Autoantibodies analysis in Long COVID and ME/CFS

Dr. Keyla Sà presented research investigating whether autoantibodies contribute to the development of Long COVID and ME/CFS. Large population studies involving more than six million individuals across multiple countries showed that COVID-19 increases the risk of developing autoantibodies, leading her team to investigate whether autoantibodies might be involved in Long COVID pathology. Using cohorts of Long COVID patients, recovered COVID-19 patients, healthy controls, and patients with ME/CFS, the researchers purified immunoglobulin G (IgG) antibodies and examined their binding patterns in human and mouse tissues. They found that autoantibodies from approximately 60% of Long COVID patients bound strongly to human tissues, particularly components of the vasculature, including endothelial cells and pericytes. This suggested that infection-induced autoantibodies may target blood vessels and potentially contribute to neurological dysfunction. The team also found that Long COVID patients possessed more than 7,000 unique antibody targets not found in controls. Many of these targets overlapped with those observed in ME/CFS patients, suggesting shared biological mechanisms. Tissue-enrichment analyses revealed that the majority of these targets were associated with neurological tissues, particularly the brain, although some peripheral tissues were also affected. A key observation was the remarkable heterogeneity among patients. No single autoantibody target was shared by all Long COVID patients. Instead, each patient exhibited a unique pattern of autoantibody reactivity, indicating that Long COVID may involve a broad autoimmune response rather than a single disease-causing antibody. Cluster analyses identified two distinct subgroups of Long COVID patients with different autoantibody profiles. One subgroup showed a higher prevalence of chronic pain, and several targets correlated with symptom severity. Among all symptoms examined, headache showed the strongest association with specific autoantibody responses. The team further validated their findings in experiments using human brain homogenate followed by mass spectrometry. Additional validation showed elevated autoantibodies against several candidate targets, including proteins associated with endogenous retroviruses, multiple G protein-coupled receptors (GPCRs), and the N-methyl-D-aspartate (NMDA) receptor, which emerged as one of the most striking findings. To determine whether these autoantibodies actively contribute to disease, the researchers purified IgG from Long COVID patients and injected it into mice. Mice receiving autoantibodies from Long COVID patients developed increased pain sensitivity, demonstrating reduced latency in pain-response tests. Importantly, autoantibodies from patients who reported chronic pain produced pain-related behaviors in mice, whereas autoantibodies from patients without pain symptoms did not. This suggested a direct relationship between patient symptoms and autoantibody pathogenicity. Mice receiving Long COVID autoantibodies also showed clear damage to nociceptors, including reductions in nerve fiber density and volume. These structural abnormalities persisted over time and were particularly pronounced when autoantibodies originated from patients experiencing chronic pain. Dr. Sá concluded that both Long COVID and ME/CFS are characterised by diverse autoantibody responses that predominantly target neurological tissues and blood vessels. The findings support the hypothesis that autoimmune mechanisms contribute to the neurological manifestations of Long COVID and suggest important biological overlaps with ME/CFS. Future work will focus on determining exactly how these autoantibodies cause disease, including whether they act through immune cells such as macrophages and neutrophils or by triggering neuroinflammatory processes such as microglial activation.