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.
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Review: The SARS-CoV2 pandemic was unprecedented in numerous ways including the world-wide devastating impact on lives, health and health care resources, the implementation of unprecedented public health measures (2), introduction and mandated use of novel vaccines and vaccine strategies (3, 4), a remarkable explosion of literature, particularly in the link of COVID-19 to autoimmune diseases and autoimmunity, in some individuals manifest as a spectrum of neurologic, cardiac, gastrointestinal and musculoskeletal diseases, referred to as “Long COVID” (5). The etiology of autoimmune diseases has long been attributed to multiple interacting factors (genetic predisposition and environmental factors) (6)including infectious disease “triggers’, a link that has not been particularly clear to date (7). Hence, it is only natural that immunologists such as Flak et al (1) are vigorously studying the association of COVID-19 with autoimmunity.
The report of Falk, et al (1) is one of several that have explored in detail the association of COVID-19 with known and novel autoantibodies. In this study, more than 20 autoantibody targets were identified by immunoscreening “in house” human peptide arrays with sera from health care workers (HCW) and hospitalized individuals who had contracted COVID-19. Of the more than 20 putative autoantigens identified, many were “unique” and directed to intracellular and extracellular components. A limitation of the study is the lack of non-COVID-19 contemporaneous patient comparators admitted to hospital with a severe respiratory (or other clinically similar features) (7). Indeed, this is a limitation of numerous previously published studies that reported various biomarkers attributed to COVID-19; many used normal health individuals as comparators. Two studies that used contemporaneous patients admitted to an intensive care did not find significantly different autoantibodies to previously reported target autoantigens (8, 9). It is noteworthy that previous coronavirus epidemics (i.e., SARS-CoV1, Middle Eastern respiratory syndrome coronavirus (MERS-CoV)) were not reported to be associated with the appearance of disease risk-increasing autoantibodies (e.g., anti-Type I interferon) or a wide range of others cited in the manuscript. Hence, the specificity of biomarkers attributed to SARS-CoV2/COVID-19 remains largely unresolved.
By definition, since long-term follow-up was important, this study did not include patients who succumbed to COVID-19 or its complications. Perhaps this is why there is no mention of interventions (i.e., mechanical ventilation, ECMO) or medications that were used in the patients or HCW, which might be critical features of autoantibody induction or abrogation. Interestingly, anti-SNURF (SNRPN upstream reading frame protein) was associated with COVID-19 vaccine administration. SIGLEC1 is listed in Table 1 ( but not mentioned again) is of particular interest because it has been reported to be a surrogate marker for Type1 interferon signatures (10-12) especially in the context of the studies reporting that antibodies to Type1 IFN were a key factor in COVID-19 outcomes (7, 13) (and several citations in this manuscript).
A questionable aspect of this study is the notion that molecular mimicry may play a role in breaking immune tolerance leading to the appearance of certain autoantibodies listed in Table 1. The claim is that a domain of the amino terminus of the SARS-CoV2 spike glycoprotein shares some sequence identity with 13-14mer peptides of some target autoantigens: notably CCDC63 (175-189), NPC1 (566-580), SNURF (50-64), TPO (918-932), TRIM63 (234-247), TRIM63|236-249, and ANO2 (135-149). First, it needs to be recognized that the SFIEDLLFNK spike decapeptide is widely expressed in other viruses and is not unique to SARS-CoV2. This begs the question raised earlier, why autoantibodies have not been reported to be a key feature or sequelae of other coronavirus infections. Second, a BLASTp search reveals that numerous human proteins share higher sequence identity with the SFIEDLLFNK decapeptide than the proteins identified in this study. Four or five shared residues out of 14 amino acid matches is hardly a compelling case for molecular mimicry especially when many other human proteins share much higher sequence identity with the N-terminal spike domain: (e.g., E3 ubiquitin ligase (UBR3) at 75% and various myosin isoforms at ~63% have higher sequence identity scores than the proteins (highest being CCD73 showing only 56% sequence identity) identified in this study. Therefore, the claim implicating molecular mimicry requires much more study and thus far, it does not explain the appearance of the various autoantibody targets identified in this report.
References
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Gheorghita R, Soldanescu I, Lobiuc A, Caliman Sturdza OA, Filip R, Constantinescu-Bercu A, et al. The knowns and unknowns of long COVID-19: from mechanisms to therapeutical approaches. Front Immunol. 2024;15:1344086.
Mahrokhian SH, Tostanoski LH, Vidal SJ, Barouch DH. COVID-19 vaccines: Immune correlates and clinical outcomes. Hum Vaccin Immunother. 2024;20(1):2324549.
Stehlik P, Dowsett C, Camacho X, Falster MO, Lim R, Nasreen S, et al. Evolution of the data and methods in real-world COVID-19 vaccine effectiveness studies on mortality: a scoping review protocol. BMJ Open. 2024;14(3):e079071.
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Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, De Roos AJ. Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J Autoimmun. 2012;39(4):259-71.
Damoiseaux J, Dotan A, Fritzler MJ, Bogdanos DP, Meroni PL, Roggenbuck D, et al. Autoantibodies and SARS-CoV2 infection: The spectrum from association to clinical implication: Report of the 15th Dresden Symposium on Autoantibodies. Autoimmun Rev. 2022;21(3):103012.
Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis. 2021;80(9):1236-40.
Trahtemberg U, Fritzler MJ, On behalf of the C-cotLBiLIsg. COVID-19-associated autoimmunity as a feature of acute respiratory failure. Intensive Care Med. 2021;47(7):801-4.
Oliveira JJ, Karrar S, Rainbow DB, Pinder CL, Clarke P, Rubio Garcia A, et al. The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus. Arthritis Res Ther. 2018;20(1):152.
Graf M, von Stuckrad SL, Uruha A, Klotsche J, Zorn-Pauly L, Unterwalder N, et al. SIGLEC1 enables straightforward assessment of type I interferon activity in idiopathic inflammatory myopathies. RMD Open. 2022;8(1).
Rose T, Grutzkau A, Hirseland H, Huscher D, Dahnrich C, Dzionek A, et al. IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2013;72(10):1639-45.
Bastard P, Gervais A, Le Voyer T, Philippot Q, Cobat A, Rosain J, et al. Human autoantibodies neutralizing type I IFNs: From 1981 to 2023. Immunol Rev. 2024.
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