The findings are tentative and need to be validated, but if they hold up they could signal a fundamental split between people who’s chronic fatigue syndrome (ME/CFS) was triggered by an infection and those who came down with ME/CFS some other way. If your ME/CFS was triggered by an infection, your immune system may have been tilted in an autoimmune direction. If your ME/CFS was triggered in another way, it may have been tilted towards inflammation.
Time will tell.
Autoimmunity and ME/CFS
Chronic fatigue syndrome (ME/CFS) has long been thought to be a possible autoimmune disease. The infectious onset, the gender imbalance (almost 80% of people with autoimmune diseases are female), the age of onset, even the wide variety of symptoms, all suggest autoimmunity might be present.
One might ask why infectious mononucleosis, which was recently linked to no less than seven autoimmune diseases, would not – given that it’s a common trigger for ME/CFS – also have produced an autoimmune disease in ME/CFS?
Establishing that a disease is autoimmune in nature is not easy, however – and while we’re not nearly there yet – the evidence and interest appears to be growing. Dr. Scheibenbogen was the senior author of a Euromene paper, “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease“, which argued that a startling array of immune findings in ME/CFS pointed toward some sort of autoimmunity.
The review paper – which was published prior to the publication of the failed Rituximab trial in ME/CFS – asserted “there is compelling evidence that autoimmune mechanisms play a role in ME/CFS”, while warning that subgroups of patients likely have different “pathomechanisms”. Recently, a hypothesis paper suggested that people with ME/CFS are caught in a kind of weird limbo state between autoimmunity and pathogen persistence.
Given the heterogeneous immune findings found in ME/CFS, the authors of the review paper concluded that it was critical to “identify clinically useful diagnostic markers”; in this case very small genetic changes – a shift in just one nucleotide – called single nucleotide polymorphisms as well as immune factors.
The Polymorphism Story
Polymorphisms have been looked at before. A fascinating 2017 review paper which examined no less than 50 studies on the genetic polymorphisms found in ME/CFS, cancer-related fatigue and other fatiguing diseases. It suggested that slightly altered forms of TNFα, IL1b, IL4 and IL6 genes put people at risk for high levels of fatigue.
The connections found between ME/CFS and polymorphisms in HLA, IFN-γ, 5-HT (serotonin) and NR3C1 (glucocorticoid) genes, in particular, were cited in that paper. Several of these altered genes could be tied to autoimmunity or other immune dysfunction. The link between the HLA genes tasked with spotting an invader and autoimmunity is well known. Given the role the HPA axis plays in regulating the immune system, the glucocorticoid polymorphism documented in ME/CFS could play a role as well.
The COMT gene that appears to play a big role in fibromyalgia, and perhaps ME/CFS, breaks down catecholamines like norepinephrine. Both it and the beta 2 adrenergic receptors that are under investigation in ME/CFS modulate the immune response. All in all, it appears that ME/CFS patients’ genetic makeup provides plenty of opportunity for their immune systems to go awry.
Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset. Sophie Steiner1, Sonya C. Becker1†, Jelka Hartwig1, Franziska Sotzny1, Sebastian Lorenz1, Sandra Bauer1, Madlen Löbel2, Anna B. Stittrich3,4, Patricia Grabowski1 and Carmen Scheibenbogen1,3* Front. Immunol., 09 April 2020 https://doi.org/10.3389/fimmu.2020.00578
This present study – another Carmen Scheibenbogen and company production from Germany – assessed whether small changes in immune genes (called polymorphisms) that have been associated with autoimmunity were present in ME/CFS. These polymorphisms usually affect the activation of T or B cells or the production of immune factors called cytokines.
This large study included 305 people with ME/CFS (205 female/100 male) and 201 (103 female/98 male) healthy controls.
The goal was to determine if the immune systems of ME/CFS patients were genetically skewed towards autoimmunity. This is not the be-all and end-all of genetic studies – it examined the frequency of just five polymorphisms in immune genes that have been associated with autoimmunity. They included:
- tyrosine phosphatase non-receptor type 22 (PTPN22) SNP rs2476601,
- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) SNP rs3087243,
- interferon regulatory factor 5 (IRF5) SNP rs3807306,
- gene tumor necrosis factor (TNF) SNP rs1800629,
- gene rs1799724 (TNF) SNP Rs1799724
Two of these gene polymorphisms code for production of a key gene in the pathogen response – higher tumor necrosis factor – (TNF-a); one coded for higher IFN-y production, and two affected T and/or B cell activity or signaling.
Given the limited search, any positive result probably would have been greeted with celebration. The study did better than that, though, as two of the five polymorphisms assessed were upregulated in ME/CFS patients compared to healthy controls.
Infectious Subset Stands Out
There was a catch, though. The polymorphisms were only found with more frequency in the 2/3rds of patients with post-infectious onset.
Both of the polymorphisms (PTPN22 rs2476601, CTLA4 rs3087243) have been associated with several autoimmune diseases such as type I diabetes, lupus and rheumatoid arthritis.
The PTPN22 rs2476601 polymorphism is a major autoimmune factor. It is believed to make it more difficult to delete autoreactive T cells, to reduce the activity of the Treg cells in charge of ensuring autoimmunity does not occur, and to impair B-cell clonal regulation.
- This study assessed the frequency of five single nucleotide polymorphisms (SNPs) that are associated with autoimmunity.
- Single nucleotide polymorphisms are small changes to the genetic code affecting just one nucleotide which, nevertheless, can sometimes dramatically affect the functioning of a gene.
- Two of the five SNPs were increased in ME/CFS patients with an infectious onset. Two other immune factors that have also been associated with autoimmunity were also found.
- In contrast, no autoimmune markers were found in the non-infectious onset group, the frequency of several of the SNPs was decreased and a marker of inflammation (CRP) was increased.
- The authors speculated that the illness in non post-infectious onset ME/CFS may be more akin to that found in post-cancer fatigue.
- Post-cancer fatigue appears to be more associated with HPA axis and sympathetic nervous system dysfunction.
- The study added a bit more evidence to the idea that at least a subset of ME/CFS patients have some sort of autoimmune process going on.
- Twenty percent of the study participants reported that their illness was triggered by an EBV infection. Infectious mononucleosis has been linked to an increased risk of autoimmune diseases.
- Larger studies are needed to determine if the immune systems of post-infectious and non post-infectious ME/CFS patients are indeed tilted in different directions.
The form of CTLA4 found enhanced in the infectious onset group, on the other hand, makes it more difficult to turn off the activated T cells that can drive some autoimmune diseases.
The EBV Autoimmune ME/CFS Group?
Almost 20% of those with a post-infectious onset of ME/CFS reported that their illness was triggered in adolescence by an Epstein-Barr virus (EBV) infection (infectious mononucleosis, glandular fever). EBV, as was noted above, is a known for autoimmunity. A 2018 paper provided a reason why EBV may be so adept at turning an infection into an autoimmune disease.
Virtually everyone carries EBV in its latent state in their cells. It turns out that even in its latent state, when EBV isn’t replicating, a transcription factor in EBV is still busy turning on and off genes that just happen to increase the risk of developing a host of autoimmune diseases (lupus, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease , celiac disease, type 1 diabetes.) Fully 50% of the gene regions associated with an increased risk for lupus, for example, appear to have been turned on by EBV.
EBV or any other virus isn’t the end of the story with autoimmunity. Most people who come down with infectious mononucleosis or another infection don’t come down with an autoimmune disease but these stressors, perhaps like other significant stressors in childhood, adolescence or adulthood, can tilt the immune system in a direction which makes it susceptible to producing autoimmunity for some people.
A Non-Infectious Onset Inflammatory Subset?
Interesting, two findings suggested that the immune systems of the non-infectious ME/CFS cohort may be tilted in the opposite direction of the post-infectious cohort. Instead of having higher frequencies of the of IRF5 and TNF risk variants, they had significantly lower frequencies compared to the infectious group.
Finding some genetic alterations in immune genes, the researchers took the next step to see if the unusual gene forms resulted in immune alterations as well.
They did. Several autoimmune-like factors jumped out. Reduced C4 levels in the infectious onset group were reminiscent of systemic lupus erythematosus (SLE), while reduced CD19+ B cells (B cell lymphocytopenia) are found in both SLE and rheumatoid arthritis (RA).
(“Lymphocytopenia” refers to a count of less than 1,000 lymphocytes per microliter of blood in adults). CD19+ cells are the major immunoglobulin-secreting B-cell found in the blood, bone marrow, spleen and tonsils. Reduced CD19+ cells have been associated with an increased susceptibility to infection in animal studies.
Compare those findings to the increased c-reactive protein (CRP) levels in the non-infectious group of patients, suggesting a more pro-inflammatory profile. The authors suggested the disease in the non-infectious group may be more akin to that found in cancer-related fatigue.
No federal agencies funded this study – it was solely the result of your donation dollars. It was supported by a 2016 Ramsay Grant Program award, the Solve ME/CFS Initiative, as well as by several German foundations.
Cancer-Related Fatigue and the Non-infectious ME/CFS Group
HPA axis problems are present in ME/CFS and recent cancer-related fatigue studies have found a link between HPA axis problems and inflammation in post-cancer survivors with fatigue. A 2020 study found that reduced sensitivity of the immune system to glucocorticoids (cortisol) resulted in increased levels of pro-inflammatory markers and cytokines (C-reactive protein, interleukin 6, and tumor necrosis factor α.) in the fatigued patients. Apparently, the HPA axis was having trouble tamping down inflammation in the fatigued cancer patients.
A head and neck cancer study uncovered a possibly revealing distinction between pathogen (papillomavirus) triggered and non-pathogen triggered cancer. The gene expression results suggested that the two types of cancers triggered different immune responses.
The non-pathogen triggered cancer triggered something called a “Conserved Transcriptional Response to Adversity (CTRA)” immune response. In this response, those beta adrenergic signaling pathways that we’ve been looking at lately in ME/CFS jacked up inflammation via the sympathetic nervous system. The CTRA response was diminished, on the other hand, in the infectious cancer cohort – and so was the fatigue.
While it’s a bit of a stretch to compare infectious onset cancer and infectious onset ME/CFS, it’s intriguing that in both cases the infectious onset was associated with less inflammation.
It brings up the question whether the fatigue in post-infectious onset and non-post-infectious onset ME/CFS patients could be coming from different places. Could the HPA axis/sympathetic nervous system-triggered inflammation be playing more of a role in ME/CFS patients with non-infectious onset?
A 2019 study suggested, though, that an infectious onset may not be so clear a trigger as one might think. Almost 40% of the participants reported that it took 7 months or more from whatever happened for ME/CFS to manifest itself. Twenty percent reported that it took more than two years. Eighty-eight percent, though, felt they could identify a specific triggering event.
While infectious onset seems like it would trigger a quicker decline into ME/CFS, people with infectious onset were no more likely to quickly come down with ME/CFS than people with other triggers. Only 14% of those citing an infectious onset said their ME/CFS developed within a month of the infection.
The study found that two gene variants – including one in “the archetypal non-HLA autoimmunity gene”. found in autoimmune diseases were also increased in people with post-infectious ME/CFS. Plus, several immune factors associated with autoimmunity were increased as well. While autoimmunity hasn’t been proven in ME/CFS, the study provided more evidence that autoimmune processes may be at play in a large subset of ME/CFS patients.
The story appeared quite different in people with ME/CFS who didn’t have an infectious onset. Two of the polymorphisms associated with autoimmunity were significantly decreased in the non-infectious onset ME/CFS patients. Plus high levels of an inflammatory marker were found as well. That suggested that the pathology in the non-infectious group might be more akin to that which occurs in post-cancer fatigue.
Studies suggest that the post-cancer fatigue and non-infectious onset ME/CFS patients may have a balky HPA axis that has difficulty reigning in inflammation. Interestingly, given the focus on the sympathetic nervous system in ME/CFS, non-pathogen triggered cancer was associated with more sympathetic nervous system-induced inflammation than pathogen-triggered cancer.
While larger studies need to be done, these preliminary findings suggest that the kind of triggering event (or the absence of a triggering event) could have tilted the immune system in different directions in different sets of patients.
With the Nath intramural study focusing on documented post-infectious ME/CFS cases underway, and his new study on post COVID-19 patients beginning, plus all the media attention being given to problems recovering from COVID-19, some real insights may be in store for the post-infectious group.