Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity. DOI: http://dx.doi.org/10.7554/eLife.07218.001 eLife digest The human immune system works to protect individuals from harmful microbes, such as the parasites that cause malaria. One line of defense is to produce a large array of proteins called antibodies that specifically bind to microbes to mark them for destruction by the immune system. The immune system also produces long-lived memory B cells that are able to mount a quicker and more effective antibody response if the microbe enters the body again. This means that most people only become ill with a particular disease the first time they encounter the microbe that causes it. However, malaria is unusual in that it can take many years of exposure to the parasite that causes it before an individual produces enough antibodies and memory B cells to be protected from the disease. There is also no vaccine that provides effective and long-lasting protection against malaria. Vaccinations rely on stimulating the body’s natural defenses, and so understanding more about antibodies and memory B cells in relation to malaria may aid future efforts to develop a vaccine. Researchers have discovered that many of the memory B cells that accumulate in people who have been exposed to the malaria parasite over long-periods of time are different from the normal memory B cells. But it was not clear what role these ‘atypical’ cells play in immunity to malaria. To address this question, Portugal et al. studied the genetics and activity of B cells collected from children and adults living in Mali who—by living in a region where malaria is common—had been repeatedly exposed to the parasite. The experiments indicate that atypical and normal memory B cells both develop from the same precursor cells. However, the genes that are active in each cell type are different, resulting in the atypical cells being less able to respond to the parasite than the normal memory B cells. Portugal et al.’s findings suggest that the atypical cells develop from normal memory B cells during long-term exposure to malaria, which may delay the development of immunity to this disease. Future challenges include understanding what drives the formation of the atypical memory B cells in malaria, and finding out why they are less active than the normal cells. This could aid the development of vaccines and/or therapies that restore their activity in patients. DOI: http://dx.doi.org/10.7554/eLife.07218.002
【저자키워드】 Human, malaria, Plasmodium falciparum, atypical memory B cells,