Data from: Autoantibody landscapes in neurological Long COVID and post-COVID cognitive impairment show heterogeneity without a shared disease signature

Neurologic Long COVID (n-LC) includes persistent cognitive and autonomic
symptoms after SARS-CoV-2 infection. Prior studies of post-COVID
conditions have described diverse humoral autoreactivity, but findings are
heterogeneous, and it remains unclear whether n-LC is associated with a
consistent CNS-directed humoral signature. We performed a cross-cohort
case-control analysis to detect autoantibodies in cerebrospinal fluid
(CSF) and serum from n-LC participants. In the Yale COVID Mind Study, CSF
from n-LC participants and from pre-pandemic and post-COVID asymptomatic
controls was assessed by mouse brain immunofluorescence and proteome-wide
phage immunoprecipitation sequencing (PhIP-seq), with candidate
reactivities evaluated by orthogonal assays and supervised modeling. In
the Epidemiology, Immunology, and Clinical Characteristics of Emerging
Infectious Diseases with Pandemic Potential (IDCRP EPICC) cohort,
post-COVID sera collected prior to iPhone- or iPad-based cognitive
screening were profiled by PhIP-seq and compared between participants with
and without cognitive impairment. CSF immunoreactivity on mouse brain
tissue was observed in both n-LC and controls, with similar overall
frequencies, although n-LC participants more often showed
nuclear-predominant staining patterns. PhIP-seq identified sparse, largely
patient-specific peptide reactivities to nuclear and neuronal proteins in
CSF and serum. Supervised models provided limited discrimination between
cases and controls. Candidate autoantigens had limited disease specificity
on orthogonal testing. EPICC serum profiling similarly failed to
distinguish individuals with and without cognitive impairment. Across
cohorts and compartments, n-LC did not exhibit a shared autoantibody
signature. These findings support the absence of a dominant, common CNS
autoantibody-mediated mechanism in n-LC.