A causal link between autoantibodies and neurological symptoms in long COVID

Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in Long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluorescence, ELISA, human protein array, and mass spectrometry assays, we identified a broad range of AAB targets among individuals with LC. Individuals with neurocognitive symptoms showed increased AABs against central and peripheral nervous system proteins. Purified IgG reacted with human locus coeruleus, thalamus, adrenal gland, thyroid, and cross-reacted with mouse sciatic nerve and meninges. CNS-reactive AABs correlated with several neurological symptoms. MED20-targeting IgG from patients with LC showed enhanced antibody-dependent phagocytosis. Passive transfer of IgG from individuals with LC into mice induced fatigue-like behavior, loss of balance/coordination, thermal hyperalgesia, small fiber nerve damage, and increased pain-related neuronal activity, recapitulating patients symptoms. These findings suggest that targeting AABs might offer therapeutic benefits for this LC subgroup.