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Important effects of type I interferon (IFN) autoantibodies on COVID-19

The emergence and rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused a pandemic of Coronavirus Disease 2019 (COVID-19). To date, more than 118 million cases have been confirmed and more than 2.6 million have died. The magnitude of the outbreak is complex and is only supported by the magnitude of the heterogeneity of clinical manifestations of the infection.

New preprint released in bioRxiv* The server describes the etiology of this condition by referring to autoimmune phenomena involving the major antiviral type I interferon pathway.

Unpredictability of COVID-19

For every 100 people infected with SARS-CoV-2, only about 15% develop symptoms.Less than one-tenth becomes serious illness, characterized by shortness of breath, pulmonary infiltrates, and low blood pressure Oxygen saturation.. Approximately one-quarter of hospitalized COVID-19 patients eventually develop serious illness and are intubated and ventilated.

These patients contribute to most deaths from COVID-19 and occupy most of the time in the health care worker during the course of the illness. Therefore, it is important to understand how these patients get sick.

Elucidate the immunological effects of SARS-CoV-2 infection and the underlying immunological causes of significant COVID-19, stratify patients in the early stages of their disease course, and available or new treatments Treatment should be targeted using the method. “

Interferon autoantibodies in COVID-19

The role of genes and existing immune dysfunction in disease progression after SARS-CoV-2 infection is an important area of ​​research. For example, type I interferon (IFN) is important in the earliest antiviral immune response in infected host cells.

Congenital errors in these cytokines, or the development of autoantibodies to these interferons, can make individuals more susceptible to severe COVID-19. Studies have shown that anti-type I IFN autoantibodies are extremely rare in healthy individuals and are absent in the case of asymptomatic COVID-19. However, they are found in more than one-tenth of important COVID-19 patients.

These are important in significant COVID-19 causes that are already associated with these individuals prior to infection, and in certain autoimmunity, hereditary diseases such as autoimmune polyglandular syndrome type 1 (APS-1). There may be.

Current studies seek to determine the development of such autoantibodies in patients without significant COVID-19, the levels of such antibodies over time, and their effect on circulating leukocytes.

Researchers will also examine the dynamic white blood cell profile of the disease as a whole, comparing it to changes seen in patients hospitalized with the same type of respiratory function for other conditions.

And finally, they examine potential predictors of changes in the patient’s innate and adaptive immunity, with or without such autoantibodies, for the adverse consequences of COVID-19.

How was the result?

This study focused on a cohort of 4,500 individuals, including a community of SARS-CoV-2 infections of varying grades of severity, convalescent COVID-19 patients, and almost asymptomatic individuals. I am.

Researchers found that of the 284 patients with recorded infections, one-fifth of those with serious illness had type I IFN autoantibodies, compared with severe and moderate illness. Then it was 6% and 0%, respectively. The overall proportion of men in the group was about 70%, while in the important group with autoantibodies it was about 80%.

About one-third of the community cohort consisted of Caucasian and Hispanic / Latino individuals, respectively, and 2% and 9% were black or Asian / Pacific Islands, respectively. All were asymptomatic, even if they were infected with the virus.

The prevalence of anti-IFN-α2 autoantibodies was only 0.3%, with no sexual orientation or preferred ethnicity. Therefore, such autoantibodies appear to be present infrequently before this infection is acquired.

Convalescent plasma Analysis from 175 donors showed a deficiency of anti-IFN-α2 antibody. This again gave zero positive results. This may be good news in the context of the use of convalescent plasma to treat patients with severe COVID-19.

Important COVID-19 leukocytes

The researchers used data from the COVID-19 Multiphenotyping (COMET) cohort for effective treatment in San Francisco, California. This effort included a longitudinal follow-up of approximately 70 inpatients with both peripheral blood mononuclear cells (PBMC) and serum samples.

All these patients COVID19 SymptomsHowever, only 54 were positive for the virus. Of the positives, 19 had serious illness and 18 and 17 had moderate and severe illness, respectively.

Anti-IFN-α2 autoantibodies were recovered from one-fifth of critical patients, all from the initial sample and beyond, but not from other patients. All critical patients showed an increase in B cells, plasma cells, and classical monocytes in circulating PBMCs.

CD8 + and gamma delta T cells (Tgd) have been found to be less frequent in critical cases. Interestingly, the presence of autoantibodies to IFN-α2 was associated with a lower frequency of these cells, but classical monocytes were more than important COVID-19 patients without these autoantibodies. it was high.

Although these changes are probably not due to a serious illness that justifies hospitalization, the difference in magnitude of these cell changes is between significant COVID-19 and other virus-negative but hospitalized patients. It is unique to critical COVID-19 because it was significant in. Symptoms like COVID-19.

Cell frequency tended to normalize over time, with the exception of classical monocyte overshoots.

The general equivalent composition of circulating leukocytes in important C19 + patients with or without anti-IFN autoantibodies is more widely conserved under the serious illness, especially in additional IFN-related pathologies in autoantibody-negative patients. Suggests the existence of a mechanism.. “

Impaired ISG expression in critical COVID-19

Researchers have observed that type I and type II interferon-stimulating genes (ISGs) are expressed at low levels of COVID-19, which is important on admission, compared to moderate or severe disease. .. The lowest levels were those of four important patients with autoantibodies, comparable to those of healthy individuals.

In all cases of moderate or severe illness, type I ISG expression was initially high but declined rapidly.

Low ISG expression levels were inversely associated with expression of surface proteins on bone marrow cells. One example is the classical monocyte inhibitory leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). This protein showed the highest levels in 4 severely ill COVID-19 patients who had autoantibodies to IFN-α2.

These findings may indicate that type 1 ISG suppression by a common underlying mechanism underlies important COVID-19, regardless of the presence of autoantibodies to anti-IFN-α2. The lack of such autoantibodies may indicate a defect in the type I IFN response.

In addition, LAIR-1 may be a specific biomarker for type I IFN response disorders.

What is the impact?

This study shows the presence of type I IFN autoantibodies in about one-tenth of patients with important COVID-19 across multiple ethnic groups, and more often in men with an average age of 55 years.

These autoantibodies clearly precede SARS-CoV-2 infection, and some individuals may indicate an increased risk of serious illness due to their presence. The inability to detect these antibodies in asymptomatic infections or outpatients with COVID-19, as well as convalescent plasma samples, indicates that their presence is universally correlated with serious disease.

The finding that high type I ISG expression is seen early in mild illness and then declines rapidly indicates the following, along with impaired type I ISG response in critical COVID-19 patients:Impaired type I IFN immunity during the first hours and days of infection can cause a long course of disease, including lung and systemic inflammation.. “

They are proposing an important two-stage model of COVID-19. Here, impaired type I IFN response in the early stages of infection allows the virus to multiply as a first step. This then leads to the induction of leukocyte-mediated hyperinflammatory pathways in the lungs and other organs within the first two weeks of infection.

This study also reveals the potential importance of LAIR-1 as an important COVID-19 biomarker due to impaired type I IFN response. Combined with an assay for antibodies to IFN-α2, it may be possible to identify patients at high risk of serious illness on admission.

Finally, the presence of antibodies to IFN-α2 may favor treatment with beta-interferon if these patients are identified early in the course of the disease. For all these reasons, this study points to the need to identify these patients early to improve their outcomes or prevent infection in these individuals.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.

Important effects of type I interferon (IFN) autoantibodies on COVID-19

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