Autoimmunity is where the immune system mistakenly targets the body’s own cells. The question of whether it is involved in ME/CFS has been asked for many years, with mixed results. Some studies say “maybe yes,” others say “maybe not.” The study we are summarising in this article falls into the yes camp.
A quick recap – What are antibodies?
Antibodies, also known as immunoglobulins, are proteins produced by white blood cells as part of the body’s immune defense. Their job is to recognise and bind to antigens – molecules that act like “flags” identifying foreign invaders such as viruses or bacteria. Once an antibody binds to an antigen, it marks that target for destruction by the immune system.
Sometimes, though, antibodies can mistakenly target the body’s own cells. These are called autoantibodies, and when they appear, they can contribute to autoimmune diseases.
A study – EBV and autoimmunity
Epstein-Barr virus (EBV) is a virus that has been repeatedly implicated in ME/CFS, hence why there are many studies exploring this topic. Interestingly, a recent study, using data from patients at Charité hospital in Berlin hypothesised that certain ME/CFS symptoms might arise because antibodies against certain EBV protein sequences also mistakenly bind to similar sequences in human proteins – a process called molecular mimicry. In other words, the immune system may be confusing “self” for “virus.”
Methods
The researchers analysed blood samples from:
- 45 females (aged 18–59) with long COVID (referred to as PCS, for post-COVID syndrome), including 26 who also met the Canadian Consensus Criteria diagnostic criteria for ME/CFS (this subgroup was called pcME/CFS, for post-COVID ME/CFS).
- 36 females with non-COVID-related post-infectious ME/CFS (piME/CFS), who “developed ME/CFS after an infection most commonly following non-SARS-CoV-2 viral respiratory tract infections or EBV infection.”
- 34 healthy female controls, 26 “of whom 26 reported a SARS-CoV-2 infection at least 6 months prior”.
Data about the participants such a disease and symptom severity and functional disability were collected.
The antibody they focused on was Immunoglobulin G (IgG) – the most common antibody in the bloodstream. They referenced a previous study which had found that some ME/CFS patients had strong IgG responses to two EBV peptides (small viral protein fragments) named EBNA4_0529 and EBNA6_0070. These EBV peptides are also referred to as arginine-rich EBV sequences.
In the present study, the researchers looked for human protein sequences that closely resemble those arginine-rich EBV fragments – since this similarity could cause the same antibodies to cross-react and mistakenly attack human proteins. Following an extensive database search and reviewing peer-reviewed literature, the researchers selected eight human proteins with sequences similar to the EBV peptides and tested whether participants’ blood samples reacted to these EBV-derived and human-derived proteins/peptides. The human proteins selected had “known functions” potentially relevant to key ME/CFS and long COVID and ME/CFS disease mechanisms related to autonomic, neuronal, mitochondrial, and vascular processes.
Findings
1. Elevated autoantibody responses in long COVID and ME/CFS
- Compared with healthy controls, individuals with long COVID and ME/CFS showed higher frequencies and reactivity of IgG autoantibodies against certain human peptides/proteins. These autoantibodies targeted peptides/proteins involved in autonomic, neuronal, mitochondrial, and vascular processes.
2. Symptom associations
- Several of these autoantibodies showed positive correlations with the severity of certain symptoms, including autonomic dysfunction, post-exertional malaise (PEM), fatigue, cognitive impairment, and pain.
3. Distinct patterns between patient groups
- Individuals with long COVID “showed the highest levels and frequencies of autoantibodies to several human peptides.” Furthermore, autoantibodies to several arginine-rich peptides were “significantly associated with the severity of autonomic dysfunction, fatigue, and PEM” in long COVID.
Conclusion
This study adds to evidence pointing to a role of autoimmunity in ME/CFS and long COVID, through mechanisms such as molecular mimicry, nevertheless it remains an area requiring further exploration.
Several autoantibodies against certain human peptides/proteins were detected more often and demonstrated increased reactivity in the disease cohorts than in healthy controls, and their levels correlated with key symptoms such as fatigue, autonomic dysfunction, pain, and cognitive impairment.
However, it’s important to note that this was a small exploratory study involving only women. The proteins studied were pre-selected “proteins for autoantibody analysis based on their potential relevance to core pathomechanisms proposed” for long COVID and ME/CFS. Furthermore, the findings show correlation, not proof of cause. Larger, more diverse, and longer-term studies, in addition to further validation of findings, will be needed to confirm whether there is autoimmune involvement (in the form of molecular mimicry) in ME/CFS and long COVID.
Further implications
Within the paper the authors also contemplate whether other viruses implicated in ME/CFS, e.g. the Torque Teno virus (TTV), adenoviruses, and human papillomavirus (HPV), that contain arginine-rich sequences could be contributing to autoimmunity through mechanisms such as molecular mimicry. However, they acknowledge that further studies would be need to test this hypothesis.
