“Exhausted” T Cells Found to Be Hugely Important in ME/CFS

Do ME/CFS patients have the same level of exhausted T cells as AIDS patients?

Chinese scientists published a research paper in early October that described surprising immune and neurologic profiles in CFS/ME patients that are similar to those found in Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease) as well as Parkinson’s disease (PD), Huntington’s disease (HD), prion-related disease and—although they didn’t place it on their list—AIDS. Yujing Sun and colleagues at a research center studying chronic metabolic diseases (in Jinan, China) examined a curated set of immune system components found in circulating blood: B cells, T (CD) cells, natural killer (NK ) cells, monocytes, conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). The stated goal of their research was to identify a biomarker and/or potential therapeutic targets for ME/CFS. (1)

The authors acknowledge that their sample size was small, but participants were carefully chosen from among many applicants to the study: four ME/CFS patients (three men and one woman) had to qualify under the research criteria of the International Chronic Fatigue Syndrome Study Group, the Canadian consensus criteria, and the 2015 diagnostic criteria from the U.S. Institute of Medicine. They were matched against four healthy controls (HC), two men and two women.

“Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases,” Sun et al. reported. “These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.” (1)

Their study “focused exclusively on the primary immune cell types” listed above. “...A remarkable increase in the proportion of T cells was observed in the ME/CFS group, accompanied by significant decreases in the proportions of NK cells, monocytes, cDCs and pDCs,” Sun and colleagues noted at the beginning of the study. “No significant changes were observed in the proportions of B cells.” (1)

A quick aside about dendritic cells (DCs): Conventional dendritic cells (cDCs) “present” antigens to B and T cells so they can be eliminated before causing disease. The primary role played by plasmacytoid DCs (pDCs) “is thought to be in response to viral infections, where they produce large amounts of type I interferons,” which fight viral infections. (2)

And as to the rest of the immune cell team, in brief: Monocytes fight infection by engulfing invaders (as well as dead cells); B cells create antibodies; T cells (CD cells) either kill invaders directly (CD4+ T cells) or they alert B cells to destroy them (CD8+ T cells); NK cells can directly destroy any type of infected, damaged, or malignant cells, without being activated by any other cells or immune molecules. (1)

Sun et. al found that CD4+ T cells—formerly referred to as “helper T cells” because they coordinate immune responses—showed a “significant upregulation” in ME/CFS patients. CD8+ T cells—which, like NK cells, directly destroy infected and malignant cells—“also show activation of T cell signaling and upregulation of the neurodegenerative disease pathway” in patients, but not in HCs. (1)

What does that mean?

In this study, it appeared that CD4+ and CD8+ T cells are hyper-stimulated and may be responsible for upregulation of the immune system sometimes seen in ME/CFS patients. The study also “revealed significant upregulation in cellular senescence and neurodegenerative signaling pathways.”

Senescence occurs when immune system cells can no longer reproduce themselves; they are alive but helpless and are sometimes referred to as zombie cells. These zombies can accumulate in clumps, which are thought to contribute to the aging process.

Likewise, neurodegeneration describes a progressive loss of neurons’ function and structure. Depending on where this occurs—along which pathway—it can result in Alzheimer’s disease (AD), PD, and the other neurodegenerative diseases discussed in this research report.

But that’s not all—computer analysis revealed even more bad news for ME/CFS patients: “Further classification within the category ‘human diseases’ [in a computer program] revealed a significant enrichment of pathways related to neurodegenerative diseases and infectious diseases.”

So, the immune systems of ME/CFS patients, as we already knew, aren’t really functional. Did we learn anything new?

Yes. This is a very technical, detailed study, and I am only scratching the surface here. I encourage anyone who wants to delve into the details to do so by reading this free, public-access research report. (1)

For example, one of the studies Sun and colleagues performed was “pseudotime analysis.” That’s a “computational method that uses single-cell RNA-sequencing (scRNA-seq) data to study biological processes over time. It involves ordering cells along a trajectory based on their changing transcriptomes [types of messenger RNA] and assigning each cell a pseudotime value that indicates its position on the trajectory.” (2)

In other words: Cells and their RNA change over time as they mature and age. Pseudotime analysis places the cells on a timeline, just as is done with events.

From their pseudotime analysis, Sun et al. observed “dynamic changes in CD8+ T cell states” over time in ME/CFS patients, but not in HC. (1)

Sun and colleagues summarized their data as having shown “increased total numbers” of most types of T cells, as well as in antibody-producing B cells. “And we observed substantial decreases in the proportions of monocytes and NK cells,” they confirm. (1)

A very different picture was painted by their gene expression studies of the blood cells’ RNA. Although they first observed an increase in numbers of T cells in ME/CFS patients, these investigators were taken aback to find that many of those T cells were not viable.

“Three aspects” of their gene expression studies, they commented, “are particularly noteworthy.”

And here—forgive me—I’m reprinting a portion of the most significant two paragraphs of Sun and colleagues’  Discussion. Added emphasis is mine.

“First and foremost, we identified numerous transcription factors and the interactive gene expression that drives the differential processes of immune cells. ... Secondly, we were taken aback by the discovery of numerous cellular pathways that are implicated in certain well-known diseases. Our attention was drawn to two classes of diseases within the ‘Human Disease’ category [in the computer program used]. One is the virus infection-related pathways, which include non-specific viral processes and specific virus-specific pathways (such as HSV, HPV, CMV, EBV, or COVID-19). ... The second unexpected category of diseases consisted of amyloid neurodegenerative disorders, such as AD, ALS, PD, HD, or Prion diseases. It is intriguing that the aforementioned pathways, which involve both infectious and noninfectious amyloidosis, were ‘coincidentally’ upregulated in specific peripheral immune cell subsets in ME/CFS. 

“Finally, the gene expression patterns substantially increased the signal pathways involved in cell senescence and exhaustion, particularly in T cells. The state of cellular senescence is characterized by the irreversible arrest of the cell cycle and is linked to chronic inflammatory conditions and aging. The notion that immune dysfunction may be associated with chronic inflammation and aging-related processes is emphasized by the presence of senescent T cells in ME/CFS patients. ... The complexity of immune perturbations in ME/CFS is underscored by the involvement of the cellular senescence, T cell receptor signaling, NF-κB pathway, and pathways related to infectious and neurodegenerative diseases. In this condition,immunodeficiency and autoimmunity appear to be the two sides of the same coin. ... This implies that the impaired immune function of ME/CFS patients may be attributed to a fundamental alteration in energy metabolism in T cells. Consistent with previous research, ME/CFS patients often exhibit an abundance of exhausted T cells—a reversible state associated with chronic viral infections that impairs cell proliferation, survival, and cytotoxicity.” (1)

So, while ME/CFS patients appear to have an overall increase in T cells, in fact, many of them are “exhausted,” suffering the irreversible state of being unable to replicate themselves and, therefore, unable to function in the immune systems of ME/CFS patients.

And, depending on the “staging” of each ME/CFS patient—currently unmeasurable, anyway—the overall number of T cells has been shown to decrease dramatically. In fact, they can decrease to the level that would qualify them for a diagnosis of AIDS or “HIV-negative AIDS”—discovered in 1992 and hurriedly renamed “idiopathic CD4 lymphocytopenia” by the Centers for Disease and Prevention. (4)

T cell exhaustion in AIDS remains a major area of research. A 2019 report in Immunological Reviews by a group of Swiss scientists investigated how T cell exhaustion led to chronic illness in AIDS patients. (5)

Giuseppe Pantaleo and colleagues from the Lausanne University Hospital pointed out that “The T‐cell response is central in the adaptive immune‐mediated elimination of pathogen‐infected and/or cancer cells.”  They continued:

“However, in conditions of chronic infection, persistent exposure of T cells to high levels of antigen results in a severe T‐cell dysfunctional state called exhaustion. T‐cell exhaustion leads to a suboptimal immune‐mediated control of multiple viral infections including the human immunodeficiency virus (HIV).” (5) [Emphasis mine.]

Which raises an important question: Why is AIDS research segregated from the rest of medical research? If terrifyingly disabling diseases like ALS, Parkinson’s disease and Huntington’s disease can be referenced in an article about ME/CFS, why is AIDS never mentioned? We now know that similar levels of T cell senescence occurs in ME/CFS and AIDS—what else might be learned if data from all of these diseases were examined together?

Sun et al. concluded their research report by, like many investigators before them, expressing hope that their research results “will be beneficial for future research in the development of potential therapeutic strategies and the identification of the underlying causes of the debilitating symptoms [in ME/CFS].” (1)

And it seems like they should, pending replication on a larger number of patients and healthy controls.

But for how many years—30+, at least—have we heard that mantra, without any biomarker or reliable test for ME/CFS being created, evaluated, approved and available?  How many other researchers have found solid markers of immune dysfunction in ME/CFS and voiced their hopes that a diagnostic test could be created using them?

If you want to read about all of them, you can read the updated 2^nd Edition of my 30-year-old book, America’s Biggest Cover-Up, which you can buy (or read for free) on Amazon.

Because I don’t have the heart to revisit them.

BIBLIOGRAPHY
1.        Sun, Y., Zhang, Z., Qiao, Q. et al. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. J Transl Med 22, 925 (2024). Shandong Provincial Engineering Research Center for Advanced Technologies in Prevention and Treatment of Chronic Metabolic Diseases (Jinan, China). https://doi.org/10.1186/s12967-024-05710-w
2.        Chinta Sidharthan. “What are Dendritic Cells?” Medical Life Sciences News. https://www.news-medical.net/health/What-are-Dendritic-Cells.aspx
3.        Hou, W., Ji, Z., Chen, Z. et al. A statistical framework for differential pseudotime analysis with multiple single-cell RNA-seq samples. Nat Commun 14, 7286 (2023). https://doi.org/10.1038/s41467-023-42841-y
4.        Ostrom, Neenyah; “Fauci Snows Larry King: Looking anxious, Fauci tries to play down the seriousness of ‘non-HIV AIDS’ “; New York Native, issue 487, August 17, 1992.
5.        Fenwick C, Joo V, Jacquier P, Noto A, Banga R, Perreau M, Pantaleo G. “T-cell exhaustion in HIV infection.” Immunol Rev. 2019 Nov;292(1):149-163. doi: 10.1111/imr.12823. PMID: 31883174; PMCID: PMC7003858.