‘There must be a persistent antigen’: NIH researcher discusses new PI-ME/CFS data
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A recent NIH study of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome suggests that the condition is a “distinct entity,” with somatic and cognitive issues that are centrally mediated.
The researchers, who published their findings in Nature Communications, reported central autonomic dysfunction among patients with fatigue, and noted “distinct sex signatures” of immune and metabolic dysregulation, suggesting “persistent antigenic stimulation,” they wrote.
“It all points to the hypothesis that there must be persistent antigen,” co-author Avindra Nath, MD, clinical director of the National Institute of Neurological Diseases and Stroke at the NIH, told Healio. “That is how we came up with the idea that there is a persistent antigen driving this whole process. However, we still do not know why that is happening.”
In the paper, Walitt and colleagues at the NIH described post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) as a “disabling disorder.” However, a poorly defined clinical phenotype and unknown pathophysiology have inhibited treatment paradigms for this disease.
In their analysis, the group matched PI-ME/CFS patients with controls to further understand parameters surrounding clinical phenotype. They determined that an alteration in effort preference, as opposed to physical or central fatigue, separated patients from controls. Moreover, this effort preference is attributed to “dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation,” which is driven by dysfunction of the neuroimmune axis, according to the findings.
The consequences of this dysfunction were observed in both autonomic functioning and physical conditioning.
Further analysis of the immune system of both patients and controls led the researchers to believe that “chronic antigenic stimulation with increase in naïve and decrease in switched memory B cells” may be implicated in PI-ME/CFS disease processes.
Sex differences also were observed. Specifically, peripheral blood analysis showed that alterations in gene expression profiles of mononuclear cells and metabolic pathways validated previous cellular phenotypic studies that revealed differences between those with male and female sex.
Healio sat down with Nath to discuss the importance of findings in the peripheral blood, the observed sex differences and what these results might mean for therapeutic intervention in this patient population.
Healio: Could you give us some background on this patient population?
Nath: This disease is an interesting one. It is marked by a wide variety of symptoms that are quite similar. A lot of patients complain of an event that triggered it, and then they never get better. One such trigger is an infectious process. This leads to a variety of neurological and systemic symptoms. They go from doctor to doctor but nobody finds anything. Nobody believes their symptoms, so they end up frustrated and stigmatized.
Healio: What symptoms do they experience?
Nath: Some of the most common symptoms are post exertional malaise, cognitive difficulties, exercise intolerance, sleep disturbances, postural hypotension, dysautonomia and the like.
Healio: How did you become involved in the study?
Nath: I am a neurologist. I specialize in neurovirology and neuroimmunology, so when asked to study ME/CFS, we designed a study targeting patients with ME/CFS with a clear infectious process.
Healio: How was the study conducted?
Nath: We started with about 300 patients, enrolled 21, and ultimately ended up studying 17. The inclusion criteria were very strict. That is good and bad. It is good because we know exactly what we are studying but bad because it ended up being a small population.
Importantly, patients had to be healthy otherwise, with no significant comorbidities. In fact, each of the four patients who were excluded had other significant conditions like cancer or Parkinson’s disease.
This is an important lesson for your readers. Patients with ME/CFS should be taken seriously and followed prospectively, since over time you may find some other underlying condition that can account for the symptoms and may be treatable.
Healio: Was the rest of the enrollment process so strict?
Nath: Yes. They needed peer documentation of the infectious process. Also, there are three sets of criteria for diagnosis of ME/CFS, and patients had to satisfy [at least one of three criteria]. Then we had a committee of five experts in ME/CFS, who all had to agree unanimously that the patient had ME/CFS.
Healio: What happened after patients were enrolled?
Nath: They came into the NIH for a 2-week evaluation on two separate visits. They went through a huge battery of tests. Matched controls went through the same process, so we could guarantee that the comparison can be well studied.
Healio: You found an increase in the percentage of naïve B cells, and a decrease in switched memory B cells, in patients with ME/CFS. What does this mean and why is it important?
Nath: If I were to say that there is an important underpinning mechanism that we discovered in this study, it might be the switched memory B cells. Normally when we face a foreign antigen, the B cells will recognize it. They will go from a naïve state, producing IgM, and switch to a mature state producing IgG. This maturity of the B cell can occur in a T-cell dependent or independent manner. If the B cells fail to switch to the mature or memory B cells, the ability to clear the antigen is going to be impaired. If it is impaired, the immune system would have to depend on T cells for antigen clearance. This creates exhaustion in the T cells from persistent antigen stimulation.
So, now you have a combination of exhausted T cells and B cells that are unable to switch. This leads to reliance on the innate immune system, activation of which can be detrimental to the host. This is not a good way to fight infectious processes.
Healio: What conclusion did you draw from this result?
Nath: It all points to the hypothesis that there must be persistent antigen. That is how we came up with the idea that there is a persistent antigen driving this whole process. However, we still do not know why that is happening. In my mind, that is the next important immunological question to ask.
Healio: You also found no group differences in percentage of CD4, CD8, and CD19 cells in peripheral blood and cerebrospinal fluid. What does this mean and why is it important?
Nath: The total cells by themselves did not really change. They do not change unless there is some severe immune complication. It was only when we started looking at subsets within these cell types that we saw abnormalities.
Healio: We are additionally interested in the sex differences you observed. What genes were expressed differently in men and women and why is this information important?
Nath: This is very fascinating. When we looked at gene expression in blood lymphocytes and categorized them by the pathways they represent, we found sex differences in a number of parameters. Using a principal component analysis, we found men and women had activation of totally different clusters of genes.
This is really telling us that the males are expressing what women are not and vice versa. Also, the secondary signaling pathways activated were different in men and women. In women, the B-cell pathways were affected and in men it was the T cells. This is really bizarre. We are wondering why.
Healio: Do you have any thoughts on why this may be?
Nath. Well, your readers who are rheumatologists may appreciate that a lot of autoimmune diseases happen in women compared with men, and many are B-cell mediated. One possibility is they are programmed to produce B cell mediated responses better than men because during childbearing age the antibody can cross the placenta and protect the fetus. However, this has not been tested or proven.
Healio: What do your findings tell us about potential therapeutic targets in ME/CFS?
Nath: I am a neuroimmunologist, so I think in terms of immune targets. In the paper, you will see that we discovered a number of targets which include the autonomic nervous system, metabolites, microbiome and others. If there is antigen persistence and T cells are exhausted, one could consider using checkpoint inhibitors. If you have T-cell activation and they are not exhausted, we have plenty of drugs to block T-cell activation. For B-cell activation you can use immunotherapies that block B cells. For issues with innate immunity, you can use an interleukin (IL)-1, IL-6, or TNF inhibitor.
Now, I am not advocating any of these treatments be tried among these patients. I am suggesting that these treatments could or should be tested in clinical trials. If not used under supervision of an expert, they could cause harm.
Healio: Do you have thoughts on how to go about conducting those trials?
Nath: You can’t try one after another because it would take too long. Investigators should consider doing a platform study, with multiple arms and multiple agents at the same time.
Healio: Our readers are primarily practicing rheumatologists. What is the overall take-home message of these findings for them?
Nath: The first is that they should take these patients seriously. They need to use sophisticated tools to define abnormalities in this population. The other thing they should consider is doing clinical trials in these patients. Disease pathogenesis can be studied in the context of clinical trials. This is right up their alley and they are the experts.
Editor's note: This story has been edited to more accurately describe the study's methodology.
References:
Walitt B, et al. Nat Comm. 2024;doi:10.1038/s41467-024-45107-3.
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