The disease course of COVID-19 is diverse, ranging from asymptomatic to fatal respiratory failure. Emory University scientists have been working to uncover the immunological reasons behind this heterogeneity. A recent study on B cells, published on the preprint server medRxiv* in April 2020, shows that extrafollicular B cells could be a marker of severe infection in the early stages, predicting the need for earlier immunomodulatory therapy.
B Cells and the extrafollicular pathway
B cells (B lymphocytes) in the blood are involved in early effector responses via the production of protective antibodies, as well as in initiating the production of memory cells. Among the former class of responses, B cells take part in the extrafollicular (EF) pathway that is also active in systemic lupus erythematosus (SLE) flareups.
B-lymphocyte and red blood cells. Image Credit: Kateryna Kon / Shutterstock
The EF pathway is associated with peripheral inflammation, and a high level of proinflammatory cytokines interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10), both of which are associated with poor outcomes.
This is triggered by newly activated naïve B cells, resulting in a large number of antibody-secreting cells (ASCs) that produce a large concentration of autoantibodies. These ASCs come from the expansion of a B cell precursor that has been epigenetically primed, and which lacks naïve IgD and memory CD27 markers, making them double negative (DN). They also fail to express CXCR5 and CD21 markers, so that they are termed DN2.
These very active cells express CD11c and T-bet molecular markers at high levels and respond to stimulation of Toll-like receptors (TLR7) by single-stranded RNA (ssRNA). TLR7 is essential in clearing viruses from infected cells.
As a result, researchers consider DN2 cells taking part in the EF pathway to be a significant part of the COVID-19 illness. Supporting evidence comes from the association of EF pathway B cell activity in SLE, in African-Americans, who also have a high reported incidence of severe COVID-19 cases.
This finding is in contradiction to earlier studies of vaccinated patients who show better protection with higher numbers of ASCs. Instead, in critically ill patients with COVID-19, higher ASC generation and maturation counts predict a poor outcome.
How was the study done?
The study was made up of 17 patients with confirmed COVID-19 infection, with a control group of 22 adults. Of the 17 patients, nine were hospitalized as critically ill, requiring intensive care. Three of them eventually died.
Blood samples were taken from these patients at 12 days after symptoms appeared to study the peak immune response to the virus. Two different patient clusters resulted:
- One group showed a strongly upregulated EF pathway, with a striking increase in B cell activation within the EF pathway, resulting in a dramatic surge in the number of ASCs. Simultaneously, they showed a loss of some unique transitional B cell populations, which are linked to better outcomes from the illness.
ASC expansion was significantly higher in this group, well above frequencies typically observed with robust responses to vaccines like hepatitis A, tetanus toxoid, and yellow fever vaccines.
- The other had a low level of EF activity but higher transitional B cell activation levels.
Summary of study findings
The four crucial findings of the study are summarized below:
- The study found that while COVID-19 patients with severe symptoms develop a higher number of antibody-secreting cells (ASCs) in the early stages of infection, this does not appear to increase their immunity significantly.
On the other hand, this increase worsens the prognosis, either because of hyperactivation of the immune response or due to their involvement via disease-causing antibodies or cytokines that worsen inflammation.
Both IL-6 and type 1 interferons are significant influences in plasma cell differentiation in humans. IL-6 was also found to be linked to increased markers of inflammation,
- Secondly, the researchers also found that the EF pathway of peripheral inflammation associated with serious SARS-CoV-2 infection appeared to share a lot in common with the inflammatory responses found in severe autoimmune disorders, like lupus.
- Thirdly, a reduction in transitional B cell pathways was related to poor disease outcomes. It needs to be determined whether this means a decline in B cell regulatory function. However, lower levels of these B cells are linked to higher Sequential Organ Failure Assessment (SOFA) scores which predict critical illness severity), and a corresponding decrease in PaO2 to FiO2 ratios which evaluates gas exchange in the lungs, and predicts a poor outcome with mechanical ventilation
- Finally, the wide spectrum of clinical features of COVID-19 illness makes it necessary to exercise caution when using immunomodulatory therapy, since they may have unintended effects on different patient groups.
Why is the study important?
The researchers say, “This patient cluster associates tightly with biomarkers of poor outcomes and exhibits high rates of mortality.” 5 out of 6 patients in this group developed kidney failure, and over half died or were expected not to survive.
The study also points out that the EF pathway of B cell activation, which is markedly present in African-American women with SLE, may account for the much higher representation of this group in severe COVID-19 disease. In other words, the genetic predisposition of this group to a hyperactivated EF pathway along with negative socioeconomic factors may contribute to the poor outcome in this group.
Of practical importance, say the researchers, “This B cell phenotype might serve as an immunological marker of severe COVID-19 infection at early stages and could, therefore, identify a patient subset likely to benefit from targeted immunomodulatory therapy aimed at alleviating disease burden.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.