Autoimmune diseases complicate the course of COVID-19. So, in 10-15% of patients with critical COVID-19 pneumonia, autoantibodies to type I interferons (IFN) are found. Sometimes it is the coronavirus that causes the formation of autoantibodies. In some reports, over 50% of patients hospitalized with moderate to severe COVID-19 have circulating autoantibodies.

In the summer of 2021, the Noel R. Rose Colloquium on COVID-19 and Autoimmune Diseases, hosted by the American Association for Autoimmune Diseases (AARDA), brought together researchers working at the intersection of COVID-19 and autoimmunity to discuss two questions:

  • Do autoimmune diseases predispose to severe COVID-19?
  • Can SARS-CoV-2 infection cause autoimmunity?

COVID-19 Severe Form Immunopathology

A symptom of a severe form of COVID-19 is damage to the lungs’ small blood vessels with signs of thrombosis. In addition, infiltration of neutrophils, monocytes, and macrophages is observed in the heart, central nervous system, and liver. Lesion of small blood vessels activates protective blood proteins both locally and systemically. Patients with severe COVID-19 have been found to have increased deposition of protective blood proteins in various tissues, including the lungs.

Some COVID-19 patients develop hyperinflammation with high levels of cytokines and chemokines. The pattern of this inflammation is similar to the autoinflammatory macrophage activation syndrome, which complicates autoimmune diseases such as systemic juvenile idiopathic arthritis and systemic lupus erythematosus. Immunomodulatory drugs, especially dexamethasone, improve survival in severe COVID-19. Clinical trials of cytokine inhibitors or their receptors for the treatment of COVID-19 have also been conducted.

Do Autoimmune Diseases Predispose to Severe COVID-19?

Congenital immunological abnormalities increase the risk of severe COVID-19.

IFN-I role in COVID-19

IFN-I triggers the expression of many interferon-stimulated genes (ISGs) required for antiviral immunity. SARS-CoV-2 suppresses the IFN-I response, so the virus multiplies unhindered and causes severe COVID-19. IFN-I and ISG protect in the early stages of infection. However, some patients with severe COVID-19 show sustained IFN-I responses that lead to organ damage.

Genetics and autoantibodies that disrupt the work of the IFN type I system

Critical influenza pneumonia is based on congenital disabilities of the type I interferon system associated with the loss of functions of the TLR3 pattern recognition receptor and the interferon regulatory factor IRF7. About 3.5% of patients with severe COVID-19 had the same congenital disabilities in the international cohort.

In the same cohort, but other patients without these congenital disabilities, neutralizing autoantibodies against type I interferons was found in 10% of patients with critical COVID-19 pneumonia, but not in asymptomatic patients. Since autoantibodies to IFN-I have been found in some patients before infection with SARS-CoV-2, these autoantibodies may be the cause rather than the consequence of critical COVID-19. The autoantibodies of patients with critical COVID-19 primarily target IFN-ω and IFN-α, but not IFN-β, IFN-κ or IFN-ε. Therefore, patients with these autoantibodies may benefit from the early administration of IFN-β.

In the 1980s, neutralizing autoantibodies against IFN-I were found in patients treated with IFN-α2 and IFN-β, patients with systemic lupus erythematosus, thymus tumors, and myasthenia gravis, and in almost all patients with type 1 autoimmune polyendocrinopathy syndrome (APS-1). These autoantibodies are usually not clinically apparent. However, most APS-1 patients infected with SARS-CoV-2 developed severe COVID-19. This fact confirms that IFN-I autoantibodies increase the risk of severe COVID-19. Several studies have also demonstrated that autoantibodies to IFN-I underlie at least 10% of cases of life-threatening COVID-19 pneumonia.

Scientists recently discovered autoantibodies that neutralize lower and more physiological concentrations of IFN-I in 14% of patients with critical COVID-19 pneumonia, including 21% of over 80 years old. These autoantibodies have been responsible for 20% of COVID-19 deaths. In addition, scientists have found IFN-I neutralizing autoantibodies in 4% of uninfected people over 70 years of age. Study details – in the article “Interferon autoantibodies increase the risk of critical COVID-19 in the elderly.” The research is published in the Science Immunology journal.

Summarizing these facts, we can conclude that in some patients, due to congenital disabilities of the immune system or autoantibodies at an early stage of SARS-CoV-2 infection, an insufficient response of type I interferon develops. Therefore, the virus multiplies and spreads unhindered, leading to pulmonary and systemic hyperinflammation. Treatment that enhances IFN-I signaling should be given in the first few days after SARS-CoV-2 symptoms appear.

Can SARS-Cov-2 Infection Cause Autoimmunity?

Some of the clinical signs of moderate to severe COVID-19 are similar to those in autoimmune diseases such as inflammatory arthritis and systemic lupus erythematosus. Scientists have also reported cases of patients developing autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and type 1 diabetes simultaneously or immediately after infection with SARS-CoV-2.

Viruses such as cytomegalovirus, parvovirus B19, and Epstein-Barr virus can trigger autoimmunity in genetically susceptible people. For example, reactivated Epstein-Barr virus predisposes to systemic lupus erythematosus (SLE) and enhances disease activity in patients with established SLE.

Viruses that trigger autoimmunity have several characteristic features:

  • Cause widespread, persistent infection.
  • Deprive immunity of tolerance due to the production of autoreactive lymphocytes.

American scientists found autoantibodies associated with rheumatologic diseases in 49% of patients hospitalized with COVID-19, compared with less than 15% of healthy controls. Many autoantibodies are associated with rare autoimmune disorders such as autoimmune myositis. In addition, 60% to 80% of patients hospitalized with COVID-19 had at least one anti-cytokine autoantibody capable of regulating immune responses.

Another group of American scientists has also found a wide range of autoantibodies targeting cytokines and chemokines in the plasma of patients with COVID-19. Some autoantibodies appeared after infection with SARS-CoV-2. It suggests that COVID-19 contributes to the loss of immunological tolerance to their tissues.

Autoantibodies linked to thrombosis in COVID-19

Abnormal coagulation and microvascular and macrovascular thrombosis are associated not only with severe COVID-19 but also with antiphospholipid syndrome. Antiphospholipid syndrome is an autoimmune disease characterized by the presence of antiphospholipid autoantibodies (aPL), which promote thrombosis by activating endothelial cells and platelets and stimulating neutrophils to release extracellular traps (NET). Patients hospitalized with COVID-19 have elevated NET levels that correlate with disease severity and thrombosis. American scientists found that nearly half of the patients hospitalized with COVID-19 had aPL. The presence of aPL has been associated with neutrophil activation, more outstanding NET release, decreased oxygenation efficiency, and more severe disease.

Patients with antiphospholipid syndrome and other rheumatologic diseases have elevated levels of antibodies that bind to NET, disrupting NET degradation and activating protective blood proteins. Anti-NET antibody levels also increase in patients hospitalized with COVID-19. The highest levels are in patients requiring mechanical ventilation. Antibodies against NET correlate with blood NET residues, COVID-19 severity, and platelet count and are inversely correlated with oxygenation efficiency and NET clearance.

How Autoimmunity Affects Protracted COVID-19?

German scientists found antinuclear antibody (ANA) titers of more than 1: 160 in 43.6% of patients 12 months after the onset of COVID-19 symptoms. In these patients, the incidence of attention problems was significantly higher than in the group with titers less than 1: 160.

Conclusions

Preexisting autoantibodies can explain some severe cases of COVID-19. Autoantibodies to IFN-I increase the risk of severe COVID-19. The autoantibodies of patients with critical COVID-19 primarily target IFN-ω and IFN-α, but not IFN-β, IFN-κ or IFN-ε. Therefore, patients with these autoantibodies may benefit from the early administration of IFN-β. Treatment that enhances IFN-I signaling should be given in the first few days after SARS-CoV-2 symptoms appear.

SARS-CoV-2 promotes the formation of autoantibodies. Scientists have reported cases of patients developing autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and type 1 diabetes simultaneously or immediately after infection with SARS-CoV-2. Autoantibodies are detected during hospitalization of patients with severe COVID-19, cause thrombosis, resist cytokine signaling, and increase neurological symptoms in prolonged COVID-19.

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The intersection of COVID-19 and autoimmunity

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