Opinion: An autoimmune-like antibody response is linked to severe COVID-19

I am an immunologist at Emory University working under the guidance of Dr Ignacio Sanz, Head of Rheumatology for Emory. Immune dysregulation is our specialty.

Inflammation in COVID-19

A heart-wrenching turning point in the COVID-19 pandemic has come with the realization that the power of the immune system in fighting infection is sometimes pyrrhic. In patients with severe COVID-19 infections, it appeared that the inflammatory process used to fight the SARS-CoV-2 virus was, in addition to fighting the virus, potentially responsible for harming the patient.

The clinical studies described cytokine storms in which the immune system produces an overwhelming amount of inflammatory molecules, antibodies that trigger dangerous blood clots and inflammation of several organ systems, including blood vessels, in children recovered by COVID. All of these signs were warning signs that in some patients, immune responses to the SARS-CoV-2 virus, which causes COVID-19, may have gone from healing to destruction.

Quick thinking and courageous decisions made by primary care physicians led to the steroid use, drugs that dampen the immune response, at the onset of infection in hospitalized patients. This approach has saved lives.

But it’s not yet clear which parts of the immune system doctors weaken and which have this effect. Understanding the nature of immune deregulation in COVID-19 could help identify patients for whom these treatments are most effective. It may even justify more targeted and more powerful approaches to modulating the immune system currently reserved for autoimmune diseases.

Good antibodies take time

Antibodies are powerful weapons. Produced by white blood cells called B cells, they attach themselves to infectious agents like viruses and bacteria and prevent them from infecting your healthy cells. These antibody-virus aggregates trigger powerful inflammatory responses and serve as feedback beacons that allow the rest of your immune system to effectively target pathogens. In some circumstances, they can even kill.

Antibodies are so powerful that cases of mistaken identity – when a B cell produces antibodies that attack a person’s own cells – can lead to widespread organ damage and set up a perpetual cycle of immune self-targeting. We refer to this state of self-destruction as a autoimmune disease.

To prevent an autoimmune catastrophe and to ensure an effective response against the invading pathogen, B cells undergo a process of formation. Those who respond to the virus refine their antibodies and mature, ensuring strong antibodies capable of inactivating the invader. The B cells that target your own tissues are destroyed.

But this maturation process takes time. Two weeks of B cell “training” during a severe infection can be the difference between life and death. Faster antibody responses are needed. To fill this gap, the immune system has another form of B cell activation – called extrafollicular activation – that generates fast-acting antibodies that seem to bypass many of the known safety checks that accompany a more precise response.

Extrafollicular responses develop rapidly, are short-lived by design, and die off when more targeted responses emerge on the scene.

Except when they don’t.

Autoimmune-like responses in COVID-19

Between 2015 and 2018, our lab found that these extrafollicular immune system responses are a common feature of people with autoimmune diseases, such as lupus. Patients with this disease exhibit chronically active extrafollicular responses that have led to high levels of self-targeting antibodies and destruction of organs such as the lungs, heart, and kidneys.

The presence of specific types of B cells generated by extrafollicular responses in the blood can be an important indicator of the severity of the disease in lupus, and now also COVID-19.

In a recent published article, my colleagues and I have identified extrafollicular B cell signatures in severe COVID-19 cases similar to those we have seen in active lupus. We have shown that at the start of the response to infection, patients with severe disease undergo rapid activation of this accelerated pathway of antibody production. These patients produce high levels of specific viral antibodies, some of which are able to neutralize the virus. However, in addition to these protective antibodies, some that we have seen look suspiciously similar to those found in autoimmune diseases such as lupus.

Ultimately, patients with these autoimmune-like B cell responses fare badly, with high incidences of systemic organ failure and death.

Tempering immune responses in COVID-19

Let me be clear here: COVID-19 is not an autoimmune disease. The autoimmune-like inflammatory responses my team discovered might simply reflect a “normal” response to an already out of control viral infection.

However, even though this kind of response is “normal”, that does not mean that it is not dangerous. These prolonged extrafollicular responses have been shown to contribute to the severity of autoimmune disease both through the production of self-targeted antibodies and by inflammation that can damage tissues like the lungs and kidneys. This suggests that these early immune responses to a viral infection like COVID-19 are in tension with the targeted antibody response later; in other words, the body’s rapid production of antibodies to catch the virus runs the risk of targeting not the virus, but the patient’s own organs and tissues.

Immunologists like me need to know more. Why do only some patients activate such strong extrafollicular B cell responses? Are the antibodies that result from this response particularly likely to attack and destroy the host’s organs? Would a continued autoreactive response help explain ‘persistent’ COVID-19 cases even after the viral infection has cleared?

Despite these uncertainties, the medical community must recognize that, in appropriate patients, dampening immune responses with steroid therapy (or perhaps even more potent autoimmune therapies) is a critical weapon in the fight against COVID- 19. Doctors and scientists must continue to build our arsenal of therapeutics around the idea that in some cases of COVID-19, controlling your response to the virus may be as important as controlling the virus itself.

Matthew Woodruff is an instructor at the Lowance Center for Human Immunology at Emory University in Atlanta. This was first posted by The conversation.