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Review 1: "Brain-targeted Autoimmunity is Strongly Associated with Long COVID and Its Chronic Fatigue Syndrome as Well as Its Affective Symptoms"

Reviewers were overall positive in evaluating this preprint, finding it reliable to strong. Reviewers thought it was overall methodologically sound and important in advancing knowledge about Long COVID.

Published onNov 09, 2023
Review 1: "Brain-targeted Autoimmunity is Strongly Associated with Long COVID and Its Chronic Fatigue Syndrome as Well as Its Affective Symptoms"
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key-enterThis Pub is a Review of
Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms
Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Background: Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objectives: To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B. Methods: IgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof. Results: Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801. Conclusion: Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



The study investigated whether Long COVID, and its accompanying affective symptoms are associated with autoimmune response against neuron associated proteins and found that the increase in autoantibodies against myelin basic protein, myelin oligodendrocyte glycoprotein, and synapsin is closely associated with Long COVID disease. 

The World Health Organization (WHO) Delphi Consensus defined Long COVID as the post-COVID-19 condition that occurs in individuals with a history of SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. This definition indicates that the Long COVID seems to be COVID-19 with persistent symptoms and more serious cases. In some sense, Long COVID is post sequalae of COVID-19 and the damage of the body requires longer time for recovery. Although Long COVID involves multi organs and multi systems of the body, the most common, persistent and disabling symptoms are due to the damage in the nervous system. The pathological mechanisms underlying Long COVID remain to be elucidated.

Many hypotheses have been proposed as the mechanisms of Long COVID, including single or multiple organ damage, the existence of a persistent SARS-CoV-2 reservoir or latent virus reactivation (such as Epstein–Barr virus), immune response and inflammatory reaction, and autoimmunity 1. 

In the regard of autoimmunity, autoantibodies have been found in acute phase of infection with neurological symptoms 2; 3. Antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens (ENA) were found in convalescent 4. ANA levels were significantly higher in COVID-19 patients 3 months after recovery and decreased thereafter. In particular, the higher autoantibody titers, the greater severity of acute disease patients had. In Long COVID, autoantibodies against cytokines were found with antibodies against IL-2, CD8B, and thyroglobulin IgG in over 10% of the patients 5. However, no clear association between the levels of autoantibodies with the severity of symptoms has been investigated 1.

The gap was filled by the paper “Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms”. In this article, Almulla AF et al. investigated the link between autoimmunity against neuron associated proteins and the symptoms or severity of Long COVID. They not only found that brain reactive autoantibodies directed against myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), tubulin, CP2, and synapsin are elevated in patients with Long COVID disease, but also illustrated that the severity of the physio-affective phenomena of Long COVID correlates with increased levels of IgM/IgA-synapsin, IgA/IgG-MBP, IgG-MOG, and CRP and AOPP, suggesting that autoimmune responses directed at neuron associated proteins play a key role in Long COVID disease.

The weakness in this article is that the authors selected targets limited to some neuron associated proteins, given so many neurological associated proteins could be candidates. In addition, the autoimmune response in COVID-19 seems to be systemic. The study focused on neuron-associated markers, only illustrating the tip of the iceberg and the conclusion is primary. It is premature to claim that these are predictive parameters for Long COVID. 

The recruitment of patients in part 1 in Iraqi and part 2 in California is not generalized, possibly resulting in error of geographic bias of selection. In addition, there are some typos in the article, such as phenome. For more specific, the target proteins of this study are not all neuron specific, they are better described as neuron associated proteins in cluster. Anyway, the publication of this article will contribute to the literature pool in progress for exploring the pathogenesis of Long COVID.


  1. Altmann DM, Whettlock EM, Liu S, Arachchillage DJ, Boyton RJ. The immunology of long COVID. Nat Rev Immunol 2023; 23: 618-34. https://doi:10.1038/s41577-023-00904-7

  2. Wong AKH, Woodhouse I, Schneider F, Kulpa DA, Silvestri G, Maier CL. Broad auto-reactive IgM responses are common in critically ill patients, including those with COVID-19. Cell Rep Med 2021; 2: 100321. https://doi:10.1016/j.xcrm.2021.100321

  3. Chang SE, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun 2021; 12: 5417. https://doi:10.1038/s41467-021-25509-3

  4. Son K, et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms. Eur Respir J 2023; 61. https://doi:10.1183/13993003.00970-2022

  5. Rojas-Macetas A, et al. Potential polymorphic CYP1A2 and CYP2D6-mediated pharmacokinetic interactions between risperidone or olanzapine and selected drugs intended to treat COVID-19. Drug Metab Bioanal Lett 2022. https://doi:10.2174/1872312815666221125112724 

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