Transient Increase of Pre-existing Anti-IFN-α2 Antibodies Induced by SARS-CoV-2 Infection

Steels, Sophie; Elslande, Jan Van; Cockx, Maaike; Frans, Glynis; Imbrechts, Maya; Dillaerts, Doreen; Meyts, Isabelle; Geukens, Nick; Wauters, Els; Vermeersch, Pieter; Wauters, Joost; Munter, Paul De; Bossuyt, Xavier

doi:10.1007/s10875-022-01235-3

Cited by 15 publications

(12 citation statements)

References 4 publications

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“…While this broadly contrasts with the findings of others who noted an association between presence of anti-IFN autoantibodies and increased COVID-19 disease severity parameters [2,3,5,7], this difference could be explained by a lack of power in our exploratory study or masking effects of the high standard of care in a high-resource setting. Nevertheless, the proportion of critically ill COVID-19 patients in our cohort with anti-IFN autoantibodies is remarkably consistent with the findings from several independent severe COVID-19 cohorts recently studied across Europe, Asia, and the Americas, despite the use of different detection assays [2][3][4][5][6][7][8][9][10][11]24,25]. Indeed, in the future, it will probably be important to have standardized quantitative assays and reporting standards for such anti-IFN autoantibodies, as varying assay sensitivities may mean that their presence is under or overestimated.…”

Section: Discussionsupporting

confidence: 90%

“…We did not identify any patients who were unambiguously positive for anti-IFNβ autoantibodies. The identification of anti-IFN autoantibodies in approximately 10% of severe COVID-19 patients is fully in line with previous reports from others [2][3][4][5][6][7][8][9][10][11].…”

Section: Plos Biologysupporting

confidence: 91%

“…The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has highlighted a previously unappreciated type of functional IFN deficiency mediated by autoantibodies that neutralize the action of several type I IFNs, particularly the IFNα or IFNω subtypes [2], and rarely IFNβ [3]. Across multiple independent studies, around 10% of critically ill Coronavirus Disease 2019 (COVID-19) patients, but not those with very mild infections, have serum autoantibodies that inhibit the antiviral function of IFNα and/or IFNω in vitro [2][3][4][5][6][7][8][9][10][11]. Furthermore, presence of anti-IFN autoantibodies has been associated with 20% of all COVID-19 deaths, and this has disproportionately affected older individuals [3,12].…”

Section: Introductionmentioning

confidence: 99%

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Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

et al. 2022

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Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with predisposition to severe Coronavirus Disease 2019 (COVID-19). Here, we screened for such autoantibodies in 103 critically ill COVID-19 patients in a tertiary intensive care unit (ICU) in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFNα or anti-IFNα/anti-IFNω IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFNα IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically ill COVID-19 cohort appeared to predict herpesvirus disease (caused by herpes simplex viruses types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV)), which has been linked to worse clinical outcomes. Indeed, all 7 tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesviruses, and analysis revealed that these patients were more likely to experience CMV than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for age, gender, and systemic steroid treatment (odds ratio (OR) 7.28, 95% confidence interval (CI) 1.14 to 46.31, p = 0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates the likelihood of latent herpesvirus reactivations in critically ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04410263.

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Section: Discussionsupporting

confidence: 90%

Section: Plos Biologysupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

et al. 2022

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“…Suppression of IFN production has been shown by the nucleocapsid proteins of both Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1 [60] . However, the debate of whether SARS-CoV2-mediated IFN signaling is delayed/disrupted or robust has been the focus of numerous COVID-19 studies [ 3 , 8 , 9 , 59 , [61] , [62] , [63] , [64] , [65] , [66] , [67] ].…”

Section: Serping1 Gene Regulation In the Context Of Sars Infectionmentioning

confidence: 99%

“…SARS-CoV-2 may not elicit strong type I IFN responses; however, the initial type I response seems to be critical for curbing life-threatening COVID-19 symptoms [ 58 , 59 ]. Recently published studies have shown that loss-of-function mutations in proteins critical to type I IFN responses and auto-antibodies against type I IFNs are associated with COVID-19 biomarkers and disease severity [ 58 , 59 , 64 , 65 , 67 ]. Moreover, pre-existing antibodies against cytokines and IFNs may predispose autoimmune disease patients to severe COVID-19 pneumonia [66] Thorne et al determined that type I IFN induction and sensitivity to IFN mediated inhibition were decreased with the SARS-CoV-2 Alpha variant.…”

Section: Serping1 Gene Regulation In the Context Of Sars Infectionmentioning

confidence: 99%

C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

Hausburg

Williams

Banton

et al. 2022

Clinical Immunology Communications

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Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

Hale

2023

Eur J Immunol

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The type I IFN (IFN‐I) system is essential to limit severe viral disease in humans. Thus, IFN‐I deficiencies are associated with serious life‐threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN‐Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti‐IFN‐I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti‐IFN‐I autoAbs, such as reduced self‐tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti‐IFN‐I autoAbs following “autoimmunization” with IFN‐Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN‐I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti‐IFN‐I autoAbs appear to have towards viral diseases such as severe COVID‐19, influenza, or herpes (e.g., varicella‐zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live‐attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti‐IFN‐I autoAbs will be key to implementing effective prophylactic and therapeutic measures.

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Transient Increase of Pre-existing Anti-IFN-α2 Antibodies Induced by SARS-CoV-2 Infection

Cited by 15 publications

References 4 publications

Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

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