Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms.
Almulla, Abbas F, Maes, Michael, Zhou, Bo et al. · Journal of advanced research · 2025 · DOI
Quick Summary
This study found that people with Long COVID have unusual immune responses targeting the brain and nerve cells. Researchers measured antibodies (immune proteins) in people with Long COVID and healthy controls, discovering that Long COVID patients have significantly higher levels of antibodies attacking several brain proteins. These brain-targeted immune responses were strongly linked to fatigue severity and mood symptoms like depression and anxiety.
Why It Matters
This research provides biological evidence that brain-targeted autoimmunity contributes to Long COVID and ME/CFS pathology, potentially validating patient experiences of cognitive and emotional symptoms as disease mechanisms rather than psychological. Identifying specific antibody signatures could lead to diagnostic biomarkers and targeted treatments for this disabling condition.
Observed Findings
Long COVID patients showed significantly elevated IgG antibodies to tubulin, MBP, MOG, and synapsin compared to healthy controls.
Elevated IgM antibodies to MBP, MOG, CP2, synapsin, and blood-brain-barrier proteins were found in Long COVID group.
IgM and IgG antibodies to viral proteins (SARS-CoV-2 and HHV-6) correlated with brain-targeted antibodies.
IgG-MOG, CRP, and AOPP together explained 41.7% of the variance in chronic fatigue severity.
Seven specific antibodies and CRP achieved 80.1% predictive accuracy for affective (mood) symptoms.
Inferred Conclusions
Brain-targeted autoimmunity significantly contributes to Long COVID pathogenesis and disease severity.
Specific antibody profiles (particularly IgM-MBP and IgG-MBP) are the strongest predictors of Long COVID diagnosis.
Brain-targeted autoimmunity plays a major role in both the physical fatigue and emotional/affective symptoms observed in Long COVID and ME/CFS.
Viral reactivation or persistent viral antigens may trigger or sustain the brain-targeted autoimmune responses.
Remaining Questions
Does brain-targeted autoimmunity precede Long COVID symptoms, or does it develop as a consequence of infection and tissue damage?
What This Study Does Not Prove
This study demonstrates association but cannot establish causation—elevated antibodies may be consequences rather than causes of Long COVID. The cross-sectional design prevents determination of whether these autoimmune responses precede, follow, or occur simultaneously with symptom onset. Results cannot yet be generalized to all ME/CFS populations, as this cohort was specifically Long COVID patients.
Are these autoimmune responses specific to SARS-CoV-2-triggered Long COVID, or do they occur across different ME/CFS etiologies?
Could therapeutic removal or reduction of these brain-targeted antibodies improve symptom severity and functional outcomes?
What percentage of Long COVID patients outside this cohort would be identified by these antibody signatures, and do they vary by demographics or symptom phenotype?