Long COVID develops in more than 10% of individuals following SARS-CoV-2 infection and is frequently accompanied by neurological abnormalities.
Neurological symptoms of long COVID include fatigue, brain fog, dizziness, headache, memory impairment, sleep disturbances, mood changes, burning and tingling sensations, disorientation, hearing problems, fainting episodes, and facial numbness.
Because these symptoms occur more frequently in women, similar to many autoimmune diseases, researchers at Yale University hypothesized that autoantibodies may play an important role in the development of long COVID.
To test this hypothesis, the researchers analyzed IgG antibodies isolated from the blood of patients with long COVID. They examined which proteins and tissues these antibodies recognized using a protein microarray containing more than 21,000 human proteins.
The detection of autoantibodies against CNS and peripheral nervous system proteins in long COVID patients underscores their potential as biomarkers for selecting candidates for immunotherapeutic interventions.
Autoantibodies May Directly Contribute to Neurological Manifestations of Long COVID
Some patients with long COVID produce autoantibodies that target CNS structures, including the locus coeruleus and the thalamus – brain regions involved in regulating attention, stress responses, arousal, sensory processing, autonomic function, and emotional regulation.
Autoantibodies targeting regions such as the locus coeruleus and the meninges are linked to symptoms such as loss of smell, headaches, and nausea, underscoring their role in long COVID neurological manifestations.
Autoantibody Targets in Long COVID
One identified autoantigen was the protein MED20. Antibodies against MED20 may contribute to neurological symptoms of long COVID because other proteins within the same complex, MED12 and MED23, are already known to be associated with neurological disorders.
Patients with anti-MED20 antibodies displayed a more pro-inflammatory effector profile. They exhibited a reduced IgM-to-IgG ratio, indicating class switching toward the production of more specialized antibodies. This process was accompanied by activation of Fc receptors and antibody-dependent phagocytosis. However, anti-MED20 antibodies were detected in only a subset of patients, further highlighting the biological heterogeneity underlying long COVID.
Another autoantibody target was the NR2C subunit of the NMDA receptor. NMDA receptors play a critical role in neuronal signaling, learning, and memory. Disruption of NMDA receptor function by autoantibodies may lead to neurological and psychiatric symptoms, similar to those observed in anti-NMDA receptor encephalitis.
Transfer of Autoantibodies to Healthy Mice Induced Neurological Symptoms
When antibodies from long COVID patients were transferred into healthy mice, the mice developed symptoms similar to those in patients, underscoring the translational relevance of this research.
The mice exhibited damage to intraepidermal nerve fibers, which may correspond to the burning and tingling sensations reported by patients. They also showed activation of brain regions associated with pain perception, fatigue, and emotional dysregulation.
Potential Immunotherapy for Long COVID
If autoantibodies drive long COVID symptoms, immunotherapies like IVIG could offer promising treatment options, encouraging optimism among professionals.
One of the most promising approaches is intravenous immunoglobulin (IVIG) therapy, which may neutralize pathogenic autoantibodies and facilitate their removal. IVIG has shown benefit in patients with neurological manifestations of long COVID, including chronic fatigue, myalgic encephalomyelitis, and small-fiber neuropathy.
In addition to IVIG, other therapeutic strategies may be employed to reduce pathogenic antibody levels or block their effects. These include drugs that accelerate the degradation of circulating antibodies, agents that neutralize antibody activity, procedures that temporarily remove antibodies from the bloodstream, and therapies that suppress antibody-producing cells.
Reference
A causal link between autoantibodies and neurological symptoms in long COVID
