Autoantibodies Neutralizing Type I Interferons Found Responsible For 20 Percent Of All COVID-19 Deaths

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French researchers from Robert Ballanger Hospital-France, Necker Hospital for Sick Children-France and University of Paris have in a new study found that that autoantibodies neutralizing type 1 interferons found responsible for 20 percent of all local COVID-19 deaths.

The study findings shocking also found persistence of neutralizing Auto-Abs almost 1 year after COVID-19 infection in certain patients. Risk associated with this persistence is not known to date but must be explored, especially given the potential impact of these auto-Abs on the severity of other viral diseases, as described for adverse reactions following yellow-fever vaccination.
 
The study team aimed to assess the prevalence and clinical impact of the auto-Abs to type I IFNs in the Seine-Saint-Denis district, which was one of the most affected areas by COVID-19 in France during the first wave.
 
The study team tested for the presence of auto-Abs neutralizing type I IFNs in a cohort of patients admitted for critical COVID-19 pneumonia during the first wave in the spring of 2020 in the medicine departments at Robert Ballanger Hospital, Aulnay sous Bois.
 
The team found circulating auto-Abs that neutralized 100 pg/mL IFN-α2 and/or IFN-ω in the plasma (diluted 1/10) of 7.9% (11 of 139) of the patients hospitalized for critical COVID-19.
 
The presence of neutralizing auto-Abs was associated with an increased risk of mortality, as these auto-Abs were detected in 21% of patients who died from COVID-19 pneumonia. Deceased patients with and without auto-Abs did not present overt clinical differences.
 
The study findings confirmed both the importance of type I IFN immunity in host defense against SARS-CoV-2 infection and the usefulness of detection of auto-Abs neutralizing type I IFNs in the management of patients.
 
The study findings were published in the peer reviewed Journal of Clinical Immunology. https://link.springer.com/article/10.1007/s10875-021-01203-3


Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection.

Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis.

Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.

referene link : https://www.nature.com/articles/nri3787#:~:text=Type%20I%20interferons%20(IFNs)%20have,for%20host%20defence%20against%20viruses.


Recent studies showed the important role of type I Interferons (IFNs) in protective immunity against SARS-CoV-2. Inborn errors of type I IFNs immunity were described in patients with life threatening COVID-19.

Rare inborn errors of autosomal genes controlling Toll-like receptor 3 (TLR3) and interferon regulatory factor 7 (IRF7)-dependent type I IFNs immunity were initially described [3] and more recently X-linked recessive TLR7 deficiency [4].

These inborn errors impair the production or amplification of type I IFNs in response to SARS-CoV-2. Deficiency of the TLR3 pathway incriminated pulmonary epithelial cells, while that of the TLR7 pathway incriminated plasmacytoid dendritic cells.

Interestingly, several studies showed that at least 10% of patients with life threatening (critical) COVID-19 pneumonia presented autoantibodies (auto-Abs) neutralizing type I IFNs, mostly the thirteen individual IFN-α and IFN-ω [5]. These auto-Abs were present before infection by SARS-CoV-2 in the patients tested and in 0.33% of uninfected controls from before the pandemic.

They were not detected in patients with asymptomatic or mild SARS-CoV-2 infection. They were also shown to block the anti viral activity of correspondent type I IFNs against SARS-CoV-2 in vitro and in vivo [5].These findings were replicated in other cohorts in Amsterdam, Madrid, San Francisco, Lyon, and New Haven [6,7,8,9,10,11,12,13].

Recently, auto-Abs neutralizing lower, more physiological concentrations of type I IFNs (100 pg/mL, in 1/10 dilutions of plasma) were detected in 15 to 20% of patients with critical COVID-19, notably in more than 20% of critical patients over 80 years of age. When also considering auto-Abs to IFN-β, they were present in about 20% of deceased patients across all ages [14].

Surprisingly, the study of more than 34,000 individuals showed that the prevalence of these auto-Abs in the general population increases with age, notably after the age of 70 (4%), providing an explanation for the increased risk of severe COVID-19 with age [14].

In this context, we aimed to assess the prevalence and clinical impact of the auto-Abs to type I IFNs in Seine-Saint-Denis department, which was one of the most affected areas by COVID-19 in France during the first wave of the pandemic [15]. We thus tested for the presence of auto-Abs to type I IFNs neutralizing different doses in a cohort of patients admitted for critical COVID-19 pneumonia during the first wave in the spring of 2020. Moreover, a commercial ELISA kit for the determination of anti–IFN-α2 auto-Abs was also evaluated.

. . . .

Previous studies showed that patients with neutralizing auto-Abs against type I IFNs were mostly men (94%) and that half were older than 65 years [5]. Moreover, it was recently shown that proportion of patients with critical COVID-19 having neutralizing auto-Abs increased with age [14]. In our study, although differences were not significant with regard to the patients without neutralizing auto-Abs, most of patients (82%) with neutralizing auto-Abs were men and over the age of 65 years.

The full engagement status was significantly less frequent in patient with auto-Abs than in patients without auto-Abs but like other studies [7, 9], there was no difference for comorbidities. Unlike to study by Troya et al. [7], where a significant correlation between the presence of auto-Abs neutralizing type I IFNs, raised levels of C-protein reactive, and low lymphocytes counts was observed, in our study, no difference was seen for these biological characteristics.

It is nevertheless important to note that we compare biological characteristics obtained at hospital admission, and not maximum levels of C-protein reactive and minimum levels of lymphocytes count.

Neutralizing antibodies against type I INFs was described in almost all of patients with auto immune polyendocrinopathy syndrome type I [18,19,20] but also in patients with thymoma, myasthenia gravis [21] and systemic lupus erythematosus [22,23,24]. In our cohort, these autoimmune diseases were not described in patients with neutralizing auto-Abs, although 2 of 11 (18%) patients with neutralizing Auto-Abs against type I IFNs had a history of psoriasis. Research of antinuclear antibodies (ANA) did not reveal high titer of ANA in the 6 patients that were analyzed.

Like in a previous study [14], the presence of neutralizing auto-Abs is associated with a more frequent mortality. Up to 21% of patients who died of COVID-19 pneumonia in our study had auto-Abs capable of neutralizing 100 pg/mL type I IFNs in plasma 1/10. Deceased patients with auto-Abs did not present overt clinical differences with deceased patients without auto-Abs. These results confirm importance of the IFN-I pathway in the defense against SARS-CoV-2 infection.

Overall, the detection of neutralizing Auto-Abs against type I IFNs is therefore important due to clinical applications, notably therapeutics. All COVID-19 patients should be screened for these autoantibodies in order to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Moreover, early identification of COVID-19 patients with auto-Abs should prompt early treatment and preventive management.

As high titers auto-Abs against IFN-2 in ELISA are well correlated with neutralizing activity of auto-Abs, this commercial ELISA should be used to detect easily, in routine clinical practice, neutralizing anti IFN-2 auto-Abs. Nevertheless, to our knowledge, no commercial ELISA exists to detect anti IFN- auto-Abs. It would be necessary to complete detection of anti IFN-2 auto-Abs with a functional evaluation of neutralizing anti IFN- auto-Abs, notably if low IFN-2 auto-Abs levels or no IFN-2 auto-Abs are detected.

Lastly, our study describes persistence of neutralizing Auto-Abs almost 1 year after COVID-19 infection in two patients. Risk associated with this persistence is not known to date but must be explored, especially given the potential impact of these auto-Abs on the severity of other viral diseases, as described for adverse reactions following yellow-fever vaccination [25].

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