Sequential, Ordered Acquisition of Antibodies to <i>Plasmodium falciparum</i> Erythrocyte Membrane Protein 1 Domains

Cham, Gerald K. K.; Turner, Louise; Lusingu, John; Vestergaard, Lasse S; Mmbando, Bruno P.; Kurtis, Jonathan D.; Jensen, Anja T. R.; Salanti, Ali; Lavstsen, Thomas; Theander, Thor G.

doi:10.4049/jimmunol.0901331

Cited by 114 publications

(153 citation statements)

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“…Levels of P. falciparum-specific (including PfEMP1-specific) IgG increase with age, generally plateau at adolescence, and may even decline in older age groups (44,49). In agreement with this, we did not find a significant correlation between PfEMP1-specific IgG levels and age in the current study, which included only adults (Fig.…”

Section: Resultssupporting

confidence: 79%

“…The particularly high levels in the positive-control women probably reflect the fact that many had recently received the prophylactic TT booster vaccination that is a standard part of antenatal care in Ghana. These data confirm the usefulness of PfEMP1-specific IgG levels as markers of exposure (49), the existence of interclonally conserved antibody epitopes in PfEMP1 proteins from genotypically distinct P. falciparum parasites (50), and the often transient nature of PfEMP1-specific IgG responses (in the absence of regular reexposure) (5)(6)(7)(8)(9).…”

Section: Resultssupporting

confidence: 62%

See 1 more Smart Citation

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

et al. 2014

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Protective immunity to Plasmodium falciparum malaria acquired after natural exposure is largely antibody mediated. IgG-specific P. falciparum EMP1 (PfEMP1) proteins on the infected erythrocyte surface are particularly important. The transient antibody responses and the slowly acquired protective immunity probably reflect the clonal antigenic variation and allelic polymorphism of PfEMP1. However, it is likely that other immune-evasive mechanisms are also involved, such as interference with formation and maintenance of immunological memory. We measured PfEMP1-specific antibody levels by enzyme-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods (pregnancy) to responses specific for comparable antigens expressed independent of pregnancy. Our data indicate that PfEMP1-specific B-cell memory is adequately acquired even when antigen exposure is infrequent (e.g., VAR2CSA-type PfEMP1). Furthermore, immunological memory specific for VAR2CSA-type PfEMP1 can be maintained for many years without antigen reexposure and after circulating antigen-specific IgG has disappeared. The study provides evidence that natural exposure to P. falciparum leads to formation of durable B-cell immunity to clinically important PfEMP1 antigens. This has encouraging implications for current efforts to develop PfEMP1-based vaccines. P rotective immunity to Plasmodium falciparum malaria acquired after natural exposure is mediated to a large extent by IgG antibodies targeting the asexual blood stages of the parasites (reviewed in reference 1). The low rate of acquisition probably reflects the extensive clonal antigenic variation and allelic polymorphism of key antigens. However, other immune-evasive mechanisms may also be involved, such as interference with formation and maintenance of immunological memory. Indeed, it has often been speculated that such subversion is important for the slow and incomplete acquisition of clinical protection following natural exposure to P. falciparum in areas where these parasites are stably transmitted (reviewed in references 2, 3, and 4). The evidence supporting the hypothesis of a fragile or dysfunctional immunological memory to P. falciparum includes the often transient IgG responses in children with malaria (5-9), apparent interference with antigen presentation (10, 11), "masking" of surface-exposed IgG epitopes (12), and expansion of "atypical" or "exhausted" B cells after prolonged exposure to P. falciparum antigens (13,14). Conversely, the hypothe...

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 62%

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

et al. 2014

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“…47). Parasites expressing group A PfEMP1 proteins occur predominantly among children with limited immunity (7), and IgG to this group of Ags is acquired faster than IgG to other PfEMP1 groups (48,49) and appear to be more cross-reactive (39,50). The data presented in this study underpin these earlier findings and support the hypothesis that IgG to relatively conserved and functionally important Ab epitopes in group A PfEMP1 proteins are of importance in acquisition of clinical immunity to malaria.…”

Section: Discussionsupporting

confidence: 80%

A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies

Bengtsson

Joergensen

Rask

et al. 2013

The Journal of Immunology

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175

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Cerebral Plasmodium falciparum malaria is characterized by adhesion of infected erythrocytes (IEs) to the cerebral microvasculature. This has been linked to parasites expressing the structurally related group A subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of IE adhesion ligands and to IEs with affinity for ICAM-1. However, recent evidence has cast doubt on both these associations, tempering hopes of the feasibility of developing a vaccine based on ICAM-1–binding PfEMP1. In this study, we report the identification of a domain cassette (DC) present in group A var genes from six genetically distinct P. falciparum parasites. The three domains in the cassette, which we call DC4, had a high level of sequence identity and cluster together phylogenetically. Erythrocytes infected by these parasites and selected in vitro for expression of DC4 adhered specifically to ICAM-1. The ICAM-1–binding capacity of DC4 was mapped to the C-terminal third of its Duffy-binding–like β3 domain. DC4 was the target of broadly cross-reactive and adhesion-inhibitory IgG Abs, and levels of DC4-specific and adhesion-inhibitory IgG increased with age among P. falciparum–exposed children. Our study challenges earlier conclusions that group A PfEMP1 proteins are not central to ICAM-1–specific IE adhesion and support the feasibility of developing a vaccine preventing cerebral malaria by inhibiting cerebral IE sequestration.

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“…There is mounting evidence that cys2 var genes (including group A genes) may encode an antigenically restricted group of PfEMP1 variants (14,30). Our data further suggest that, relative to other var genes, expression levels of cys2 var genes are independently associated with young host age, low anti-PfEMP1 antibody levels, and disease severity.…”

Section: Discussionsupporting

confidence: 57%

Plasmodium falciparum var gene expression is modified by host immunity

Warimwe

Keane²,

Fegan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

136

248

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Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of immune targets, which play a central role in the host-parasite interaction by binding to various host molecules. They are encoded by a diverse family of genes called var, of which there are Ϸ60 copies in each parasite genome. In subSaharan Africa, although P. falciparum infection occurs throughout life, severe malarial disease tends to occur only in childhood. This could potentially be explained if (i) PfEMP1 variants differ in their capacity to support pathogenesis of severe malaria and (ii) this capacity is linked to the likelihood of each molecule being recognized and cleared by naturally acquired antibodies. Here, in a study of 217 Kenyan children with malaria, we show that expression of a group of var genes ''cys2,'' containing a distinct pattern of cysteine residues, is associated with low host immunity. Expression of cys2 genes was associated with parasites from young children, those with severe malaria, and those with a poorly developed antibody response to parasite-infected erythrocyte surface antigens. Cys-2 var genes form a minor component of all genomic var repertoires analyzed to date. Therefore, the results are compatible with the hypothesis that the genomic var gene repertoire is organized such that PfEMP1 molecules that confer the most virulence to the parasite tend also to be those that are most susceptible to the development of host immunity. This may help the parasite to adapt effectively to the development of host antibodies through modification of the host-parasite relationship.antigenic variation ͉ escape ͉ malaria ͉ PfEMP1 ͉ virulence

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Sequential, Ordered Acquisition of Antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 Domains

Abstract: Material

Cited by 114 publications

References 40 publications

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies

Plasmodium falciparum var gene expression is modified by host immunity

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