Autoantigen profiling reveals a shared post-COVID signature in fully recovered and long COVID patients

Abstract

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as long COVID. The underlying pathophysiology of long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of SARS-CoV-2 infection and certain other post-COVID sequelae, their potential role in long COVID is important to investigate. Here, we apply a well-established, unbiased, proteome-wide autoantibody detection technology (T7 phage-display assay with immunoprecipitation and next-generation sequencing, PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected that separated individuals with prior SARS-CoV-2 infection from those never exposed to SARS-CoV-2, we did not detect patterns of autoreactivity that separated individuals with long COVID from individuals fully recovered from COVID-19. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and long COVID was apparent by this assay.

The breadth of the neutralizing antibody response to original SARS‐CoV‐2 infection is linked to the presence of Long COVID symptoms

“…We previously utilized PhIP‐Seq technology to identify an autoreactive signature distinctive of prior SARS‐CoV‐2 infection within our LIINC cohort. However, the autoreactivities contained within this signature were similarly present in individuals with and without Long COVID symptoms 30 . To determine whether participants with a high breadth of SARS‐CoV‐2 cross‐variant neutralization as defined above and in Figure 3B had a distinctive autoantibody signature, we reanalyzed these PhIP‐Seq data for this particular study population.…”

“…To determine whether high neutralization breadth was associated with autoimmunity, we reanalyzed previously described PhIP‐Seq data corresponding to certain individuals within this cohort (i.e., those with the top 15% of neutralization ID 50 s in both the original SARS‐CoV‐2 and BA.5 variant) which is publicly available at: https://doi.org/10.7272/Q6Z60M99 30 . Logistic regression machine‐learning classifiers were performed using our described methods, which have been previously used to feature‐weight autoantibody signal in multiple autoimmune and COVID‐related diseases 30,31 . Utilizing the Scikit‐learn package, logistic regression classifiers were applied to z ‐scored PhIP‐Seq values from individuals with a designated disease category versus the designated control.…”

“…30 Logistic regression machine-learning classifiers were performed using our described methods, which have been previously used to feature-weight autoantibody signal in multiple autoimmune and COVID-related diseases. 30,31 Utilizing the Scikit-learn package, logistic regression classifiers were applied to z-scored PhIP-Seq values from individuals with a designated disease category versus the designated control. A liblinear solver was used with L1 regularization.…”

Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy

“…We have previously shown that large numbers of healthy samples are required to control for this natural confounder and avoid false positive associations 17 . To better understand the variation of the autoreactive antibodies between and within healthy individuals, we obtained serum from 79 pre-COVID healthy blood donors (“Healthy” demographics in Extended Data Table 1) and used our customized, previously described 768,000 element phage immunoprecipitation and sequencing platform(PhIP-Seq) 11,17–21,34 to determine the proteome-wide set of autoreactivities present within each individual (hereafter referred to as the “autoreactome”).…”

“…donors ("Healthy" demographics in Extended Data Table 1) and used our customized, previously described 768,000 element phage immunoprecipitation and sequencing platform(PhIP-Seq) 11,[17][18][19][20][21]34 to determine the proteome-wide set of autoreactivities present within each individual (hereafter referred to as the "autoreactome"). To determine inter-and intra-individual similarity by PhIP-Seq requires high reproducibility as measured by technical replicate.…”