TLRs innate immunereceptors and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1α-driven human polyclonal B-cell activation

Abstract

Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt’s lymphomas (BL) in children living in malaria endemic areas. Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested. In this report, we extend the analysis of the PfEMP1–CIDR1α B-cell interaction and demonstrate that PfEMP1–CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1–CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1–CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1–CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.

Dysfunctional Adaptive Immunity During Parasitic Infections

“…These interactions appear to be largely mediated by the cysteine-rich interdomain 1α (CIDR1α) of P. falciparum erythrocyte membrane protein 1 (PfEMP1), which has been shown to drive the polyclonal activation of CD27+ (memory) B cells [69]. The phenotypic and functional changes in these CIDR1α-activated B cells included the activation of MAPK and NFκB pathways, and altered gene expression profiles, which are distinct from B cell receptor (BCR) induced changes [70].…”

“…It was originally believed that CIDR1α-induced activation of B cells renders those cells hypo-responsive to subsequent activation and signaling through the BCR. However, experimental evidence shows that B cells activated by CIDR1α are equally responsive to BCR crosslinking as resting CD27+ B cells [69]. Although direct proof that these interactions occur in vivo is lacking, it is possible that B cell interaction with CIDR1α (or related parasite proteins) effectively lowers the threshold of activation for B cells.…”

BAFF and BAFF Receptor Levels Correlate with B Cell Subset Activation and Redistribution in Controlled Human Malaria Infection

“…While the complex nature of the parasite (2, 5) and the high degree of antigenic variation (8) certainly contribute to this apparently impaired generation of humoral immune memory, there is also increasing evidence that the malaria parasite actively alters B-cell function (9). This includes not only polyclonal activation and modified responsiveness of B-cells in vitro and in vivo (10–14), but also profound changes to the composition of the peripheral blood B-cell compartment as recently described in naturally malaria-exposed populations (15–20). These changes observed in acutely infected or continuously exposed individuals include increased levels of transitional B-cells (15, 17), reduced levels of IgD+CD27+ marginal zone-like non-switched MBCs (17) and an enlarged proportion of atypical MBCs (atypMBCs), which have become a recent research focus (16–20).…”

Epidemiology: clues to the pathogenesis of Burkitt lymphoma

“…Initially, however, malaria preferentially activates the B cell memory compartment via a Plasmodium membrane protein known as cysteinrich-inter-domain-region1alpha (CIDR1a), which is expressed on the surface of infected red cells. This protein can also induce virus production from infected B cells (Chêne et al, 2007;Simone et al, 2011), which is almost certainly relevant to the increase in Epstein-Barr virus (EBV) -containing circulating B cells that occurs in acute malaria ( A role for Toll-like receptors in the induction of genetic change?…”