Overlooked white cells may be key to better malaria vaccines
A class of white cells that has long been thought to play a relatively minor role in the body’s defenses against malaria infection may, in fact, be a potent weapon against the malaria parasite. These cells may be key to developing more effective vaccines, according to a report today in the journal Immunity. UW Medicine and Seattle Children’s researchers headed the study.
The findings suggest that these white blood cells, called IgM memory B cells, may bemore important in the body’s early response to malaria re-infection than another group of cells, called IgG memory B cells, that for years have been the focus of malaria-vaccine research, said Marion Pepper, University of Washington assistant professor of immunology. She led the research project.
“The focus on IgG memory B cells in malaria vaccine development may be why malaria vaccines developed to date have not proven very effective,” Pepper said.
Malaria is a parasitic infection that is spread through the bite of infected mosquitos. It is widespread in tropical and subtropical regions of Asia, Latin America and Africa. The malaria parasite causes more than 200 million cases of illness and 430,000 deaths a year. The need for an effective vaccine is urgent: Drug-resistant parasites are becoming more common, as are malaria-carrying mosquitos resistant to the insecticides.
So far, however, even the most promising malaria vaccines have proven to provide only weak, short-lived protection.
B cells are a class of immune cells that produce antibodies to fight invading viruses, bacteria, and parasites. As newly formed cells, they are in an inactive, or naive, state. In this state, they have two kinds of antibody-like receptors on their surfaces, called IgM and IgD. When they encounter a protein, called an antigen, from a pathogen that matches those cell-surface receptors, the B cells become active.
When this happens, some of these activated B cells immediately begin pumping out either IgM or IgD antibodies, thereby launching the immune system’s initial defense. But others move to specialized centers in the spleen and lymph nodes, where they undergo a process called somatic hypermutation. This results in production of B cells that secrete antibodies that have higher affinity for the antigen and are thereforemore effective. Many also undergo a process called class switching in which they changed the type of antibody they produce, typically switching from IgM and IgD to primarily IgG. This movecreates a large population of IgG-producing B cells.
After the infection has been cleared out, some of the activated B cells become dormant “memory B cells.” These cells, which can persist for years, even for a lifetime, can be quickly reactivated should a second infection occur. They are ready to produce large amounts of the refined, high-affinity antibodies so that the invader can be neutralized before it can take hold.
Because of this tendency to provide long-term protection, researchers have sought to develop vaccines that generate memory B cells capable of producing a strong IgG response to an infection. In fact, the ability of a vaccine to generate high levels of IgG in the blood is a standard measure of an experimental vaccine’s potential effectiveness and a goal of vaccine developers.
plasmodium infected mouse blood cells
IgM B cells, on the other hand, were thought to provide only a transient initial response to infection and to play only a minor role in generating a memory B cell response to re-infection.
In the new study, the UW researchers used a fluorescent marker that bound to B cell receptors for a malaria parasite antigen called Merozoite Surface Protein 1. This tag allowed them to track memory B cells in previously malaria-infected mice when they were reinfected with the parasite.
The scientists found that, although there were far fewer IgM memory B cells compared to IgG memory B cells at the time of reinfection, the IgM memory B cells began to multiply far more rapidly than the IgG memory B cells. They observed that early in the immune systems’s response most of the newly formed antibody-producing cells were in fact IgM-secreting cells, not IgG-secreting cells. What’s more, they found that the IgM antibodies these cells produced had undergone somatic hypermutation. They were producing high-affinity antibodies whose affinity for the Merozoite Surface Protein 1antigen was equal to that seen with IgG antibodies.
“The big picture here is that in vaccine trials, researchers are just looking at IgG responses,” said Pepper. “What our findings suggest is that we may be missing a highly effective component of the immune response: IgM memory B cells. Those cells are producing refined, somatically hypermutated, high-affinity antibodies well before IgG memory B cells are producing their antibodies. Our findings also show that IgM memory B cells are capable of producing high affinity IgG antibodies, thereby implicating them in both IgM and IgG protective responses.”
Pepper designed the experiments with Akshay T. Krishnamurty, a UW graduate student who also performed the experiments with help from Gladys Keitany and Karen Kim. David J. Rawlings designed and Christopher D. Thouvenel performed the sequencing analysis, cloning and generation of the monoclonal antibodies. They are both from UW Medicine and the Seattle Children’s Research Institute. Anthony Holder and Jean Langhorne, of the Francis Crick Institute, London, provided the Merozoite Surface Protein 1. Peter D. Compton, of the National Institute of Allergy and Infectious Diseases, provided expertise with human experiments and human samples.
This work was supported by grants from the National Institutes of Health (R01AI108626-01A-A87299, T32-AI10667701) and by the Seattle Children’s Research Institute, the Benaroya Family Gift Fund, and the National Institute of Allergy and Infectious Diseases.