Immune Exhaustion Different in Men and Women | Dr Avindra Nath, Visible Podcast #32

Added: 2026-05-22

[00:00:00]Welcome back to Make Visible, and hello Jez. How are you doing? I'm doing okay today. Thank you very much, Emily. Okay, and tell me I tried to talk to you yesterday, and you said you were not doing well.

[00:00:11]>> Yeah. But, you didn't know why, and I pressed you on that. I just wanted to talk to you about that what you've learned over 6 years in terms of listening to your body about the days that you're not feeling great, and whether these things do come out of the blue, whether you can sort of see the patterns. Well, so the funny thing here is that you're trying to measure something that's so difficult to measure and get a sense on it. So, there is, as much as your symptoms are probably, if you are suffering from energy-limiting complex chronic illness, they are probably correlated to how much you try and do, and there will be some symptomatic consequence of that, whether it's 24 or 48 hours later. I've got used now to the pattern that when I have a really busy day, and on my Visible, on my Visible device, my pace points, normally I try and keep them under seven a day. And obviously, it's going to be different depending on what your heart rate zone is set to, but I did well over 30 on Saturday. And so, Sunday, I felt pretty bad, and Monday, I felt really quite bad. And that's my standard pattern is that I have one day directly afterwards that's pretty grim, and then the one after that's the worst. Then on Tuesday, so that's day three afterwards, I thought, "Ah, I've come out the other side of this. It was just a two-dayer.

[00:01:23]That's perfect. That fits the pattern.

[00:01:26]I'm very happy about it." And only then this guy jumped out the bushes with a big wet fish and slapped me around the face on Wednesday and told me, "Ah, not this time." So, what I guess what I'm trying to say is that some of the correlation is due to what you've been doing, and sometimes there's some ebb and flow, cuz the condition is by its nature relapsing and remitting. So, there's a degree of that going on. And then there's a degree of cumulative effect as well. And actually, I've just been doing too much for too many weeks, and I think that's what got me. It was essentially just a a delayed plan from having been pushing it for 3 weeks. So, so there usually are some reasons, but you can't always pin all of them down.

[00:02:02]>> And I think that's it, isn't it?

[00:02:03]Sometimes it can be really frustrating cuz you think, "Okay, I've got this down in terms of what I can manage and when I'm going to take the hit." And when you get the hit out of the blue, when you get that real crash, when you weren't anticipating it, there's something emotionally that's slightly harder because you're prepared sometimes. It's more crushing. It's more crushing. If you know you're going to be slammed, you're like, "Okay, it's fine. I was expecting this." But when it gets you by surprise, yeah, there is something that's emotionally much harder. And personally, I also find that my mood is often lower on those days where I'm crashy, as well. And it's not just because I'm crashy. It genuinely feels like I wake up and I there's just a default level of misery. I'm normally quite a happy person, but it's almost like that happiness has been replaced with some misery that goes along with the crash, which makes the crash even harder to deal with because you don't quite have the emotional tools to handle it as well as you might otherwise.

[00:03:02]Avindra Nath is the clinical director at the NINDS for the NIH in America. And he has done a huge deep phenotyping study into ME/CFS um a year or so ago. And here is just an overview of the entry point of his work.

[00:03:25]Tell me about that deep phenotyping and the results that you found from it. I believe came to understand more of the biological basis of what is driving ME/CFS and the three different areas that it really really impacts. Can you tell me about that, please? So, the um um So, what we can do at NIH is we cannot do very large studies here. You know, we cannot bring in hundreds of patients to study. What we do really well over here is study small sample sizes, but study them in depth.

[00:03:58]So, this study that we designed was such whereby we brought in about 20 patients.

[00:04:03]We Well, we wanted to bring in some more, but the pandemic kind of occurred at the same time, so that paired our ability to do so. But, nonetheless, we brought in uh these patients uh with uh controls, uh healthy controls.

[00:04:18]And we kept them for 2 weeks, 1 week at a time here in the hospital.

[00:04:22]Um and that's the other nice thing we can do at NIH. We can admit patients here at the clinical center, and we can study them.

[00:04:29]Uh otherwise, in an academic institution, it's very hard to do that elsewhere.

[00:04:34]So, um we said uh and then we asked all kinds of experts here at NIH to help us with that. And I'm just really so grateful to about 70-some researchers here at NIH who really contributed their own resources and time and expertise to study everything. They studied >> in the neurology section, or that was cross-disciplinary?

[00:05:01]>> Yeah, yeah, cross-disciplinary. So, you know, the cardiologists looked at the heart. We had the immunologists look at the immune system. We had the electrophysiologists do the electrophysiology, you know, they did muscle biopsies, they did skin biopsies, they did spinal taps, they you know, >> [snorts] >> uh they exercised them, they did brain MRIs, they did transcranial magnetic stimulation, they put them in a metabolic chamber uh for 2 to 3 days. Uh we did sleep studies on them, we monitored their glucose uh uh intake, um oxygen uptake, CO2 production, you know, they controlled their diet so we can look at their microbiome, how they metabolize food, you know, we looked at every single aspect that we possibly could.

[00:05:47]We wanted to go in unbiased. I mean, say, "Let's just look at the entire thing the best that we can."

[00:05:52]And then we did every single omics that you can think of, you know, metabolomics, proteomics, and the uh look at the immune profiling, and transcriptomics, right? So, uh and so we collected a huge amount of data on these patients. And we said, "Okay, now let's put this together. Can we make any sense of it?"

[00:06:12]So, this is probably the largest study I've ever done uh in my career.

[00:06:16]And uh so we found a few things.

[00:06:19]Um uh you know, I cannot be an expert in all these aspects. So, but I'm grateful to all the experts who uh then helped us interpret their aspect of it. And then we tried to put it together and make some sense of it.

[00:06:32]So, at least from my area, there with the way I look at it, uh what we found was that there was evidence of immune activation and persistent immune exhaustion in these patients.

[00:06:43]And those were ME/CFS patients who um had a mean uh average of how long with the illness?

[00:06:51]Yeah.

[00:06:52]So, uh I forget what the mean value was, but they entry criteria required that it should be symptoms should have been at least 6 months >> Right. and not more than 5 years.

[00:07:04]>> Okay. Okay.

[00:07:05]So, >> But even some up to 5 years, you can still see that immune activation in the profiling that you did.

[00:07:11]>> Yes, that's correct. So, they And the other fascinating thing was it was different in men and women.

[00:07:17]Tell me about those differences.

[00:07:18]>> Yeah.

[00:07:19]So, what we found was that um we found more B cell activation in men and T cell activation in women.

[00:07:27]And uh but they're also exhausted cells, both and so they're more naive cells and less of the more differentiated cells in these individuals, suggesting that there was a block.

[00:07:40]And um And just to explain for our audience, what do the B cells and the T cells do?

[00:07:46]Yeah, so the B cells are ones that produce antibodies, okay? And the T cells are ones that directly interact with whatever pathogen it is and go and kill them, okay?

[00:07:58]Now, antibodies can also kill, but they do it on a totally different mechanism.

[00:08:04]So, one of the interesting observations was that if you were to now, because we had a small sample size, if you were to just mix the men and women and then compare with the healthy control men and women, you probably wouldn't find any difference. Right.

[00:08:16]But when you say, "Okay, I'm going to compare men to men and women to women," they just you see there's night and day.

[00:08:21]They just separate out totally, totally.

[00:08:24]Does that suggest that there's a difference in the way that our immune systems operate generally or just when we're under uh that sort of situation?

[00:08:36]>> different? Okay, so here we are looking at a pathological circumstance.

[00:08:40]So, what I can certainly tell you, I'm sure there are differences in men and women anyhow and normally, but that's not an area that I have studied that much, but I'm sure there's abundant literature to show those kinds of subtle differences, but here it's very clear that in response to a pathogen, their response, at least in this situation, is certainly very different.

[00:09:04]Now, are there genetic factors on top of it that are really making these kind of difference? Because ultimately, you know, neither of them are clearing things, right?

[00:09:13]And that's why their immune system is exhausted.

[00:09:16]So, that I think requires some further investigation, but to me what it means is that if you're going to develop treatments and to model it the immune system, you again have to take into consideration that you know, their immune responses are going to be different in different individuals and you got to pre-select them before you treat them, and you can't just helter-skelter or treat everybody with the same drug and expect that you're going to get the same answer.

[00:09:45]Yeah, so one of your recommendations from it was to have tailored immunomodulatory therapies for for um each patient, which is a disease-modifying treatment, essentially. But, what you're saying is that you have to treat everyone differently. In terms of that, how can you How would it be possible to scale out that kind of profiling to be able to establish what treatment is required for which individual? Were there markers it from the study that you did that could give you that indication in patients on a clinical level, perhaps a normal clinical level, rather than when people have access to the NIH? Yeah, so you know, uh with any discovery, initially, it's complex because it starts at a research lab. You, you know, make some observations that only you have made, and um uh so, that's the stage we are at. We can do flow cytometry on these things.

[00:10:46]We can define the patients, but it's not really available to a clinical lab at the moment. But, once we sorted these things out, then it becomes a feasible to develop a test because then we'll narrow it down. We'll say we'll figure out, okay, these are one or two or three markers that are really going to differentiate these individuals. Now, let's make it available on a broader and wider scale. And that's how most tests evolve, right?

[00:11:12]And so, I my hope is that this will follow the same course. So, that gives you a sort of marker or biomarker for potential treatment, does it? Is there something from your study that gives you the idea for what might be an actual biomarker for the condition itself for ME/CFS?

[00:11:32]Uh that's harder, Um, you know, because if you knew what the pathogen was, then it's easier.

[00:11:37]Right? If you can If you have an infection, you got to go after the pathogen. It's just simple as that, right? If I say you have AIDS You have, you know, AIDS, you've got a virus, let's say HIV, right? So, same thing here. The problem here is that often times with ME/CFS, there was a pathogen, we don't know what it is.

[00:11:58]And if it They're bits and pieces of it stuck somewhere in the body. You're not going to find them in the blood, you know, the these Because you don't necessarily >> Yeah, so now you're looking at indirect evidence. And the indirect evidence are the abnormalities in the immune system.

[00:12:11]The problem with the abnormalities in the immune system is they're not going to be specific.

[00:12:15]Um, cuz you can probably see them in other conditions, too.

[00:12:18]So, that will remain a challenge. Um, but it still gets you closer to the answer.

[00:12:25]So, that is various people that I've spoken to have said that long COVID is actually a puts us in a unique position because it enables us to study um, this uh, viral associated consequence when we actually know what the pathogen is, and we can do it on such a um, such a a wide level because we have so many patients with long COVID. So, that in a way makes it easier to study than ME/CFS, would you say?

[00:12:57]>> Yes.

[00:12:58]So, you know, as I told you, we were in the unfortunate situation whereby we were studying ME/CFS, and we had to stop it abruptly because long COVID came around. But it was also a fortunate situation because, in a way, as soon as COVID came, uh, you know, we were became aware here in January of 2020. By March, I already had put out editorial saying that these patients are going to develop something like ME/CFS.

[00:13:25]Really?

[00:13:25]>> Okay.

[00:13:26]And so, I started looking for that possibility and people used to call it then people started calling it call it long haul CSF and you know they were long haul COVID. And so, and so we went after it immediately. How did you know? How did you know that it was going to have a that long-term consequence because you were saying >> Because the respiratory infection, we knew a lot of these respiratory infections yet people were developing these MECFS type things, you know, and we knew for a lot of other viral infections you get these kind of long-term symptoms. So, to me it wasn't that much of a leap in thinking that this could potentially have it too and we need to look out for it. I mean >> [snorts] >> it would be it would be good if it didn't, but if it does occur we better be looking out for it.

[00:14:16]Jess, tell me what you thought were interesting in the findings of that study. Well, first of all, I think having really well as far as they can crystal clear physiological differences found between men and women. Absolutely fascinating.

[00:14:31]>> that was fascinating cuz so far we've been thinking well why do women seem to get the conditions with twice the frequency that men do? What's the difference? Is it hormonal? Is it immune system? And if it is the immune system, well what part of the immune system is it? And I think what we've found here is that we've got a pretty clear idea that it's the difference between the T cell and the B cell function that differentiates men and women. And not just that, I thought the other thing that was particularly interesting about this was that if you were just randomizing selection of people and comparing it you wouldn't have found the differences. It's only when you Separate out that data. When you separate out the data and compare men suffering versus men who were not and the same with women, only then do you start to see the differences. And I think this has huge implications about about the entire medical system.

[00:15:16]>> Everything.

[00:15:17]>> [laughter] >> But it about all of the research that's going to be happening specifically for long COVID and ME/CFS because what else does this mean? If we've got this clear difference in the immune system reaction between men and women, are we going to need to be selecting people accordingly for trials? It raises questions everywhere. Absolutely. And you and I have had this conversation before and we've had this conversation with experts before. The way in which everyone is uh potentially bucketed together when it comes to these studies is possibly causing detrimental impact on the results of the studies because if you group everyone together, you don't get the results. If you break them out into subsets, be that men and women, be that symptom set wise, however you choose to break it down, your data can be completely different and it can have such different implications. As he said, for the potential immunotherapy, the potential targets, the way in which we treat these people, it's completely altered on the basis of the way that the immune system has been impacted. Yeah, I I I think one of the huge challenges here is that we don't have agreement on how to stratify people yet. We don't know how to phenotype people. We don't know in what ways we need to split people up and put which people into what trials. We need to have more of exactly this kind of research so that we can start to phenotype the conditions better and only then can we start to design trials better. It's such a complex puzzle. It really is. And maybe when we finally find the missing piece that ties everything together, we'll get, "Oh, if only we'd done that from the start." But we are still hunting for that missing cog that sort of makes this whole connect four kind of machine start to work and all the bits fall out the bottom. The differences between male and female is absolutely one of it's a it's a subject of huge passion for me because of the way that historically so much of the medical system, it's only men that have been studied. and a lot of the time in terms of drug regimens, in terms of treatment protocols, a lot of the time women are given men's treatments with the dosage altered for the size of a female body. And this kind of science opens up for me how inappropriate that might be. And yeah, I don't want to be too heavy into the breaking down of the patriarchal medical system, but >> Well, for for some for for some conditions, it's obviously absolutely critical. For a broken leg, probably less so, but for something like this where we're starting to get the evidence. And the evidence is actually fairly obvious that we ought to be considering men and women differently when we see that women have twice the frequency of the condition. That tells you something straight up front that something different's going on there physiologically. So, almost raises the question why have we not been separating people for the last 6 years already cuz we knew this 6 years ago.

[00:18:11]>> We did with the with the COVID and also remember that if we look specifically at COVID, this study was about ME/CFS, but if we bring the relevance of COVID into this, remember how different the immediate reaction was in the middle of the pandemic. It was men that were being hospitalized, men that had a higher mortality rate from the acute version of it. It is women that have been impacted in far, far greater numbers in terms of the long term. And that alone shows that the immune systems have mounted a different response to the same virus.

[00:18:50]>> Absolutely. So, I mean, fantastic work.

[00:18:52]His other research that he talked about, I was punching the air when he was describing these studies. I'm like, yes, I'm really pleased to hear that some of this research is happening.

[00:19:16]>> Mhm.