An autoimmune-like antibody response is linked with severe COVID-19

Are patients with severe COVID-19 victims of their own immune response? JOAQUIN SARMIENTO / Getty Images
In the earliest days of the pandemic, many immunologists, including myself, assumed that patients who produced large amounts of antibodies when the infection started would be disease free. We were wrong.
A few months after studying COVID-19, like other scientists, I found that the picture is far more complicated. A research study recently published by my colleagues and I confirms the idea that, in some patients, preventing dysregulated immune system responses can be as important as treating the virus itself.
I am an immunologist at Emory University and I work under the direction of Dr. Ignacio Sanz, Emory's head of rheumatology. Immunodeficiency is our specialty.
Inflammation in COVID-19
A harrowing turnaround in the COVID-19 pandemic came with the realization that the immune system's ability to fight infections was sometimes pyrrhic. In patients with severe COVID-19 infections, there was evidence that the inflammatory process used to fight the SARS-CoV-2 virus, in addition to fighting the virus, may have been responsible for the harm to the patient. Clinical studies have described what are known as cytokine storms, in which the immune system produced overwhelming amounts of inflammatory molecules, antibodies that trigger dangerous blood clots, and inflammation of several organ systems, including blood vessels, in COVID-restored children. All of these were warning signs that in some patients, the immune response to the SARS-CoV-2 virus that causes COVID-19 may have shifted from healing to destruction.
Quick thinking and bold decisions by frontline doctors led to the use of steroids, drugs that dampen the immune response, early in the course of infection in hospital patients. This approach saved lives.
However, it is not yet clear which parts of the doctors' immune system dampen the effects. Understanding the nature of the immune deficiency in COVID-19 could help identify patients for whom these treatments are most effective. This could even warrant more targeted and powerful approaches to modulating the immune system, which is currently reserved for autoimmune diseases.
The right antibodies take time
Antibodies are powerful weapons. Produced by white blood cells called B cells, they attach to infectious agents such as viruses and bacteria and prevent them from infecting your healthy cells. These antibody-virus aggregates trigger strong inflammatory reactions and serve as target signals that the rest of your immune system can use to fight the pathogens efficiently. In certain circumstances they can even kill.
Antibodies are so powerful that cases of false identity - when a B cell produces antibodies that attack a person's own cells - can lead to widespread organ damage and establish an ongoing cycle of self-targeting by the immune system. We refer to this state of self-destruction as autoimmune disease.
In order to avoid an autoimmune disaster and to ensure an effective reaction against the invading pathogen, B cells are subjected to a training process. Those who respond to the virus refine and mature their antibodies, ensuring effective antibodies that can deactivate the invader. B cells that target your own tissues are destroyed.
However, this maturation process takes time. Two weeks of B-cell training during a severe infection can mean the difference between life and death. Faster antibody responses are required. To fill this gap, the immune system has an alternative form of B-cell activation - called extrafollicular activation - that creates fast-acting antibodies that appear to bypass many of the well-known security checks that go with a more accurate response.
Extrafollicular responses develop quickly, are inherently short-lived, and die off when the more targeted responses hit the scene.
Except when they don't.
Autoimmune-like reactions in COVID-19
Between 2015 and 2018, our lab found that these extrafollicular immune system responses are a common characteristic of people suffering from autoimmune diseases such as lupus. Patients suffering from this disease show chronically active extrafollicular reactions that lead to high levels of self-directed antibodies and the destruction of organs such as the lungs, heart and kidneys.
The presence of certain types of B cells created in the blood by extrafollicular reactions can be an important indicator of the severity of the disease in lupus, and now also in COVID-19.
In a recent article, my colleagues and I identified extrafollicular B-cell signatures in severe COVID-19, similar to what happens in active lupus. We have shown that patients with severe illness experience rapid activation of this rapid pathway for antibody production early in the response to infection. These patients produce high levels of virus-specific antibodies, some of which can neutralize the virus. In addition to these protective antibodies, some we've seen look suspicious like those found in autoimmune diseases like lupus.
In the end, patients with these autoimmune-like B-cell responses do poorly, with a high incidence of systemic organ failure and death.
Mitigating 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 could simply reflect a "normal" response to a viral infection that is already out of control.
Even if this type of reaction is "normal", it does not mean that it is not dangerous. These prolonged extrafollicular responses have been shown to contribute to the severity of the autoimmune disease through both the production of self-targeting antibodies and inflammation that can damage tissues such as the lungs and kidneys. This suggests that these early immune responses to a viral infection such as COVID-19 are in conflict with the later targeted antibody response; In other words, the body's rapid production of antibodies to the virus carries the risk of targeting the patient's own organs and tissues rather than the virus.
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Immunologists like me have more to learn. Why do only some patients turn on such strong extrafollicular B-cell responses? Are the antibodies that result from this reaction particularly susceptible to attacking and destroying the host's organs? Would a sustained autoreactive response help explain cases of “lingering” COVID-19 even after the viral infection clears?
Despite these uncertainties, the medical community must recognize that in suitable patients, dampening immune responses through steroid treatment (or perhaps even more powerful autoimmune-oriented therapies) is a crucial weapon in fighting COVID-19. Doctors and scientists must continue to build our arsenal of therapeutics on the idea that in some cases of COVID-19, controlling your response to the virus can be as important as controlling the virus itself.
This article was republished by The Conversation, a non-profit news site dedicated to exchanging ideas from academic experts.
Continue reading:
What does "survival of the fittest" mean in the coronavirus pandemic? Look at the immune system
Which drugs and therapies have been shown to work against COVID-19 and which not?

Matthew Woodruff's research is supported by the National Institute of Health (NIH).
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