Cytokines may prevent COVID-19 patients from producing the 'best' antibodies

By Samantha Black, PhD, The Science Advisory Board editor in chief

August 20, 2020 -- High levels of some cytokines associated with COVID-19 could prevent long-term antibody responses to the SARS-CoV-2 virus, according to a new study published in Cell on August 19. The findings could explain why immunity to the novel coronavirus does not last long among individuals after they recover from the disease.

Studies in convalescent COVID-19 patients indicate that humoral immunity is often short-lived, and most SARS-CoV-2 antibodies exhibit limited somatic hypermutation -- adaptation to new foreign elements.

"We've seen a lot of studies suggesting that immunity to COVID-19 is not durable because the antibodies decline over time," said co-senior author Dr. Shiv Pillai, PhD, professor at Harvard Medical School and member of the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, in a statement. "This study provides a mechanism that explains this lower-quality immune response."

Long-lasting B-cell memory and the highest affinity pathogen-specific antibodies are derived within germinal centers (where somatic hypermutation occurs) in secondary lymphoid organs. Life-long memory of a pathogen allows the body to quickly and effectively identify and attack pathogens in the case of reinfection. The formation of germinal centers relies on differentiation of T follicular helper cells, which are antigen-experienced CD4+ T cells found in the secondary lymphoid organs.

Evasion of antiviral aspects of innate immunity and overly aggressive activation of inflammation by SARS-CoV-2 might prevent the generation of T follicular helper cells. As a result of the failure of these cells to differentiate, the early development of high-affinity antibodies that could help stop viral spread may be compromised.

In the new study, a group of researchers from the Ragon Institute sought to understand what prevents these cells from differentiating during SARS-CoV-2 infection.

The researchers used quantitative multicolor immunofluorescence combined with multispectral imaging and cell-cell interaction analyses of autopsy specimens and peripheral blood samples in cohorts with acute SARS-CoV-2 infection to interrogate how the adaptive immune system is modulated in severe COVID-19 cases.

Previous malaria-based mouse models have demonstrated that defective germinal centers have been linked to a defect in T follicular helper cell differentiations that could be reversed by tumor necrosis factor alpha (TNF-α) blockade. These models show that elevated cytokines and chemokines can cause the loss of germinal centers during serious infections.

When the researchers studied the lymph nodes of patients who had died of the disease, they found high levels of TNF-α -- one of the most abundant cytokines present in cases of COVID-19 -- in these organs. This finding led them to conclude that TNF may be preventing the germinal centers from forming in people with COVID-19 as well.

The authors suggested that the very high local levels of TNF-α and possibly other cytokines in COVID-19 lymph nodes block the final step in T follicular helper cell differentiation, which is required for the formation of germinal centers.

"Without the formation of germinal centers, there is unlikely to be long-term memory to this virus developing from natural infections, meaning that while antibodies may protect people for a relatively short time, a single person who recovers from the disease could get infected again, perhaps six months later, or even multiple times with SARS-CoV-2," added Pillai. "This suggests that developing herd immunity may be difficult."

The study suggests that developing herd immunity may be difficult in the case of COVID-19 due to impaired infection-induced protective immunity and low durability antibody responses.

The authors noted that their findings should not affect vaccine-induced immunity, as vaccines do not induce cytokine storms. A vaccine-induced immune response would likely include the development of a germinal center, thus ensuing the creation and immortalization of high-quality antibodies that would provide long-lasting protecting against COVID-19.

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