Kinetics of B Cell Responses to Plasmodium falciparum Erythrocyte Membrane Protein 1 in Ghanaian Women Naturally Exposed to Malaria Parasites

Abstract

Naturally acquired protective immunity to Plasmodium falciparum malaria takes years to develop. It relies mainly on Abs, particularly IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins on the infected erythrocyte surface. It is only partially understood why acquisition of clinical protection takes years to develop, but it probably involves a range of immune-evasive parasite features, not least of which are PfEMP1 polymorphism and clonal variation. Parasite-induced subversion of immunological memory and expansion of “atypical” memory B cells may also contribute. In this first, to our knowledge, longitudinal study of its kind, we measured B cell subset composition, as well as PfEMP1-specific Ab levels and memory B cell frequencies, in Ghanaian women followed from early pregnancy up to 1 y after delivery. Cell phenotypes and Ag-specific B cell function were assessed three times during and after pregnancy. Levels of IgG specific for pregnancy-restricted, VAR2CSA-type PfEMP1 increased markedly during pregnancy and declined after delivery, whereas IgG levels specific for two PfEMP1 proteins not restricted to pregnancy did not. Changes in VAR2CSA-specific memory B cell frequencies showed typical primary memory induction among primigravidae and recall expansion among multigravidae, followed by contraction postpartum in all. No systematic changes in the frequencies of memory B cells specific for the two other PfEMP1 proteins were identified. The B cell subset analysis confirmed earlier reports of high atypical memory B cell frequencies among residents of P. falciparum–endemic areas, and indicated an additional effect of pregnancy. Our study provides new knowledge regarding immunity to P. falciparum malaria and underpins efforts to develop PfEMP1-based vaccines against this disease.

Pregnancy and Malaria Exposure Are Associated with Changes in the B Cell Pool and in Plasma Eotaxin Levels

“…Globally, we observed an expansion of IgD 2 MBC and a nonsignificant decrease of naive B cells and MZ-like MBC in NP compared with NNP. Similarly, a recent publication reported increased atypical MBC and a borderline significant decrease of naive B cells during pregnancy in a malaria-exposed cohort (16), although the cell populations defined in that study differed in resolution from those of our study. The expansion of IgD 2 MBC may be necessary to produce enough IgGs to be transferred to the fetus through the placenta.…”

“…Although multiple studies have analyzed Ab responses to malaria parasites during pregnancy, only two recent studies have analyzed B cells in malaria during pregnancy. The first one reported an increase in B cells and activated B cells in this condition (15); the second one showed altered frequencies of B cell subsets (16). However, the phenotypic resolution of these studies was very limited.…”

“…One very recent study (16) reported pregnancy-associated differences in atypical and classical MBC proportions in a malaria-exposed cohort, suggesting that pregnancy itself drives changes in the distribution of B cells. However, due to limitations in the flow cytometry panel, these authors could not distinguish between naive and resting atypical MBC, or classical and MZ-like MBC, resulting in partial understanding of the effect of pregnancy in those B cell subsets.…”

Developing vaccines to prevent malaria in pregnant women

“…Induction of a typical primary VAR2CSA-specific memory B cell response among primigravidae and a recall expansion among multigravidae were also shown [87]. The fact that immunological memory specific for VAR2CSA can be maintained for several years after the circulating antigen vanished [88], provides evidence that natural exposure to P. falciparum leads to the formation of a durable B-cell immunity to VAR2CSA antigens. This has encouraging implications for current efforts to develop VAR2CSA-based vaccines, providing that vaccine-induced response mimics naturally acquired immunity.…”

The immunological balance between host and parasite in malaria

“…Furthermore, whether atypical MBCs differentiate from classical MBCs or whether they originate from different precursors is still controversial (Muellenbeck et al 2013;Portugal et al 2015). An expanded atypical MBC pool is found in people who are chronically exposed to or infected with malaria, and a higher frequency of atypical MBCs is found in patients who reported at least one previous malaria episode compared to no previous exposure (Weiss et al 2009(Weiss et al , 2011Illingworth et al 2013;Ampomah et al 2014;Requena et al 2014). These atypical MBCs upregulate inhibitory receptors such as Fc receptor ligand 3 (FcRL3) and FcRL5, and show diminished BCR signaling, proliferation, and cytokine production (Portugal et al 2015;Sullivan et al 2015).…”