Update on Neurologic Post-Acute Sequelae of SARS-CoV-2 Infection

The concept of “original antigenic sin” may play an important role in the pathogenesis of neurologic post-acute sequelae of SARS-CoV-2 (neuroPASC), according to research presented at the American Academy of Neurology (AAN) 2023 Annual Meeting, held from April 22-27. “Original antigenic sin” describes the process in which immunity against pathogens or antigens is created by the host's first exposure to a related pathogen or antigen. Researchers aimed to understand the role of antibodies and innate immune responses that might contribute to neuroPASC in what is primarily a respiratory pathogen (SARS-CoV-2).

Researchers used a systems serology approach to profile the antibody responses against SARS-CoV-2 and other viruses (including common coronaviruses) found in the serum of individuals infected with SARS-CoV-2, differentiating those who did (n=18) and did not (n=94) subsequently develop neuroPASC. In those who developed neuroPASC, they compared serum and cerebrospinal fluid (CSF) antibody responses and identified prognostic factors for positive versus negative outcomes.

Those with neuroPASC showed lower systemic antibody responses against SARS-CoV-2, including antibody-dependent complement deposition (ADCD), antibody-dependent NK cell activation (ADNKA), and Fcg receptor binding.No differences were foundin antibody responses to Epstein-Barr virus, influenza virus, or herpes simplex virus type 1. Researchers were surprised to see that there were expanded antibody responses to common coronaviruses, which suggested original antigenic sin.

Whereas with neuroPASC, serum analyses detected all antibody isotypes/subclasses, CSF indexes were characterized by IgG1 and absence of IgM, perhaps “suggesting compartmentalized humoral responses within the CSF through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis.”