New article we have published:
“The Genes of the Survivors: How Immunological Inheritance Drives Autoimmune Diseases, Long COVID and ME/CFS”
Certain ancestral HLA-II haplotypes (DR2–DQ6, DR3–DQ2, DR4–DQ8) provided advantage during epidemics because they produce strong and rapid immune responses; today, in the presence of persistent infections or chronic immune stimuli, that same “power” can become a Achilles’ heel and facilitate the emergence of autoimmunity and post-infectious or post-vaccinal syndromes in susceptible individuals.
1) What is the main idea?
Imagine your immune system has a genetic “accelerator”: certain HLA-II haplotypes present a greater variety of peptides and generate very intense CD4⁺ T-cell responses (more IFN-γ, more activation). This was advantageous during epidemics: those who carried this “accelerator” had a higher probability of surviving and reproducing, so those alleles increased in the population. But today, with latent infections (e.g., EBV/CMV, etc.), modern exposures and persistent stimuli, that accelerator can keep the system switched on and, over time, break self-tolerance → autoimmunity.
2) Mechanism summarized
- “Promiscuous” HLA-II = presents many peptides (pathogens and, by chance, some self or modified peptide).
- Strong early response = high IFN-γ production and T-cell activation → good control of acute infections.
- If the pathogen persists (evades, becomes latent, or hides intracellularly), stimulation continues: chronic inflammation, appearance of autoreactive lymphocytes, epitope spreading, and autoantibodies.
- Result: processes like multiple sclerosis, RA, celiac disease, type 1 diabetes, ME/CFS or Long-COVID, etc., can emerge on that genetic terrain + environmental trigger (infection).
3) Detailed mechanism: How does autoimmunity develop?
- Some “ancestral” HLA-II haplotypes (DR2–DQ6, DR3–DQ2, DR4–DQ8) present many types of peptides. That makes the immune system react fast and very strongly against infections — an advantage in ancient pandemics.
- If the infection resolves quickly, all good. But if a pathogen persists (latency, intracellular infection) or if there is continuous immune stimulus (obesity, chronic allergies, certain treatments or in rare cases specific vaccines/adjuvants), the response remains switched on.
- This chronic stimulation makes cells that normally don’t present antigens begin to show peptides via HLA-II (by the action of IFN-γ and JAK–STAT → CIITA). Thus “self-peptides” become visible to CD4⁺ T lymphocytes.
- Some autoreactive T and B cells, which exist by chance in all of us, receive help, proliferate and produce autoantibodies. Epitope spreading occurs and almost a local immune micro-system (ectopic lymphoid aggregates) forms, perpetuating damage. Result: autoimmune disease.
Highlight:
a genetic “accelerator” that once saved lives may, with modern chronic stimuli, become the Achilles’ heel that leads to autoimmunity in susceptible people.
4) Evidence and concrete examples
- HLA ↔ autoimmunity associations: DR2–DQ6, DR3–DQ2, DR4–DQ8 repeatedly appear as risk factors in 90% of autoimmune diseases (T1D, MS, RA, celiac disease).
- EBV and multiple sclerosis: strong epidemiological and mechanistic signals link EBV infection with MS risk; EBV may reactivate and maintain chronic antigenic stimulus. This fits the antigen persistence hypothesis. Same occurs in lupus erythematosus after EBV infection.
- Pandemrix and narcolepsy: a clear example of genetic interaction + vaccine stimulus: DQB1*06:02 (part of DR2–DQ6) showed greatly increased risk of narcolepsy after the Pandemrix vaccine in 2009–2010. It illustrates how a massive immune stimulus may trigger a syndrome in genetic subgroups.
- Long-COVID or ME/CFS and autoantibodies / immune dysfunction: reviews find evidence (autoantibodies, B-cell dysregulation, viral reactivation) that may explain post-SARS-CoV-2 or post-other pathogen symptoms; in individuals with predisposing haplotypes, the potent initial response + antigen persistence match this hypothesis.
5) Why didn’t natural selection “eliminate” these genes?
Because natural selection favors reaching reproductive age, not longevity. If a haplotype enabled survival during epidemics in reproductive age —even if it causes autoimmunity later— that haplotype spreads. In pandemics, immediate survival outweighs the cost of late disease.
6) Practical implications
- For researchers: this suggests studying HLA × infectious persistence interactions (EBV, CMV, other intracellular pathogens), measuring cytokine profiles and autoantibodies longitudinally, and using HLA-transgenic models.
- For clinicians: recognize that genetic subgroups may have increased risk of autoimmune reactions after certain high-stimulation triggers (oncological treatments, new adjuvants, or mass vaccination campaigns); HLA-typing could become a future risk-stratification tool.
- For the public: this does not invalidate the usefulness of most vaccines. The correct interpretation is: by understanding risk in subgroups with these HLA-II haplotypes, we can improve safety and design.
7) Conclusion
Integrative hypothesis: ancestral HLA-II haplotypes offer strong initial response → survival; their antigenic promiscuity and persistence of certain pathogens promote chronic inflammation → autoimmunity in susceptible individuals.
Detailed explanation for readers with technical interest
1) Starting point: genetic predisposition
• Ancestral haplotypes: DR2–DQ6 (DRB1*15:01–DQB1*06:02), DR3–DQ2 (DRB1*03:01–DQB1*02:01), DR4–DQ8 (DRB1*04:01–DQB1*03:02). Their repeated association with multiple autoimmune diseases and more intense inflammatory profiles is documented.
2) Antigenic promiscuity — the molecular key
• These HLA-II have binding sites that tolerate and present a broad repertoire of peptides (pathogens and, by chance, self or modified peptides — e.g., citrullinated, deamidated). This promiscuity increases the probability that self-epitopes escaping central deletion are presented.
3) Initial stimulus & cytokine profile
• After infection (or vaccine stimulus/ICIs/obesity/allergy), carriers of these haplotypes tend to generate strong Th1 responses with high IFN-γ (and TNFα, IL-21, etc.). This phase explains the evolutionary advantage: rapid control of lethal pathogens.
4) IFN-γ → JAK-STAT1 → CIITA → ectopic HLA-II
• IFN-γ activates the JAK–STAT1 pathway and induces CIITA, the master factor that increases HLA-II genes. As a result, non-professional cells (epithelial, endothelial, myocytes, tissue cells) begin to express HLA-II and present local peptides. This exposes “hidden” self-peptides to the immune system.
5) Activation of autoreactive CD4⁺ and help to B
• Ectopic HLA-II + costimulators (B7/CD28, CD40/CD40L) allow autoreactive CD4⁺ clones —that may have survived selection— to activate, proliferate and provide B-cell help. B cells differentiate into plasma cells producing autoantibodies.
6) Epitope spreading and perpetuation
• The initial response may expand: tissue damage generates neoantigens (PTMs, truncated proteins) and epitope spreading activates (response targets new self determinants). Ectopic lymphoid aggregates form — local “small lymph nodes” perpetuating autoimmunity.
7) Contributing mechanisms
Molecular mimicry: some viral/protein sequences resemble self → cross-reactivity.
Bystander activation: cytokines and tissue stress activate nearby lymphocytes without direct antigen recognition.
Antigen persistence: pathogens such as EBV/CMV or intracellular infections that aren’t eliminated maintain continuous stimulation. In some haplotypes (e.g., DRB1*15:01) presentation of certain viral epitopes may be suboptimal, facilitating persistence.
8) Clinical result: spectrum of diseases
• Depending on the tissue, peptide presented and context, the process may manifest as MS, RA, lupus, celiac disease, T1D, SLE, ME/CFS, Long-COVID, post-vaccinal syndromes and other autoimmune diseases. Tables in the article show that associations with DR2/DR3/DR4 are present in most prevalent autoimmune diseases.
9) Why obesity, allergies, ICIs and other situations increase risk when coinciding with these alleles?
- Obesity: state of chronic inflammation (metainflammation): TLR4 via LPS, NF-κB, overproduction of TNF/IL-6/IFN-γ, increased intestinal permeability → more systemic stimulus favouring ectopic HLA-II and autoreactive activation; in individuals with pro-inflammatory haplotypes, this amplifies the circuit leading to autoimmunity.
- Chronic allergies: sustained exposure to allergens generates a persistent inflammatory microenvironment; in carriers of these haplotypes the response may shift to a pathogenic Th1 profile (more IFN-γ) and increase the probability of tolerance break.
- Immunotherapies (ICIs): by “removing brakes” (anti-PD-1, anti-CTLA-4), T-cell activation is enhanced; in individuals with HLA predisposing strong responses this facilitates viral reactivation, ectopic presentation and autoimmunity (explaining greater irAEC incidence in certain genotypes).
- Potent vaccines/adjuvants: in rare cases (e.g., Pandemrix®) the combination of adjuvant+antigen+genetics may precipitate syndromes in subgroups; authors note stronger evidence for DR2-DQB1*06:02 in post-Pandemrix narcolepsy, and that duration/intensity of stimulus matters.
10) Two autoimmune pathogenic pathways that complement each other in Long COVID, ME/CFS and post-vaccinal syndromes.
Both mechanisms may coexist and reinforce each other, producing a sustained pro-inflammatory circuit.
A. Autoimmunity against the HPA axis → relative hypocortisolism
- The HPA axis regulates cortisol production, our main endogenous anti-inflammatory mechanism.
- If the pituitary or HPA axis suffers direct damage, neuroinflammation or autoimmunity (e.g., post-infectious hypophysitis), central or functional hypocortisolism may arise.
- Consequences: reduced ability to suppress inflammation, more neuroinflammation, lower tolerance to stress/exertion, and perpetuation of chronic disease.
B. Autoimmunity against cholinergic receptors (e.g., anti-M3) → loss of the “vagal brake”
- Vagal acetylcholine exerts powerful anti-inflammatory control and regulates autonomic functions (heart rate, gut motility, secretions, ocular accommodation).
- Autoantibodies or T-cell responses against muscarinic receptors (M3) or nicotinic may block cholinergic signaling, reduce parasympathetic tone and cause dysautonomia: POTS, orthostatic intolerance, tachycardia, digestive symptoms, decreased secretions (eyes, saliva) and ocular changes.
- Associated clinical picture: greater relative sympathetic activity, loss of anti-inflammatory control, and facilitation of immune chronicity. Early studies show associations between M3 responses and certain HLA-DR, supporting genetic predisposition.
11) Why these specific symptoms — dysautonomia, intestinal problems, dilated pupils and light sensitivity?
- Dysautonomia (POTS, orthostatic intolerance): loss of vagal tone increases sympathetic response disrupting vascular and cardiac regulation upon standing → dizziness, tachycardia, fatigue.
- Intestinal issues: the parasympathetic (vagus) drives motility and secretions; its blockade causes gastroparesis, intolerance, abdominal pain, altered transit.
- Mydriasis and photophobia: pupillary constriction (miosis) is parasympathetic; if compromised → more dilated pupils, less light response, more light sensitivity.
- Visual fatigue and light sensitivity (especially bright/blue light):
- The ciliary muscle for accommodation (focus shifting) is innervated by M3 receptors.
- If anti-M3 antibodies block them, accommodation becomes insufficient or slow → blurred vision and eye fatigue when reading or changing focus.
- Blue light scatters more in imperfect optical media; poor accommodation forces more effort → fatigue, headache, discomfort. Dry eyes contribute, but poor accommodation is the main cause in many anti-M3 positive patients.
12) Cold and heat: the forgotten key
→ And why these patients worsen so much with heat and, in many cases, improve with cold.
This point is entirely consistent with autonomic physiology and anti-cholinergic autoimmunity.
Cold: better tolerance (in many cases)
Cold increases sympathetic tone, but:
- Does not require sweating (via M3).
- Does not demand intense parasympathetic regulation.
- Sympathetic helps maintain blood pressure → better brain perfusion.
In parasympathetic-deficient patients, cold doesn’t demand the system that is impaired. Typical result: better tolerance, less dizziness, less exhaustion, less brain fog.
(Different from nicotinic myasthenia gravis, where cold improves neuromuscular transmission. Here it improves because it frees parasympathetic demand.)
️ Heat: enemy number one
Heat physiologically is a “stress test” for parasympathetic: the body needs to sweat to avoid overheating. Sweating depends on muscarinic receptors (M3).
If anti-M3 antibodies:
- Sweating capacity is reduced (hypohidrosis) or absent (anhidrosis).
- Body cannot dissipate heat.
- Internal temperature rises.
- Sympathetic surges to compensate → tachycardia, dizziness, racing heart, physiological anxiety.
Additionally:
- Heat produces skin vasodilation → drops blood pressure.
- In dysautonomia, parasympathetic CANNOT compensate.
- Result: even worse orthostatic intolerance.
This perfectly explains why patients worsen so much with heat:
- they don’t sweat → no regulation
- they vasodilate → dizziness
- sympathetic surges → palpitations
- exhaustion → crash
And why cold feels more tolerable.
13) Why does it (sometimes) improve with saline or volume increase?
- IV saline provides an immediate increase in intravascular volume, improving venous return, blood pressure, and brain/muscle perfusion.
- In dysautonomia due to parasympathetic loss, volume increase temporarily compensates the inability to maintain pressure upon standing → less dizziness, better brain perfusion → less fatigue and better tolerance for a few hours.
- It is a physiological bridge (not a cure), but helps explain why hydration, added salt and, in selected cases, volume infusions can improve symptoms.
14) Morning fatigue
- Morning tends to have a relatively sympathetic-favourable profile; if parasympathetic is impaired by anti-M3 antibodies, the gap worsens: orthostatic hypotension, tachycardia and intense fatigue upon rising. Also, if morning hypocortisolism is present, fatigue is even greater.
15) Mechanism interaction: the pro-inflammatory loop
- Hypocortisolism → less hormonal control over inflammation → more neuroinflammation and less cholinergic modulation.
- Loss of vagal brake → more peripheral and central inflammation → may alter HPA axis.
- Result: a vicious cycle where persistent immunity/autoimmunity, neuroendocrine dysfunction and dysautonomia feed each other and perpetuate symptoms.
16) Observed treatments and why many patients respond to Mestinon (pyridostigmine)
- Mestinon is an acetylcholinesterase inhibitor: increases acetylcholine available in synapses and autonomic ganglia. In practice, this strengthens residual cholinergic transmission, improves autonomic coordination and greatly helps orthostatic intolerance/POTS and morning fatigue. That’s why many Long COVID or ME/CFS patients feel better taking Mestinon upon waking or before standing: improves tolerance to standing, reduces postural tachycardia and gives more “start” for initial activity.
- Cevimeline (M3 agonist) acts directly on M3 receptors and is more useful for localized symptoms such as dry eyes/mouth and accommodation problems (visual fatigue) but has less effect on ganglionic transmission and orthostasis; therefore less effective than Mestinon for POTS.
- Important: none of these are cures if receptors are strongly blocked by antibodies. If blockade is partial, increasing ACh (Mestinon) may compete and improve function; if blockade is intense or causes receptor loss/internalization, increasing ACh doesn’t restore signaling because the target is unavailable.
17) Why this hypothesis fits other models (examples)
- In chronic Borrelia (Lyme) arthritis, certain HLA-DR (e.g., DR4) are associated with refractory and autoimmune forms: showing how HLA predisposition may facilitate pathogen persistence and trigger autoimmunity.
- In multiple sclerosis, HLA-DRB1*15:01 relates to poorer EBV control and higher autoimmune risk: example of how viral persistence + immune evasion can provoke autoimmune disease.
- These parallels support the plausibility that HLA-II + antigen persistence + autoimmunity explain phenomena in Long COVID and ME/CFS.
This work would not have been possible without the support of the Solve ME/CFS Initiative fellowship and the dedication of Dr. Bruno Pasiva’s team and Aintzane Zabaleta at CIMA, University of Navarra, to whom we express our deepest gratitude.
Read the full article:
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710571/full
