COVID-19 Could Be Causing Immune System Amnesia

Shiv Pillai, MD, PhD, member of the Ragon Institute of MGH, MIT and Harvard  and professor at Harvard Medical School, was senior author of a paper in Cell, “Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19,” showing that that high levels of some cytokines seen in COVID-19 patients, as part of a cytokine storm, may prevent the development of long-term immunity to SARS-CoV-2, the virus that cause COVID-19.

SARS-CoV-2, the coronavirus that causes COVID-19, is a close relative of a virus that caused a disease called SARS (Severe Acute Respiratory Syndrome), which emerged in China in 2002 and was eradicated in 2003.

Another related coronavirus causes a similar disease called MERS (Middle East Respiratory Syndrome). MERS emerged as an epidemic in Saudi Arabia in 2012 and still festers in that part of the world.

After some infections like the measles or mumps, patients who survive are protected for six or seven decades by long-lived antibodies. In both SARS and MERS, however, the antibodies made by most patients typically declined within a year after infection.

It’s too early to know how long antibodies will persist in patients recovering from COVID-19. However, in both mild and severe disease, antibodies specific to the SARS-CoV-2 virus lack certain hallmarks characteristically seen in antibodies that lead to long-lived immune responses. We sought to understand why antibodies in COVID-19 may lack the same durability.

One unique feature of our study is that we examined both the blood of COVID-19 patients, and the specific sites in the body where immune responses are initiated.

How Immune Responses Are Generated

Protective immune molecules called antibodies are created by the body after infection or vaccination. Similar to the way in which key fits into a lock, antibodies are specifically designed to bind to the pathogen that caused the infection. If the body encounters the same pathogen again, these immune cells are rapidly mobilized to prevent or limit reinfection.

Antibody responses and immune memory are not initiated at the site of infection itself, but in neighboring structures called lymph nodes. In a viral infection of the lungs for instance, fragments of the virus enter nearby lymph nodes in the chest. If a virus escapes from affected tissues, such as the lungs, and makes its way into the blood—as happens in more severe cases of COVID-19—antibody responses can also be generated in the spleen.

When fragments of a virus enter the lymph node, they encounter immune cells called B cells. Each of our B cells recognizes a different pathogen, and when a patient has COVID-19, only the specific B cells that recognize SARS-CoV-2 get activated.

Another special type of immune cell, called a helper T cell, then sends a signal to help create a structure called a germinal center. It is in these centers where B cells help rapidly evolve until they create the version best suited to fight the pathogen.

Once the ideal B cell is created, germinal centers help immortalize them as memory B cells that can literally live forever. This way, if the body ever encounters the same pathogen, memory B cells will recognize it, often for decades, and initiate an antibody response to fight the infection.

Pathogens mutate and evolve and would regularly defeat us if we did not have the ability to respond by mutating our own genes in germinal center B cells to select the best B cells to effectively engage the enemy.

COVID-19 and Immune System Amnesia

The SARS-CoV-2 virus disrupts the memory-making process by preventing the development of the T cells that help B cells form germinal centers. If the body cannot form germinal centers, it cannot create the memory B cells that remember how to fight the disease.

We believe that the culprit is likely the COVID-19 cytokine storms—large influxes of immune signaling molecules that can disrupt the immune system’s normal processes.

As a result, if a person is infected for a second time, the immune system may not remember how best to fight it, leading to “immune amnesia.” This unusual phenomenon vastly reduces the chances of developing robust and long-lived herd immunity after natural infection.

If we relied on natural infection alone to clear this virus in the population at large, there would likely be some immunity in recovered patients for a few months but there could be a chance of reinfection in perhaps six months or a year later. We have studied this phenomenon in most detail in severe COVID-19 infections, but so far there is no evidence that mild infections create memory B cells.

Germinal center loss is unique to severe infectious diseases, but it is unlikely to occur after vaccination because vaccines are designed to more efficiently induce germinal centers. Therefore, we believe vaccination may be the best way to generate robust and effective herd immunity.

Insights gained from our studies on COVID-19 may have the potential to help us design more durable vaccines in the future for a range of diseases.

https://mgriblog.org/2020/09/16/covid-19-could-be-causing-immune-system-amnesia/