世界多发性硬化症（MS）日recognizes themillionsof people worldwide who are affected by this neuroimmunological disease. The campaignsite对于世界女士，2022年就引起了乐观的和弦，将日期视为“庆祝全球团结和对未来的希望”的机会。今年，有更多的理由能够获得以前的乐观情绪。

Recognizing the immune basis of MS

Adrian Liston, a group leader at the Babraham Institute, based near Cambridge, UK, is well-placed to explain that sunny outlook. He first studied MS as part of an undergraduate project. Over the two decades since, Liston has continued to research in the MS field, watching science’s understanding of the disease deepen.

“I think the most profound change has been the recognition that MS is an immune-mediated disease,” says Liston. The symptoms of MS are neurological – patients experience a range of sensory and motor conditions, including fatigue, numbness, spasms and weakness and loss of control over muscle movement or function. While MS has long been thought to include an immune component – Jean Martin Charcot, the French doctor who firstdescribed该疾病注意到患者脊髓中存在免疫细胞 - 仅是最近完全理解了该疾病的免疫调解。现在已经认识到，神经系统症状是免疫细胞渗透大脑并攻击允许正常神经细胞传导的髓鞘涂层的结果。

Part of that understanding came from the galloping pace of genetics research. The neurological symptoms of MS are in contrast with its genetic signature, explains Liston. From a geneticist’s point of view, “MS looks a lot like Type 1 diabetes, or any of these other autoimmune diseases, and the same genes are controlling it,” he says.

这些遗传见解被添加到迅速增长的临床前研究中。Experimental autoimmune encephalomyelitis (EAE)is an inflammatory autoimmune disease seen in animals that mimics the disease course of MS. This model proved essential for the development of drugs for MS. Liston explains that these drugs came in two waves. The first was heralded by the approval of interferon beta-1b in 1993, thefirst drugcapable of altering the course of MS. The interferons, whichreducethe number of immune cells crossing the blood-brain barrier, showed success at improving MS symptoms. This provided direct evidence that adopting an immune-targeting approach could help patients.

A new generation of drugs

对于某些人来说，这些早期药物已被证明是有益的，并且在几年后仍是他们的主要治疗过程。然而，女士的药物开发继续完善了免疫系统的靶向。Liston说：“我们现在真正拥有的是第二波药物产生，在那里我们具有更复杂的免疫调节分子，我们确实可以针对造成损害的细胞的非常具体的途径。”这些新药（有23 FDA-approvedmediations for MS as of 2022) work better and for longer.

Liston says that an MS patient today can expect fewer symptoms and far longer periods of good health than in the past. 85% of MS patients have arelapsing-remitting formof the disease, which sees symptoms wax and wane. While 20 years ago MS may have induced multiple relapses each year, with potentially permanent loss of function a risk each time, today a patient that responds well to the latest treatments can expect to go five or even ten years without any further relapses, says Liston: “It gives them a life well beyond diagnosis, which wasn't the case 20 years ago.”

The focus of these treatments is to minimize the damage of any immune attack on the brain. Can we also restore function lost during these attacks? Research in this area is progressing, if at a much slower rate. Datapresentedin 2020 showed that a compound, bexarotene (full disclosure: I’ve published research on this drugmyself显示）可以恢复疾病过程中一些髓磷脂损失。药物的副作用和有限的临床影响意味着贝克索烯是不是taken forward to approval. The challenges of restoring the damaged brain aresignificant,but this research shows that, in principle, healing the brain’s myelin might one day be possible.

A vaccine to prevent MS?

同时，其他findingshave pointed a way to intercept MS earlier, stopping the disease in its tracks before it can ever cause damage to the brain.

It all begins with a virus.

Epstein-Barr virus (EBV), a type of herpesvirus, has long been联系with MS – studies had不是ed先前患有传染性单核细胞增多症（IM）后，MS收缩的风险更高，这是由EBV引起的疾病 - 但很难识别“吸烟枪”。

这是因为多达95％的成年人口具有EBV，这是一种非常成功的病毒，在感染宿主后，可能会休眠多年。因此，设计正确的研究以测试获得EBV是否会在以后增加您的MS风险是一个巨大的后勤挑战。但是，一月份，哈佛医学院的研究人员应对这一挑战。该小组使用纵向方法收集了美国军事人员的血清样本，他们必须在服役每两年开始时提交血清样本。

With samples from 10 million different people stored, the study was easily able to identify individuals who didn’t have EBV during their first sample, as well as those who developed MS during the course of their service. The study showed that, of 35 individuals who tested negative for EBV on enrolling, all but one of them went on to become infected with EBV before developing MS.

This corresponds to a 32-fold increased risk of developing MS. To put this in perspective, the strongest genetic risk factor for MS – which involves having a set of particular immune genes – confers a three-fold risk. This association is so strong, that the study, in Liston’s opinion, “finished the argument” on whether EBV plays a causal role in MS. The underlying理论is that, in some individuals, the body responds to the presence of the virus by mistakenly attacking the brain’s myelin sheath, triggering MS’s symptoms.

“Incredibly profound” implications

The finding and its implications, says Liston, are “incredibly profound”: “I'd say the best analogy is of human papilloma virus (HPV) and cervical cancer. Cervical cancer and some anal cancers as well are largely caused by infections with the virus, HPV. Now that knowledge wasvery有争议的很长一段时间。”

The evidence linking HPV and cervical cancer is now solid, Liston says: “Most people who have the virus never get the cancer. But what that allows us to do is then go and develop vaccines for HPV. By preventing the infection, you essentially prevent the cancer formation.”

If a similar approach could be taken with EBV – vaccinating every child against the virus before they are infected – future generations could essentially be protected from ever acquiring MS. That’s a hugely exciting prospect. There is much more research to be done, however, before that reality is met. Liston points out that EBV “is not a trivial virus to attack” – it tends to hidewithinpatients’ B cells and is happy to remain concealed there for a patient’s lifetime. Much more work will need to be conducted on how to target EBV and on the steps between infection and symptoms of MS.

The future of MS research

For now, says Liston, anyone interested in following the progress of the MS field should pay special attention to studies that improve the personalization of existing treatments. “We really want to be able to match up which medication is going to work on which person. In the case of MS, that is probably the single most important thing,” he explains. Currently, patients can endure multiple relapses while testing out which treatment works best for them. Work into matching patients with certain backgrounds and disease progressions with an appropriate drug could be hugely significant, says Liston.

他提到的另一个激动人心的进步是创建更好的目标药物。尽管第二代MS药物取得了进步，Liston说，就特异性而言，它们本质上是免疫大爆炸器。

“In someone with MS, only 0.1% of their white blood cells are dangerous,” he says. But current treatments hit that 0.1% alongside a vast swathe of the rest of the immune system, which can have extreme side effects. New generations of drugs, Liston explains, will be better targeted at immune culprits. One field,antigen-specific tolerance工作，希望通过混淆的免疫细胞来抑制不正确的反应，恢复免疫系统的平衡，而不会损害其保护身体免受外部威胁的重要作用。

是时候对现在感到兴奋了

Is Liston hopefully about the future of MS research? “It’s not even just the future,” he responds, “I’m actually quite positive about the present of MS compared to where we were 20 years ago.”

The promise that drugs targeting the immune system could help MS patients has been well met. “We're not talking about cold fusion, where they've been promising boundless energy in 10 years’ time, and promising that for 40 years, we’re talking about a place where the promises have been delivered over and over,” says Liston. He believes that patients are going to continue to have longer, healthier lives as drugs improve and become smarter and more targeted.

The only note of caution Liston sounds is in managing our expectations: “We're not going to have these type of ‘Eureka!’ moments where there's one tablet that just cures MS, but we will be coming closer and closer to a place where there will be a treatment regime that works on almost every patient and is almost perfect.”

Those advances will partly come from innovative use of the latest techniques – Liston’s lab recently published工作基因治疗用于编辑大脑中的一小部分细胞。编辑导致这些细胞在周围的大脑区域产生促生存的分子。转弯有助于增加大脑中调节性T细胞（TREG）的数量（TREG）（TREG）的数量 - 能够抑制受损的免疫反应的细胞。在动物模型中，较长的Treg不仅能够改善MS样症状，还可以促进脑损伤的更快愈合。

Neurological disease can so often seem intractable, beset by the complications of the brain and our still juvenile understanding of how the biological wonders in our heads function and fail. But on World MS Day 2022, there is plenty good news, at least in one small corner of brain medicine. “This is a very hopeful time for patients,” Liston concludes.