有着长期影响。

Darragh Duffy

Smoking has a strong impact on the inflammatory response to bacteria, but that's lost as soon as you quit smoking. Whereas the impact on the T cell responses are maintained even many years after you quit smoking.

人体对细菌的炎症反应很大程度上受吸烟的影响，但是一旦你戒烟，这种影响就会消失。相比之下，其对T细胞反应的影响即使在你戒烟多年后仍然存在。

Nick Petrić Howe

This is Darragh Duffy, one of the authors of the new research in Nature. Now, it’s well known that things like sex, age and genetics shape our immunity — the inflammatory and T cell responses that make up our bodies’ defences. But Darragh and the team were interested in the impacts of other things, things we have a bit more control over. Like whether or not we smoke.

这是Darragh Duffy，《Nature》杂志上这项新研究的作者之一。众所周知，性别、年龄和基因等因素会影响我们的免疫力——即构成我们身体防御机制的炎症反应和T细胞反应。但Darragh和他的团队更感兴趣的是一些我们可以控制的因素，比如我们是否吸烟。

Darragh Duffy

So we recruited 1000 healthy donors. Importantly, they're stratified for both sex and age. So half men, half women, and balanced from the ages of 20, up to 70 years old. And then to study immune response variability, we do whole blood stimulations. So we take one ml of blood and a really standardised approach, and put it in these little syringe based stimulation devices called true culture where we've already pre-incubated with different stimuli. So it can be microbes, it can be viruses, bacteria, fungi, it can be components of those microbes that we know activate specific receptors on immune cells. And then we can look at the immune response, the response to those stimuli in many different ways.

我们招募了1000名健康的志愿者。重要的是，对他们按照性别和年龄进行了分层，男女各占一半，年龄从20岁到70岁之间均衡分布。为了研究免疫反应的差异性，我们进行了全血刺激实验。我们取1毫升血液，采用一种非常标准化的方法，将其放入一种基于注射器的小型刺激装置中，称为“True Culture”，其中已经预先与不同的刺激物孵育过。这些刺激物可以是微生物、病毒、细菌、真菌，也可以是我们已知会激活免疫细胞特定受体的微生物成分。接着，我们通过多种方式观察免疫系统对这些刺激物的反应。

Nick Petrić Howe

So by seeing how people’s immune systems responded differently to various challenges, like bacteria, they could then match it up with other things they knew about those people. Like, did they have any existing infections? What was their BMI? Did they smoke? How long have they smoked for? Or how long ago did they quit?

The team actually found three things that were having a big effect on the immune responses. Whether or not the participants had a dormant cytomegalovirus infection, their BMI and, of course, smoking.

They chose to focus on smoking for a couple of reasons.

通过观察人们的免疫系统对不同挑战（如细菌）的反应，他们可以将这些反应与已知的其他因素进行匹配，比如是否有现存的感染？他们的BMI（身体质量指数）是多少？他们是否吸烟？吸烟多久了？或者戒烟多久了？

研究团队发现有三件事对免疫反应有重要影响：是否有潜伏的巨细胞病毒感染、BMI以及吸烟。

他们选择关注吸烟的原因有两个。

Darragh Duffy

One, we were quite struck by how many different associations there were with smoking. The second was the nature of those associations that when we looked a bit closer, they were really interesting. So we saw an effect of active smoking on the innate inflammatory response to bacterial stimulation. But we also saw an effect on the global T cell response. So we saw this dual effect on both the innate and the adaptive response. And then even more intriguing when we broke the smoking effect down into active and past smokers, we saw that the past smokers lost the effect on their inflammatory response, whereas they kept it on the T cell response.

第一，我们对吸烟与免疫反应之间的众多关联感到震惊。第二，当我们进一步研究这些关联时，发现它们非常有趣。我们看到吸烟对细菌刺激的先天炎症反应有影响，同时也对全局T细胞反应有影响。所以我们发现吸烟对先天和适应性反应的双重影响。更有趣的是，当我们将吸烟效应分为活跃的吸烟者和既往吸烟者时，发现既往吸烟者失去了对炎症反应的影响，但对T细胞反应的影响仍然存在。

Nick Petrić Howe

These inflammatory, innate responses, are like your body's first line of defence — they react to any kind of challenge. Whereas the adaptive, T cell response is more specific, responding to particular threats.

Now whilst both could affect how people respond to things like bacteria or viruses, Darragh and the team were intrigued as to why there was this effect on the T cell response even years after someone had quit smoking. Violaine Saint-André is another one of the paper’s authors. She had done her PhD in epigenetics — how certain changes, such as the addition or removal of methyl groups, can control the regulation of genes — so she wondered if this was what was causing the long-lasting effects they saw.

这些炎症性的先天反应类似于身体的第一道防线，它们对任何挑战都会做出反应。而适应性的T细胞反应则更为特异，针对特定的威胁做出反应。尽管两者都会影响人们对细菌或病毒的反应，Darragh和他的团队对为什么即使在戒烟多年后T细胞反应仍受到影响感到好奇。Violaine Saint-André是该论文的另一位作者。她曾在表观遗传学领域攻读博士学位，研究某些变化（如甲基化基团的增加或去除）如何控制基因调控。她猜测这可能是他们观察到的长期影响的原因。

Violaine Saint-André

So we see demethylation at some specific metabolism and signal transistor coding genes, with less methylation in active smokers, past smokers compared to non-smokers. And we see, anti-correlation between the number of years people stopped smoking, the total number of cigarettes they smoke, and anti-correlation between the years since they stopped smoking, so this all goes in the same direction.

我们在一些特定的代谢和信号转导编码基因上观察到去甲基化现象，活跃的吸烟者和过去的吸烟者相比非吸烟者有较少的甲基化。我们看到人们戒烟的年数、他们吸烟的总数之间有反向相关性，戒烟的年数越久，吸烟对甲基化的影响越小，这些现象都指向相同的方向。

Nick Petrić Howe

The fewest methyl groups were found on people who smoked for longer or more recently. And this reduction of methylation affected genes that affected T cell function. In other words, more smoking, more of an effect. Exactly what those effects are is something the team still wants to figure out, but they could hold clues to some diseases that seem to be affected by smoking.

吸烟时间越长或越近的人，体内的甲基化基团越少。这种甲基化减少影响了控制T细胞功能的基因。换句话说，吸烟越多，影响越大。具体影响是什么，研究团队仍在探索，但这些可能为某些与吸烟有关的疾病提供线索。

Darragh Duffy

Smoking has been implicated in many different pathologies, having higher T cell responses is seen in many autoimmune diseases, rheumatoid arthritis associations, in COPD and sarcoidosis, in many different disease settings. So there's still a lot to uncover but this approach is really a kind of tool for discovery that we can identify these associations. And then that gives us a strong piece to go into specific disease studies and test more clear hypotheses.

吸烟与许多不同的病理有关，T细胞反应增强与许多自身免疫性疾病有关，如类风湿性关节炎、慢性阻塞性肺疾病（COPD）和结节病。所以仍有很多待解的内容，但这种研究方法是一种发现工具，可以帮助我们确定这些关联，然后为我们提供有力的线索，以便在具体的疾病研究中验证更明确的假设。

Nick Petrić Howe

In the future, the team will try and better understand these associations between smoking and immunity. But there may be other things out there affecting our immune systems. Air pollution, much like smoking, means that people inhale harmful things, so Darragh and the team are keen to investigate further.

未来，研究团队将进一步研究吸烟与免疫力之间的这些关联。但可能还有其他因素影响我们的免疫系统。空气污染与吸烟类似，意味着人体吸入有害物质，因此Darragh和他的团队也渴望对此进一步研究。

Darragh Duffy

So one of the genes that showed the strongest methylation effects, the AHRR. So, the AHR is the receptor and AHRR is a repressor of that gene. So AHR basically, is involved in metabolising toxins that you ingest. And that's why it's strongly associated with smoking. But there's definitely evidence that it's involved in processing of other toxins that you can be exposed to in the environment. So there's definitely a strong reason to believe that this mechanism could also be implicated in other environmental exposures. The challenge there is they're harder to study. Because, you know, smoking is self reported. And it's relatively easy to quantify by an individual but environmental exposures, we're not even often aware that we're exposed to them.

我们看到甲基化效应最强的基因之一是AHRR。AHR是一个受体，AHRR是这个基因的抑制子。AHR主要参与你摄入的毒素的代谢，因此它与吸烟密切相关。但也有证据表明它参与了处理环境中其他毒素。因此我们有充分理由相信，这种机制可能与其他环境暴露也有关系。研究这些问题的挑战在于它们更难研究。因为吸烟可以通过自我报告容易量化，但我们往往意识不到自己暴露在环境中的有害物质。

Nick Petrić Howe

That was Darragh Duffy, from the Institut Pasteur in Paris. You also heard from Violaine Saint-André, from the same institution. For more on that story, check out the show notes for some links.

这是来自巴黎巴斯德研究所的Darragh Duffy。你还听到了同一机构的Violaine Saint-André的声音。如果你想了解更多信息，请查看节目注释中的链接。