E3 PreliminaryPreliminaryPEM unclearReview-NarrativePeer-reviewedReviewed
The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity.
Ruiz-Pablos, Manuel, Paiva, Bruno, Zabaleta, Aintzane · Frontiers in immunology · 2025 · DOI
Quick Summary
This review examines how certain genes related to immune system recognition (HLA genes) might make some people more susceptible to autoimmune diseases and conditions like ME/CFS. These genes were originally helpful in protecting our ancestors from infections, but in today's environment they may cause the immune system to overreact. The authors suggest that modern stressors like infections, vaccines, and obesity might trigger this hyperactive immune response in people carrying these genes.
Why It Matters
This review provides a biological framework for understanding ME/CFS within the broader context of autoimmune and post-infectious conditions, potentially explaining why certain individuals develop ME/CFS after infections or other triggers. If the proposed HLA-driven immune hyperreactivity model is correct, HLA profiling could eventually help identify at-risk populations and guide targeted treatments for ME/CFS patients.
Observed Findings
- Three ancestral HLA-II haplotypes (DR2-DQ6, DR4-DQ8, DR3-DQ2) are overrepresented in autoimmune disease populations.
- These haplotypes likely conferred survival advantage in historical high-pathogen environments by enabling strong pathogen-specific T-cell responses.
- Multiple modern stressors (chronic infections, immunotherapies, vaccination, obesity, chronic physical stress) may exacerbate immune hyperreactivity in genetically susceptible individuals.
Inferred Conclusions
- Ancestral HLA-II haplotypes selected for strong immune responses may predispose to immune hyperreactivity and autoimmunity when exposed to modern environmental conditions.
- IFN-γ and pro-inflammatory cytokine dysregulation linked to these haplotypes could contribute to ME/CFS, Long COVID, and related syndromes.
- HLA-II profiling could have clinical utility for identifying at-risk individuals and guiding personalized therapeutic approaches in autoimmune and post-infectious diseases.
Remaining Questions
- What is the direct evidence that these specific HLA-II haplotypes are overrepresented in ME/CFS patient populations compared to healthy controls?
- How do environmental triggers (infection, vaccination, stress, obesity) mechanistically interact with these HLA haplotypes to break immune tolerance and establish chronic disease?
- Can HLA-II profiling effectively predict which individuals will develop ME/CFS or other post-infectious conditions, and what preventive or early interventional strategies would be justified?
What This Study Does Not Prove
This is a theoretical review, not an original research study with patient data or experimental evidence, so it does not prove that HLA genes directly cause ME/CFS or confirm the proposed mechanisms in ME/CFS patients specifically. The authors note that evidence linking these ancestral haplotypes to Long COVID, ME/CFS, and post-vaccination syndromes remains limited. The review cannot establish causation or rule out other genetic and environmental factors contributing to ME/CFS development.
Tags
Symptom:Fatigue
Biomarker:CytokinesAutoantibodies
Phenotype:Infection-TriggeredLong COVID Overlap
Method Flag:Exploratory Only
Metadata
- DOI
- 10.3389/fimmu.2025.1710571
- PMID
- 41425584
- Review status
- Editor reviewed
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 12 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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