Rogue antibodies could be driving severe COVID-19

Khamsi, Roxanne

doi:10.1038/d41586-021-00149-1

Cited by 92 publications

(92 citation statements)

References 10 publications

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“…There is now increasing evidence that a great variety of autoantibodies may be driving severe forms of COVID-19. These autoantibodies may also play a crucial role in the extended multi-organ illness persevering for months in patients with “long-COVID-19” [ 13 ]. Furthermore, orthostatic cerebral hypoperfusion, hypotension, and small fiber neuropathy have been described [ 14 ].…”

Section: Me/cfs In Post-covid-19 Patients and Therapeutic Optionsmentioning

confidence: 99%

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Bornstein

Voit-Bak²,

Donate³

et al. 2021

Mol Psychiatry

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As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called “post-COVID syndrome” or “long-COVID” [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

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Section: Me/cfs In Post-covid-19 Patients and Therapeutic Optionsmentioning

confidence: 99%

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Bornstein

Voit-Bak²,

Donate³

et al. 2021

Mol Psychiatry

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“…Defective IFN I ( 13) , ( 14) , (15) and overactive B-cell responses and autoantibodies against interferons were detected specifically in patients with severe courses of COVID-19 (16), but the role of pathogenetically or "self-attacking" antibodies has so far not yet been clearly established (17). Previously, we had identified neutralizing autoantibodies against progranulin (PGRN) in sera from patients with primary small vessel vasculitis (18).…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19

Thurner¹,

Fadle²,

Bewarder³

et al. 2021

Preprint

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STRUCTURED ABSTRACTINTRODUCTIONHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far.RATIONALEIn the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations.RESULTSPGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL-1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN-nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF-α signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found.CONCLUSIONTo conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

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“…It might, therefore, be a perfect candidate for initiating the autoimmune process in a COVID-19 patient, as often observed [ 6 , 7 , 9 , 10 , 11 ] and even discussed to be a reason for disease severity [ 12 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, it must also be considered that the involvement of cross-reactive anti-SARS-CoV-2 antibodies in severe and long-lasting disease courses (Long-COVID) is increasingly being discussed [6][7][8][9][10][11][12][13]. These different types of anti-SARS-CoV-2 ABs have to be distinguished.…”

Section: Introductionmentioning

confidence: 99%

Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

Haberland

Krylova

Nikolenko

et al. 2021

Viruses

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COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0–21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.

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Rogue antibodies could be driving severe COVID-19

Cited by 92 publications

References 10 publications

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19

Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

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