Autoimmune Disease, MS, 
and the Immune System

David: Why did nature allow us to have autoimmune disease? It doesn't make sense at one level, but bad news for all of us: Nature doesn't care about any of us individually. Nature cares about the species.

Brent: Welcome to the Life Lab by Death Clock. I'm your host, Brent Franson. The mission of Death Clock is to help 100 million people live ten years longer. Today, we speak with Doctor David Hafler about multiple sclerosis and autoimmune diseases. Doctor Hafler has spent the last 17 years at Yale, and prior to that he spent 28 years at Harvard.

Brent: He started studying the origins of multiple sclerosis when he was a freshman undergrad at Emory, and he is credited as being one of the first scientists to prove MS is an autoimmune disease, and has been a major part in what we might call a cure for that disease. It's not fully a cure, but if you catch it early enough, we now—

Brent: thanks in no small part to his work, have a way of preventing the onset of the symptoms. He's a wonderful guest. I hope you enjoy.

Brent: Doctor David Hafler, welcome to the show.

David: Thank you. Thank you for having me, Brent.

Brent: So today we are going to talk about the immune system. But before we do that, can you give us a sense of your day job and your background?

David: Well, I spent 28 years at Harvard. I did my immunology training there and was recruited to chair the neurology department at Yale some 17 years ago. A year ago, after those 16 years, I moved back to just working in the laboratory. So my background is: I'm a clinical neurologist with a strong interest in inflammation in the brain, and I am a human immunologist who has made a lot of fundamental discoveries in the field of human immunology.

Brent: And can you speak to those quickly? Can you talk about your relationship to MS and how MS affects the human body?

David: Well, I began studying MS as a freshman in college at Emory College in 1970. You can figure out my age from there! Back then, T cells had just been discovered. If a patient came in with a diagnosis, my mentors and I would write a prescription for a wheelchair and say, "See you back in a few years." Now we basically have a good working model for what causes MS, and some very recent data is extremely exciting.

David: We have incredibly effective treatments for the early disease, which basically is 98% effective in stopping the autoimmune component of the disease.

Brent: And how do you start studying something like MS as an undergrad freshman at Emory?

David: I knew as a child I wanted to do immunology. Something about little white blood cells running around the body chewing up things fascinated me. People ask, "Well, what did your parents do?" My father was a carpet layer and an immigrant, but I was just born with a love of science. I still have a picture in my office of a micrograph I did of my blood when I was in fourth grade, where I made a smear with a pin and took a picture of it.

David: So I just liked studying the immune system, and I had a mentor at Emory who had an interest in it. How could you not be interested in the brain? So I put the two together to begin studying the disease, and 50 years later, here I am.

Brent: Can you quickly explain how it works? Someone would be genetically predisposed to MS, and then there is a reaction of the immune system that's based on environmental or behavioral factors that activates it? Can you talk about what is happening in MS?

David: I'll tell you what causes MS, if you're ready. A lot of this hasn't been published yet, but it's on bioRxiv for anyone who's interested. There's a very strong link between MS and the Epstein-Barr virus (EBV). We've known that for a long time. There was a very important paper by Alberto Ascherio showing in 10 million Army recruits that MS was almost always preceded by EBV infection, averaging about seven years from time of infection.

David: But the question was: 95% of the population has EBV infection, so why does almost 100% of MS patients have EBV, and how does it cause the disease? In animal models of MS, which are important models, you take myelin proteins and an adjuvant that revs up the immune system against self-protein, myelin.

David: With this adjuvant, you get a pathological picture that looks a lot like MS. It's obviously not MS, but something breaks tolerance so immune cells react to the brain. The study we did asked: what leads to EBV persistence in the blood? Are there genes that prevent EBV from being cleared? We looked at the UK Biobank and All of Us databases.

David: That covers millions of people who have been sequenced. When you sequence DNA, you can find Epstein-Barr virus DNA in about 15% of the population. It's very hard to do, but an incredibly talented postdoc figured out how to find this Epstein-Barr virus DNA.

David: We asked what genes are associated with not being able to clear Epstein-Barr virus. He brought this list of genes into my office, and I nearly fell off my chair. One of the main things I've worked on is identifying genes that cause MS. We've identified about 233 variants of common genes that define the risk of MS.

David: As I said earlier, it's a genetic disease. I looked at the list of genes and thought, "Oh my God, these are the MS genes!" What's happening is that you have genes that do not allow you to clear Epstein-Barr virus, which acts as the adjuvant triggering the autoimmune phase of the disease. And that phase is incredibly well-treated with B-cell depletion.

Brent: Okay, so genetic predisposition plus exposure to or contracting this virus that activates those genes—is it the combination of those two that brings on MS? How do you contract EBV, or how do you avoid it?

David: Basically 95% of the population has had EBV infection. It's usually very benign. One of my children came into the bedroom when he was about five years old and asked, "Mommy, what's this golf ball doing in my neck?" After my heart attack, we went to Boston Children's, and it was his EBV conversion—totally asymptomatic.

David: If you get EBV as a child, it's asymptomatic; it's not like measles or chickenpox where you get sick. But if you get it as a young adult, it's called mononucleosis, and you do get sick. Getting it as a child is not a risk for MS, but getting EBV as a young adult post-puberty becomes a risk for MS.

David: The immune system changes with aging, and so that becomes the risk factor.

Brent: 15% of people have this genetic predisposition where their immune system isn't good at clearing EBV. Most people get EBV at some point. As a child, it's fairly innocuous, but as a young adult, it causes mono, which is less innocuous symptomatically.

Brent: Is there a risk of getting MS if I do not have the genetic predisposition, but I do have EBV, or do I have to have both?

David: Have to have both.

Brent: How do I prevent getting EBV if I have this genetic predisposition? Let me back up and ask: is it possible to know whether or not you have this genetic predisposition?

David: We could test for it. The paper hasn't been published yet, but it was just sent out for review. Should we do genetic testing? Can we predict who's at risk? Well, if you have the genes, you have the risk of EBV persistence—they are the same.

Brent: Is it a simple blood test for either?

David: It's a genetic screen called a genome-wide association study, sequencing DNA to look at your genes. So it's a simple blood test or saliva test—you can extract DNA from saliva.

Brent: It seems like there's been a lot of progress in treating MS. Can you speak to that?

David: "Cure" is a funny word. Let me step back about words we use in science. I'm giving a Grand Rounds talk next week titled "The Cause of Multiple Sclerosis," and I'll start with the disclosure that you can never truly know the cause, because you don't know what you don't know.

David: Science is not about absolute truth. If you want absolute truth, look to mathematics or religion. We create models, and as we gather more data and do more experiments, we refine those models. The EBV story was just an idea initially, but with new data, we refine the model.

David: So we create models, and "cure" is a very strong word. We never really cure genetic diseases like MS, but we can be highly effective. B-cell depletion in particular is 98% effective in stopping the autoimmune phase of early MS, where activated T cells turn on B cells to attack the brain.

David: I can stop that almost all the time. In fact, these drugs are so effective that if a patient continues to flare while on B-cell depletion, I start looking for other diseases that mimic MS. That's the early phase. But a certain percentage of patients progress to a neurodegenerative phase.

David: We call early MS relapsing-remitting, but on treatment patients don't have relapses anymore. In the degenerative phase, we're not as good at treatment yet, though new experimental therapies soon to be approved help somewhat. When you perform single-cell analyses in the brain during neurodegeneration, it looks a lot like Alzheimer's or macular degeneration—the pathways look similar.

David: So the key is preventing the disease as starting early early treatment.

Brent: That sounds typical of how we think about cures for viral issues. I've gotten cold sores my whole life; if I take Valtrex early when I feel a tingle, or take it daily, I won't get a sore.

Brent: If I take it after the cold sore forms, it won't reverse the lesion. Is that a similar analogy?

David: Yes. Like any human disease—whether Alzheimer's, Parkinson's, or cancer—the earlier you treat, the better the outcome. Full stop.

Brent: Let's talk about what an autoimmune issue is. We all have immune systems, but in some cases, the defensive system turns against us and causes harm.

Brent: Is that what's happening in MS? The system tries to combat EBV, but lacking the right tools, the immune response ends up causing harm? Or am I thinking about that incorrectly?

David: That's pretty close. Epstein-Barr virus in MS—and likely lupus and rheumatoid arthritis—activates the immune system. Why does nature allow autoimmune disease? It doesn't make sense on one level, but nature doesn't care about us individually.

David: Nature cares about the species and generates diversity. A famous immunologist here at Yale used to say "G.O.D. stands for Generator of Diversity." In Darwinian terms, nature creates incredible diversity in a species so that if a new virus comes along and wipes out part of the population, the species survives.

David: The MS genes are good genes—they fight off infection and cancer. But too much of a good thing becomes a bad thing. If you are the 1 in 500 who inherited an accumulation of genes that are hyper-effective, it's the price paid for the species to survive.

David: About half of the genes that cause MS also cause rheumatoid arthritis or systemic lupus, so they cluster together, though each autoimmune disease is distinct.

Brent: Can treatments for MS be applied to other chronic issues arising after infections, like Chronic Fatigue Syndrome or Long COVID? We don't know why they happen or how to treat them effectively.

Brent: In a sub-10% portion of people, an infection leaves lasting chronic issues. Will what we learn from MS apply to other post-viral conditions?

David: That's a wonderful question we think about a lot. Fatigue is a major symptom of MS. 30 years ago at Harvard, there was funding to examine Chronic Fatigue Syndrome, and the NIH wanted a neurologist to examine the cohort.

David: I examined them and found that a number of enrolled patients actually had undiagnosed MS, because fatigue is such a prominent feature. A big challenge with Chronic Fatigue Syndrome and Long COVID is that we lack a specific biomarker. I know how to definitively identify someone with MS,

David: but Long COVID and Chronic Fatigue Syndrome—while very real post-viral syndromes—are hard to study without clear diagnostic markers. Akiko Iwasaki here at Yale is doing spectacular work profiling immune responses in Long COVID and Chronic Fatigue Syndrome patients.

David: We discuss this often, and while studying autoimmune diseases provides insights, the truth is we haven't gotten that far yet for those syndromes.

Brent: So we have clearer diagnostic frameworks for MS than for Chronic Fatigue Syndrome or Long COVID?

David: Yes. Committees meet regularly to update guidelines. We diagnose MS using MRI—ultimately it's a pathological diagnosis. MS is not just a loose syndrome; it's a distinct disease. We can even diagnose MS before clinical symptoms appear.

David: If an MRI looks classic for MS, we perform a spinal tap before starting treatment—not just to confirm the diagnosis, but to rule out mimicking diseases that require different treatments, like sarcoidosis or lupus. Combined with MRI, we are very good at diagnosing MS.

Brent: If someone is genetically predisposed to MS, how should they think about prevention? You can't easily avoid EBV, but could preventive medications be taken, similar to daily Valtrex for cold sores?

Brent: What does prevention look like for that 15%?

David: Vaccines are being developed and trialed, and we are talking with several companies. The study I'd love to run (and anyone interested in funding it is welcome to reach out!) has interest from both NIH and pharmaceutical companies.

David: We would take a group of post-pubertal, EBV-negative young girls—who have higher MS incidence—who have a parent with MS. We'd vaccinate half and track them for mononucleosis and subsequent onset of MS, given that mono carries a sevenfold increased MS risk.

David: That would be the ultimate study proving EBV's role. An interesting question remains: if you aren't at risk for MS, is an EBV vaccine necessarily beneficial? The immune system co-evolved with EBV infection across human history.

David: There may be benefits to natural EBV exposure for the general population. My priority is clinical trials focused on those at high risk for autoimmune disease.

Brent: Let's broaden the discussion to overall immune health. Can you describe the basic function of the immune system?

David: Where is most of the immune system located? In the gut—around 90%. Nature faced a trade-off: we must eat to get nutrition, but digesting food requires hosting bacteria like E. coli inside our GI tract. If those bacteria escape into the bloodstream, you die from sepsis.

David: So the immune system stands guard there. Beyond processing food and the microbiome, we recently discovered that T cells travel from the gut to the brain during development in mice.

David: We confirmed this in humans by analyzing spinal fluid from healthy controls. T cells sensing the gut microbiome migrate to parts of the brain involved in development. The immune system carries critical signaling information across the body.

David: It senses salt concentrations throughout the body and relays information back to the brain. It's a complex, multifaceted system.

Brent: Is immune effectiveness influenced by general health? Think of the immune system as an internal army whose fighting conditions depend on the "weather." Stress, poor diet, alcohol, or lack of sleep create harsh weather—like snow—making it harder for the army to fight.

Brent: When we eat well and sleep enough, conditions are sunnier and the immune army fights better. Is that analogy accurate?

Brent: Do basics like sleep, diet, and exercise directly impact how effectively our immune system fights off viruses and disease?

David: To be clear, I strongly advocate daily exercise, eating healthy unprocessed foods, and prioritizing sleep. As we age, eating well, avoiding fast food, and getting sufficient sleep are crucial for healthy aging.

David: How directly that impacts specific cellular immune functions is harder to measure experimentally. It makes sense, but what in the diet specifically drives systemic inflammation? Is it alcohol or high sugar? Not necessarily. What we demonstrated directly induces inflammation is dietary salt.

David: Salt is a major inducer of inflammation. In early human evolution in West Africa, average daily salt intake was around 800 mg.

David: The average Western diet contains about five grams of salt per day. We published in Nature that eating fast food more than twice a week was strongly correlated with elevated inflammatory blood markers and microbiome shifts.

David: Fast food contains fats and high salt. When we added salt directly to immune cell cultures, the cells became dramatically inflammatory.

David: When we fed animals a high-salt diet, inflammatory cells rose significantly, and disease in MS animal models worsened. Looking at MS patient tissue, we see higher tissue salt content.

David: High salt intake is a major environmental factor driving inflammation, contributing to both autoimmune and cardiovascular diseases, and we have worked out the cellular mechanisms involved.

David: Processed foods carry very high salt concentrations, making them a primary driver of dietary inflammation.

Brent: Can you speak to the relationship between immune function and inflammation? I assume you measure inflammation via C-reactive protein or similar markers?

David: We measure directly at the cellular level: isolating T cells from blood to test whether they are producing inflammatory cytokines. C-reactive protein is a useful serum marker for cardiac risk, but we directly evaluate immune cell activity.

Brent: Are an inflammatory response and an immune response essentially the same thing?

David: When we isolate immune cells and test them, an inflamed state indicates an active inflammatory immune response.

David: So the answer is yes.

Brent: You seem cautious about declaring that sleep, diet, or exercise directly alter immune function outside of salt reduction. But aren't there studies linking sleep deprivation to increased susceptibility to colds or flu?

Brent: And if that is, if that's not what you're saying, you'll correct it. But if it is what you're saying. I was under the impression there were studies related to limited sleep and then likelihood of getting the flu, or likelihood of getting a cold. That showed fairly definitively that there that there was a relationship between sleep. And I mean, what you would assume is the body's defense against those things, the immune system.

Brent: Is that not supported, or do you view those studies differently?

David: Epidemiological studies suggest correlation, though demonstrating direct causation is harder. To evaluate immune function precisely, you must measure cellular activity directly. Still, sleep, diet, and exercise are vital for overall health.

David: In science we build models rather than prove absolute facts. Strong evidence shows exercise reduces dementia and cardiovascular risk, so prioritizing sleep, healthy food, and exercise is essential.

David: How much of that directly translates to immunological parameters as immunologists define them is nuanced, but the health benefits are undeniable. I exercise daily, eat well, and aim for seven to eight hours of sleep every night.

David: Good hour, seven eight hours of sleep. So I'm a firm believer in doing all that.

Brent: I ask because while sleep, diet, and exercise matter generally, how should someone manage immune health specifically if they want to avoid reactivating viruses like EBV or cold sores during stressful periods?

Brent: Is "immune health" distinct from general health, or are they inseparable?

Brent: Or you say, no, just manage your health broadly and you know those things are going to be better. And the connection between immune health and those things, it's just for reasons we've talked about, you know, just just now or it's hard to draw an exact connection between those two.

David: As an immunologist, I find "immune health" too vague. Commercial products market "immune boosting," but the immune system consists of distinct arms (Th1, Th2, Th17), each with different triggers. It isn't a single knob you turn up or down.

David: I am skeptical of products claiming to "boost immune health." Many lack rigorous scientific validation or FDA approval, and some unregulated supplements could even be harmful.

David: It's too broad a term for me that people know more about it. I do, I'm just a country doctor who studies miss, but there are, I'm sure. But I think I'd be very cautious of these things that promote immune health because I, you know, I just don't know what it is. And I suspect a lot of it, none of it's FDA approved, none of it.

David: It goes on the gone vigorous testing and some of the things may be dangerous that promote so-called immune health.

Brent: Is this wellness marketing surrounding "immune health" problematic, similar to other medical misinformation?

Brent: And so do you think that that misconception is problematic as it can be in other areas of, I don't know, medical misinformation?

David: Most supplements are harmless, though unproven. When MS patients ask about alternative diets, I advise avoiding processed foods and high salt. So long as patients stick to proven medical treatments that stop MS progression 98% of the time, I'm comfortable if they try safe alternative practices.

David: You know you know be careful of your diet and salt probably isn't good for you and such. And a lot of patients try all so-called alternative reproaches. And my feeling is as long as you do, the treatment I know basically stops at these 98% of the time, that's fine. Don't do things that will hurt you. I'm happy to look at what you're doing, make sure there's no poison, what it is.

David: If a patient feels a complementary habit helps them mentally or physically, and it isn't dangerous, I won't discourage it.

Brent: Stick to what works medically, and any additional placebo benefit is extra.

David: Exactly. If it helps you, it isn't my place to strip away something harmless that brings benefit.

Brent: In oncology, studies show certain supplements can interfere with chemotherapy and increase mortality, whereas in neurology some complementary practices may be neutral. Having spent decades leading immunological research, how has this understanding changed how you live personally?

Brent: And so it does seem to be domain specific in terms of the concern of the clinician with those alternative modalities. So so what has changed for you. You've studied the immune system, you know, for 40 years, 28 at Harvard, 17 at Yale. You're you're, you know, you're you're you're a leader in your field. How has your understanding of the immune system changed the way that you live your life, or change the way that you manage the health of your if your kids if you have any?

Brent: I would assume vaccines are high on the list. But what has it changed? If you're like, yeah, sleep and exercise are good for other reasons.

David: I have granddaughters now, which is even better! A major risk factor for autoimmune disease is obesity. I focus on eating a healthy, unprocessed diet rather than taking supplements, because obesity promotes gut inflammation and metabolic strain.

David: Preventing obesity through healthy eating is vital for disease prevention. As for vaccines—don't get me started! Vaccination is one of the greatest public health achievements in history.

David: I was born in 1952 and remember polio vividly.

Brent: I'm 44. Yeah.

David: In summers we couldn't swim in public pools due to polio risks. When Jonas Salk released the polio vaccine, parents rushed to vaccinate their children because they saw kids suffering in iron lungs.

I had measles at age six with severe meningitis symptoms. Thankfully I recovered, but these were devastating illnesses.

David: Because vaccines eliminated polio, measles, pertussis, and chickenpox, modern generations haven't seen the devastation caused when communities don't vaccinate. Vaccines are essential to protecting public health.

David: Antibiotics and vaccines are the two greatest healthcare advances of the last millennium, alongside monoclonal antibodies today.

Brent: Losing collective memory of these diseases contributes to confusion today. Tetanus without a vaccine is a terrible way to die, but few people today have ever witnessed it.

Brent: You've never seen it. It's you know, we've solved it.

David: During my residency at Johns Hopkins, I treated a patient with lockjaw from tetanus. It is a horrific disease.

Brent: We shouldn't have to relearn why we eradicated these diseases. What research are you most excited about next in autoimmune disease?

Brent: These diseases are terrible. They're awful. And if we if we bring them back, we're all going to learn really quickly why we got rid of them in the first place. But that's that's a lesson we shouldn't have to learn. And so what are you excited for next? I mean, you know, I think you've previewed some yet to be published, kind of you know, you've previewed some of those findings here, but what are you excited about next in terms of autoimmune disease.

David: We have a paper under review regarding Parkinson's disease. A prodromal stage of Parkinson's is REM sleep behavior disorder. If a bed partner thrashes violently during REM sleep, they should see a sleep specialist.

David: If REM sleep behavior disorder is combined with loss of smell, there is nearly a 100% conversion to Parkinson's within 5 to 10 years. Funded by a $12 million Aligning Science Across Parkinson's grant, we performed spinal taps on 112 subjects.

David: We compared REM sleep behavior disorder patients against healthy controls and MS patients. We found significant inflammatory signals in the spinal fluid of patients with REM sleep behavior disorder.

David: The primary inflammatory cytokine was TNF-alpha. Anti-TNF-alpha therapies are standard treatments for rheumatoid arthritis and inflammatory bowel disease (IBD). Interestingly, IBD carries a 50% increased risk of Parkinson's, but IBD or rheumatoid arthritis patients on anti-TNF treatments have an ~90% lower incidence of Parkinson's.

David: We raised $26 million to launch a randomized clinical trial with anti-TNF-alpha agents to test whether we can prevent Parkinson's onset. We hypothesize Parkinson's may originate as a gut autoimmune response where autoreactive T cells trigger protein aggregation that travels to the brain.

David: Having developed early treatments that halt MS, evaluating Parkinson's prevention is our next major milestone.

Brent: To clarify: REM sleep behavior disorder involves physical thrashing during sleep, serving as an early indicator alongside loss of smell, distinct from general poor sleep?

Brent: And you're now making the connection between this and it sounds like loss of smell and eventual eventually getting Parkinson's. Is it? Or should everybody who doesn't sleep well start worrying? Wait, maybe I have a REM sleep disorder.

David: Yes, it is a specific disorder diagnosed via polysomnography (sleep study). Anyone experiencing persistent sleep issues should get a sleep study to check for conditions like sleep apnea.

David: But this is a very specific syndrome. It's not just not sleeping well okay.

Brent: This specific syndrome serves as an early marker, allowing trials aimed at halting Parkinson's before progression?

David: Exactly.

Brent: Are you shifting your primary research focus toward that work?

David: I mentor a group of talented young and mid-career scientists. As I enter my 70s, my role focuses on mentorship and helping build the next generation of researchers.

David: After a sabbatical at Cambridge, I focused my career phase on developing team members working across Parkinson's, MS/EBV, brain tumors, and gut-brain health.

David: So I have a group or Parkinson's disease or group working on EMS and EBV, a group working on brain tumors. When a clinical trial with a checkpoint inhibitor in glioblastoma is. So we're looking at gut brain health. So my job at this phase of career is to mentor young people. They can write the papers and they can write the grants.

Brent: To wrap up: GLP-1 receptor agonists (Ozempic) have taken center stage. What are your thoughts on GLP-1s and science funding?

Brent: Path two you can go down as you could go down. The commenting on public health policy changes with RFK etc.. So there's two paths you can you can end us on.

David: GLP-1 agonists are remarkable therapies. Regarding scientific infrastructure, funding for early-career scientists is critical. Research output internationally—such as in China—is expanding rapidly as they increase research budgets significantly.

David: We must continue supporting scientific funding and talent in the U.S. to maintain our leadership in medical research.

David: Countries like Germany are investing heavily in neurodegeneration research. We need sustained national investment in science and young researchers.

David: So I just don't get it. We were the premier scientific center on earth. We're delegating that to other countries. I'm on what's called the Senate. It in Germany, looking at their programs in neurodegeneration as an advisor. And they're putting tons of resources into it. And we are just falling behind. And we're not that pricey for what we get.

David: Science shouldn't be politicized. We need to invest in the next generation of scientists.

Brent: Hopefully public focus on foundational health habits can align with rigorous science funding.

Brent: They're very basic messages, but they're not messages we've heard out of the out of the government historically. And then there seems to be this other side around what's happening around vaccine and what's happening, what vaccines and what's happening around killing funding. And so hopefully we can find some path to, you know, keeping keeping the good and obvious changes that seem to be coming.

Brent: The scientific method itself remains objective and nonpartisan.

David: Promoting healthy, unprocessed diets is essential. We must support young scientists so we don't lose key talent.

David: Modern technologies—CRISPR, single-cell RNA sequencing, spatial transcriptomics—are transforming medicine. We are entering a golden age of medical science across GLP-1s, autoimmune therapies, and cancer checkpoint inhibitors.

David: We should build on these scientific breakthroughs to help people live healthy lives.

Brent: Doctor David Hafler, thank you so much for your contributions to research and for your time today.

David: Brent, thank you very much. I really enjoyed chatting with you.

Brent: The Life Lab by Death Clock is recorded in Boulder, Colorado, and San Francisco, California; produced by Patrick Godinho; music by Patrick Lee; and hosted by yours truly, Brent Franson, founder and CEO of Death Clock.