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Original antigenic sin influences humoral immune response to SARS-CoV-2

AAN 2023
The ‘original antigenic sin’ may play an important role in shaping the humoral immune response to SARS-CoV-2 immunity and could consequently be a key factor in the pathogenesis of neurologic post-acute sequelae of SARS-CoV-2 (neuroPASC).

The pathogenesis of neuroPASC remains unclear. The current study concentrated on the role of the patient’s antibodies and innate immune response in the mechanisms of neuroPASC [1]. Using the serum of SARS-CoV2-infected patients who did or did not develop neuroPASC, a systems serology approach enabled unbiased in-depth profiling of antibody responses against SARS-CoV-2 and other viruses (including non-Coronaviruses). Among those patients who did not develop neuroPASC, the researchers compared serum and antibody responses to identify factors predictive of good versus bad neurological outcomes.

Of 112 patients with a SARS-CoV2-infection, 18 developed neuroPASC. In patients with neuroPASC, all antibody isotypes/subclasses were detected in the serum, whereas the CSF was mainly populated with SARS-CoV2-specific antibodies (IgG), and IgM antibodies were absent. This suggests a sieve and selective transfer of antibodies across the blood-brain barrier and compartmentalised humoral responses within the CSF rather than intrathecal synthesis.

Overall, patients with neuroPASC showed a lower systemic antibody response against SARS-CoV-2 than non-neuroPASC controls. In contrast, antibody responses to Epstein-Barr virus, influenza virus, or herpes simplex virus type 1 were not different between groups. Surprisingly, there were expanded antibody responses to other common Coronaviruses in the neuroPASC group, suggesting a phenomenon referred to as the ‘original antigenic sin’ or immunological imprinting. This phenomenon occurs when prior exposure to an antigen shapes the subsequent (suboptimal) immune response to a related antigen.

This skewed humoral response was selectively enriched in the patients with neuroPASC and poor outcomes, suggesting that the original antigenic sin effect may serve as a prognostic biomarker for neuroPASC. Mechanistically, this skewed antibody activation may reduce viral clearance and increase neuro-inflammation, contributing to neurological symptoms.

  1. Spatola M. Serum and cerebrospinal fluid antibody signatures track with outcome of neurologic post-acute sequelae of SARS-Cov-2 infection (NeuroPASC). S21.006, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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