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In many infections, the immune system builds so-called germinal centers (yellow-brown rings inside the blue) in the spleen or lymph nodes to train cells that make antibodies, but the structures fail to develop in some COVID-19 cases.

Naoki Kaneko

The coronavirus may shut down the immune system’s vital classrooms

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

At the top of the long list of uncertainties about COVID-19 is whether people who recover will develop durable immune responses to the coronavirus that causes it. A research team that has autopsied people who died from COVID-19 has now discovered they lack so-called germinal centers, classrooms in the spleen and lymph nodes in which immune cells learn to mount a long-lasting antibody response to a pathogen. Although the finding may not apply to people who have mild or asymptomatic coronavirus infections, it may help explain COVID-19 progression in the sickest cases and provide important insights to vaccine developers.

The study, led by immunologist Shiv Pillai of the Ragon Institute of MGH, MIT and Harvard and published last week in Cell, may take on increased importance as a report out yesterday provided the first compelling evidence that a person can become reinfected with SARS-CoV-2, suggesting antibody protection could be fleeting in some people.

Pillai and co-workers analyzed the spleen and the thoracic lymph nodes, which drain immune cells from the lungs, of 11 people who died from COVID-19, comparing the tissues with those of six age-matched people who died from other causes. When all goes well, these sites gather antibodymaking B cells into newly formed germinal centers, distinctive microstructures where these cells mature and refine their antibody response to the virus. But germinal centers did not form in the thoracic lymph nodes and spleens of the autopsied COVID-19 patients, the researchers reported. “This is kind of shocking that they don’t, but they don’t,” Pillai says.

The work confirms a smaller study of autopsied COVID-19 patients reported online on 7 August in Current Medical Science by Duan Ya-Qi of the Huazhong University of Science and Technology and colleagues. “These two independent studies establish a profound lack of [antibody] responses in the deceased population of COVID-19 patients,” says Yang Xiang-Ping, a senior author of that paper.

Smita Iyer, an immunologist at the University of California, Davis, who published a preprint that describes germinal center formation in monkeys infected with SARV-CoV-2, says Pillai and colleagues have made “an important addition to the field,” noting that “clearly the immune system didn’t do what it was supposed to do.” But Iyer cautions that the data from her monkey studies, which may more closely mirror asymptomatic or mild disease in humans as the monkeys never develop severe disease, did not find an absence of germinal centers. “The immune response to SARS-CoV-2 is extremely heterogenous,” she says.

The tissue from a person who died of COVID-19 doesn’t show any evidence of the germinal centers found in a normal immune response.

Naoki Kaneko

A “storm” of cytokines, biochemicals that send messages to B cells and other immune system actors, occurs in response to some SARS-CoV-2 infections, contributing to inflammation and severe disease. Pillai’s team found that lymph nodes in the COVID-19 deaths had a large increase in the amount of one of these cytokines, tumor necrosis factor alpha (TNF-α), in comparison with the control autopsies. The researchers also found a lack of a type of T cell that plays a central role in forming the germinal centers and they propose the excessive TNF-α blocks its creation, as found in some mouse studies.

Yang suggests a better understanding of the lack of germinal centers in deceased patients might also help explain the cytokine storm. “The defect of [the antibody] responses may somehow be linked with the enhanced inflammation, which needs further investigations,” Yang says.

Pillai agrees with many immunologists who believe SARS-CoV-2 does not appear to be a particularly difficult virus to stop with a vaccine. “This is a piece of cake,” Pillai says. He is even confident that a properly designed vaccine could lead to durable antibody responses to SARS-CoV-2. But he hopes vaccine developers take note of his group’s findings. “If you are making too much TNF-α in the lymph nodes, maybe your vaccination won’t last that long,” he says.