Immunology and Cell Biology | 2019
Immunoglobulin M, more than just an early responder to malaria
Abstract
For millennia, malaria has exacted a heavy toll on humanity. In 2017, an estimated 219 million cases occurred worldwide. Malaria vaccine development has proven challenging due in part to the genetic complexity of the parasite and its multistage life cycle. The role of antibodies in controlling parasitemia was first demonstrated in the 1960s by passive transfer of hyperimmune serum. However, the most advanced malaria vaccine to date achieved limited vaccine efficacy (26–36%) despite eliciting high-titer neutralizing antibodies against the pre-erythrocytic sporozoite stage. Moreover, antibody levels and protection waned over time. In the traditional conceptual framework for the humoral immune response to infection or vaccination, immunoglobulin M (IgM) peaks and wanes rapidly during the primary response, whereas immunoglobulin G (IgG) produced by isotype-switched memory B cells predominates in the secondary response (Figure 1a). In 2016, memory B cells producing IgM against malaria were reported in both mice and humans. Now, in a recent publication in Science Advances, Boyle et al. have significantly added to the weight of evidence supporting the role of IgM in both early and long-lived immunity to malaria by examining the kinetics and function of the antibody response in humans (Figure 1b). The IgM antibody isotype has traditionally received much less attention than IgG in vaccine studies, but this work suggests that more emphasis should be paid to eliciting and measuring IgM in the field of malaria vaccine development. Utilizing multiple human cohorts, including a human challenge model of malaria infection, children and adults in malaria-endemic regions and returning travelers, the authors showed that merozoite-specific IgM is rapidly induced during primary infection and exhibits similar kinetics as IgG during subsequent natural infections. In addition, they showed that both IgM and IgG block in vitro invasion through complement fixation and are associated with protection from developing clinical malaria (Figure 1c). However, some notable differences between IgM and IgG include stronger binding by IgM in the primary response but weaker binding in the secondary response. This is not unexpected, because germinal center formation and subsequent affinity maturation during a primary response typically require at least 1 week from the time of exposure. Therefore, during the primary response, the pentameric structure of IgM might be advantageous by boosting its avidity for antigen. Surprisingly, although the binding strength of IgG overtakes IgM in the secondary response, IgG is inferior to IgM in blocking in vitro invasion in the presence of complement. It is possible that the improved ability of IgM to fix complement to parasite is beneficial and may be preserved in the secondary immune response to help protect against and control parasitemia. Despite this difference, both IgM and IgG are associated with protection against clinical malaria to a similar extent. It is possible that additional functional properties of IgG, for instance, antibody-dependent cellular cytotoxicity or phagocytosis, make up for its weaker ability to fix complement to malaria in vivo. One very notable observation from this study is the longevity of IgM antibodies to malaria after a primary infection in the absence of reexposure, despite a half-life for IgM of only 5 days. This finding suggests the presence of a plasma cell population replenishing IgM in the serum despite the lack of antigen stimulation from parasitemia. However, the developmental pathway of these IgM-secreting plasma cells is unknown. It is also unknown why this developmental pathway is absent in infections such as HIV, dengue virus andWest Nile virus, which elicit only a short-lived IgM response. It is possible that these long-lived IgM plasma cells Correspondence Jim Boonyaratanakornkit, Fred Hutchinson Cancer Research Center, 1100 Eastlake Avenue East, Mail Stop E5-320, Seattle, WA 98109, USA. E-mail: [email protected]