“Original antigenic sin” may play a role in the humoral immune response to SARS-CoV-2 immunity and could impact neurologic post-acute sequelae of SARS-CoV-2.
The pathogenesis of neurologic post-acute sequelae of SARS-CoV-2 (neuroPASC) remains unclear. The current study concentrated on the role of the patient’s antibodies and innate immune response in the mechanisms of neuroPASC. Using the serum of patients infected with SARS-CoV-2, a systems serology approach enabled unbiased in-depth profiling of antibody responses against SARS-CoV-2 and other viruses, including non-coronaviruses. Among those who developed neuroPASC, the researchers compared serum and antibody responses.
Of 112 patients with a SARS-CoV2-infection, 18 developed neurological complications; 94 did not. The results suggested that the antibody response to SARS-CoV-2 is compartmentalized in the cerebrospinal fluid (CSF) of patients with neuroPASC. This was suggested because, in these patients, all antibody isotypes/subclasses were detected in the serum, whereas CSF was mainly populated by less varied and less functional SARS-CoV-2-specific antibodies (IgG), while IgM antibodies were absent. This suggests a sieve across the blood-brain-barrier rather than intrathecal synthesis.
Another finding was that patients with neuroPASC had a lower systemic antibody response against SARS-CoV-2. There were no differences in antibody responses to Epstein-Barr virus, influenza virus, or herpes simplex virus type 1. Surprisingly, there were expanded antibody responses to other common coronaviruses in the neuroPASC-group, suggesting original antigenic sin, or immunological imprinting. This refers to the phenomenon in which prior exposure to an antigen shapes the subsequent (suboptimal) immune response to a related antigen. This “off-target” antibody response was even more pronounced in patients with neuroPASC with a poor outcome, suggesting it may serve as a prognostic biomarker. This skewed antibody activation may reduce viral clearance and increase neuro-inflammation, contributing to neurological symptoms.
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