Human leukocyte antigen (HLA) genes encode groups of HLA proteins, which are found on the surface of almost every cell and are unique to each individual. When a cell becomes infected by a virus or other pathogen, it breaks down proteins from the invader into smaller fragments called peptides. These peptides are then loaded onto HLA molecules and presented on the cell surface – a process known as antigen presentation – effectively signalling to the immune system that the cell is infected. HLAs essentially help the immune system distinguish self from non-self and identify cells that are foreign to the body.
The theory of viral persistence – the continued presence of viral antigens (fragments of viral proteins) in the body – as a cause for ME/CFS has been proposed for decades. Researchers based in the United States have suggested that people with ME/CFS may have reduced HLA binding affinity, meaning that their HLA molecules bind viral antigens less effectively and thus the HLAs do not present the antigen effectively on the cell surface. Thus poor binding could allow viral antigens to escape a response from the immune system, persist in the body, and continue driving symptoms.
HLA genes are located on chromosome 6 and play a central role in the defence against viruses and other foreign antigens. This region is the most highly polymorphic in the human genome, meaning it contains an exceptionally large number of possible gene variants (alleles). According to the researchers, 12 HLA alleles influence the repertoire of HLA proteins displayed on cell surfaces. Different alleles result in different binding affinities and thus may determine the strength of the immune response.
Study hypothesis
The present study examined whether certain HLA alleles influence the risk of developing ME/CFS or protection from the disease. Specifically, the researchers tested the hypothesis that this risk or protection is related to the binding affinity of the proteins associated with the alleles for antigens from human herpesviruses (HHVs), which have been implicated in ME/CFS.
A previous study had identified:
- 2 alleles with significantly higher frequency in ME/CFS than controls and suggested by the authors to confer risk: C*07:04 and DQB1*03:03
- 2 alleles with significantly higher frequency in controls and “presumably protective”: B*08:01 and DPB1*02:01
The authors proposed that the protective alleles enable efficient clearance of persistent viral antigens, while the risk alleles exhibit weaker antigen binding, impairing the immune system’s ability to recognise and eliminate the viral antigens. To test this hypothesis, they conducted in silico analyses (computer simulated experiments) to predict how strongly these 4 alleles enable binding of antigens from 9 HHVs.
The researchers also hypothesised that long COVID might be due to persistent SARS-CoV-2 fragments, a thought that “has since been supported by the identification of SARS-CoV-2 RNA and viral fragments” in affected individuals. They suggested that the same HLA alleles might similarly fail to bind and present SARS-CoV-2 antigens effectively, hence also failing to adequately trigger removal by the immune system. As a result symptoms persist.
Finally, the researchers extended their hypothesis to post-treatment Lyme disease syndrome (PTLDS) – a condition with overlapping symptoms. Lyme disease is a tick-borne disease caused by the bacterium Borrelia burgdorferi. Most cases, if treated early, recover completely, however, a fraction of individuals experience persistent symptoms beyond 6 months, associated with disability, referred to as PTLDS. The team investigated whether the ME/CFS-associated alleles also conferred low binding affinity to Borrelia burgdorferi antigens.
Findings
- The predicted binding affinities conferred by ME/CFS risk alleles (C*07:04 and DQB1*03:03) for viral antigens were significantly weaker than those of the protective alleles (B*08:01 and DPB1*02:01).
- When evaluating over 10,000 protein fragments from 9 HHVs, none showed strong predicted binding to the ME/CFS risk alleles.
This weaker binding could potentially mean that the viral fragments are not being adequately presented to the immune system to allow elimination of infected cells.
- SARS-CoV-2 and Borrelia burgdorferi antigens were similarly characterised by weak binding affinity for HLA proteins associated with the ME/CFS risk alleles. HLA alleles, presumed protective against ME/CFS, enabled substantially stronger binding with these pathogens.
Thus, these findings similarly suggest that those with long COVID and PTLDS have generally weaker binding affinities for the associated viral antigens and thus these are inadequately presented to the immune system for response.
Conclusion
The researchers conclude, “These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.”
Limitations
The researchers noted that “Despite the broader implications of this study’s novel findings, several limitations and future directions are worth noting.” Only 4 HLA alleles previously documented as associated with ME/CFS were analysed. Given the “extreme polymorphism” and “geographic variability” (differences within populations) of HLA genes, it possible that additional alleles may influence risk or protection. Similarly, pathogens beyond HHVs, which were not explored, such as enteroviruses or parvoviruses, may also be relevant in ME/CFS. The focus on ME/CFS-associated alleles does “not preclude influence of other HLA alleles” in long COVID or PTLDS.
Read more about human herpesvirus 4 (HHV-4), otherwise Epstein-Barr Virus, in ME/CFS
