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Review 1: "Prevalent and Persistent New-Onset Autoantibodies in Mild to Severe COVID-19"

The findings suggest that novel autoantibodies identified in the study may serve as important biomarkers for predicting the onset and persistence of autoimmune diseases in individuals affected by COVID-19.

Published onMar 26, 2024
Review 1: "Prevalent and Persistent New-Onset Autoantibodies in Mild to Severe COVID-19"
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key-enterThis Pub is a Review of
Prevalent and persistent new-onset autoantibodies in mild to severe COVID-19
Prevalent and persistent new-onset autoantibodies in mild to severe COVID-19

Autoantibodies have been shown to be implied in COVID-19 but the emerging autoantibody repertoire remains largely unexplored. We investigated the new-onset autoantibody repertoire in 525 healthcare workers and hospitalized COVID-19 patients in five time points over 16 months using proteome-wide and targeted protein and peptide arrays. Our results show that prevalent new-onset autoantibodies against a wide range of antigens emerged following SARS-CoV-2 infection in relation to pre-infectious baseline samples and remained elevated for at least 12 months. We demonstrated associations between distinct new-onset autoantibodies and neuropsychiatric symptoms post-COVID-19. Using epitope mapping, we determined the main epitopes of selected new-onset autoantibodies, validated them in independent cohorts of neuro-COVID and pre-pandemic healthy controls, and identified molecular mimicry between main epitopes and the conserved fusion peptide of the SARS-CoV-2 Spike glycoprotein. Our work describes the complexity and dynamics of the autoantibody repertoire emerging with COVID-19 and supports the need for continued analysis of the new-onset autoantibody repertoire to elucidate the mechanisms of the post-COVID-19 condition.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Review: The authors have performed an overall well-thought-through study, with a well-written manuscript. However, the authors neglected to discuss the anti-idiotypic autoimmune antibodies directed towards ACE2, found in most patients, and the role in dysautonomia, and role in microvascular clotting disease, which contribute to the neurologic findings of Long-COVID.

The authors use 13-15-mer peptides in their arrays. Of note, Ramaraj, BBA 2012, has studied antibody binding. It is well-known that antibodies bind to three-dimensional epitopes, which have exposed residues, and not to linear AA epitopes. Linear AA peptides of 8-16 AA are bound in HLA for T lymphocyte TcR binding and recognition. TcR and antibody epitopes are different, The antibody epitope has about 12 exposed AA residues, and the paratope ~22 exposed AA acid residues. In alpha-helical structure, the "side" of the epitope facing the paratope has an AA residue every 3.6 AA. Thus, nearly 48 AA would need to be in a peptide to allow for the 12 AA residues to be accessible for antibody paratope binding specificity. 13-15-mers would have only 3 or 4 AA residues for antibody binding. Thus antibody specificity can not be assured. When the authors mention, for example, peptide CCDC63]175-189, are these exposed or buried AA in the protein tertiary structure? The authors need to comment on this major limitation in their study. They need to specifically comment on the solution exposure of the peptides in the protein tertiary structure, or whether the AA are buried in the structure. They need to comment that the 13-15-mer peptides used in the arrays may allow for promiscuous binding of antibodies, not specific for the three-dimensional protein from which the peptide has been derived.

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