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Review 3: "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 28, 2024
Review 3: "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 of this manuscript have longitudinally investigated new-onset autoantibodies in healthcare workers and hospitalized COVID-19 patients. This study convincingly shows elevation of autoantibodies against a wide range of antigens following SARS-CoV-2 infection. Such polyreactivity after COVID-19 has been well documented and this study is a methodologically solid addition to the literature. 

However, it is unclear whether these autoantibodies are truly 'functional' in the sense that they can impair the function of the targeted proteins. Other studies have found autoantibodies that do not impair function of their target epitopes (for example ACE2). As the linear epitopes for some of these autoantibodies have been worked out, it might be possible to answer this question if functional domains are known. 

Although the authors demonstrate an association between some of these autoantibodies and neuropsychiatric symptoms after COVID-19, the link remains tentative mechanistically given that some targets like CALU are not known to be expressed in neural tissue and others like SNURF are of unknown function. Similarly, the clinical relevance of anti-SNURF IgG after vaccination is unclear. It is also unknown to what extent such polyreactivity is unique to COVID-19; other viral infections such as cytomegalovirus, hepatitis E virus etc are well-associated with autoreactivity. 

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