A causal link between autoantibodies and neurological symptoms in long COVID 2309692

Abstract Introduction Acute SARS-CoV-2 infection triggers the de novo production of diverse and functional autoantibodies (AABs), even after mild illness. Previous studies have shown that autoantibodies remain persistently elevated in a subset of individuals with Long COVID (LC). However, it is still unclear whether these autoantibodies drive pathogenesis of LC Methods Using a human protein array with over 21,000 proteins and an antibody pull-down of autoantigens followed by mass spectrometry, we identified a broad range of AAB targets among individuals with LC that correlated with their symptom profiles. In order to evaluate if those autoantibodies were pathogenic, we developed a passive transfer mouse model by injecting total IgG in mice and performing a battery of behavior analysis. Results We found increased AABs against proteins in the central and peripheral nervous systems, as well as peripheral tissues, in individuals with LC displaying neurocognitive and neurological symptoms. Purified immunoglobulin G (IgG) samples from these individuals reacted with tissue sections of human locus coeruleus, thalamus, adrenal gland, thyroid, and showed cross-reactivity with mouse sciatic nerve and meninges. Autoantibody levels reactive to CNS antigens were linked to symptoms such as headaches and loss of taste and smell. Passive transfer of IgG from patients to naïve mice caused increased fatigue-like behavior and thermal hyperalgesia, aligning with patients’ reports of chronic pain. Similarly, loss of balance and coordination in the rotarod test in mice injected with IgG matched with patient-reported dizziness. Moreover, transfer of purified IgG from patients with chronic pain caused damage to small peripheral nerve fibers and increased neuronal activity in pain-related brain regions in mice. Conclusion Our findings demonstrate that transferring IgG from LC patients into mice can reproduce certain neurological symptoms, suggesting that targeting AABs might offer therapeutic benefits for this subgroup of LC. Funding Source Pew Latin American Fellowship Topic Categories Immune Mechanisms of Human Disease (HUM)