Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-γ3 Chondroitin Sulfate A-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein 1

Abstract

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the adherence of P. falciparuminfected erythrocytes to placental syncytiotrophoblasts via interactions with chondroitin sulfate A (CSA), a characteristic of pregnancy-associated malaria. Pregnancy-associated malaria predicts increased susceptibility of newborns to malaria, and it is postulated that transplacental passage of parasite antigen induces immune regulatory activity in the neonate. We wished to examine the immune responsiveness to a CSA-binding domain of PfEMP1, the DBL-␥3 domain, in cord and maternal venous blood obtained from pregnancies with various histories of P. falciparum infection. We assessed in vitro T-cell cytokine and plasma immunoglobulin G (IgG) and IgM responses to four peptides corresponding to highly conserved regions of a DBL-␥3 domain common to central African parasite isolates. The presence of placental P. falciparum infection at delivery was associated with elevated frequencies of DBL-␥3 peptide-specific CD3 ؉ interleukin-10-positive T cells in cord blood, while treatment and clearance of infection prior to delivery was associated with elevated frequencies of CD3؉ gamma interferon-positive T cells. DBL-␥3 peptide-specific IgM antibodies were detected in 12 of 60 (20%) cord plasma samples from those born to mothers with P. falciparum infection during pregnancy. Consistent with polyclonal anti-PfEMP1 antibody responses that are associated with protection against pregnancy-associated malaria, the presence of maternal IgG antibodies with specificity for one of the DBL-␥3 peptides showed a parity-dependent profile. These data demonstrate that peptides corresponding to conserved regions of the DBL-␥3 domain of PfEMP1 are immunogenic in P. falciparum-infected mothers and their offspring.

Fetal Immune Responses to Plasmodium falciparum Antigens in a Malaria-Endemic Region of Cameroon

“…These studies have measured cytokine responses of CBMC using ELISPOT (12,24), intracellular staining (13,25,36), or in culture supernatants following stimulation with mitogen, MA extract, MSP1, and RESA (13,15,25). All of the studies concluded that malaria-specific T cell priming occurs in utero.…”

“…In 1988, Desowitz (1) reported that CBMC from newborns in Papua New Guinea proliferated when cultured with an extract of malarial parasites, whereas babies born in a malaria-free area did not. Subsequently, malaria-specific T cell proliferation and cytokine responses were found in CBMC of newborns in Kenya, Gabon, Togo, and Cameroon (12)(13)(14)(15). Thus, there is substantial evidence for in utero priming of T cells to malaria.…”

Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens

“…The nature of the initial exposure to malaria Ags likely affects the potentially diverse roles assumed by T regs in malaria infection. For some individuals, this first experience appears to occur in utero (10,12,14,17,83,84). This may have an important impact on the subsequent development of an individual's immune response to malaria and potentially to other Ags.…”

“…Substantial amounts of IL-10 are produced by CBMC in malariaexposed fetuses (14,15,17,38), which are thought to be important for immunoregulation (36,38,71). This can occur both spontaneously and in response to malaria blood-stage Ags, suggesting that expansion of IL-10-producing T cells may be important for modulating malaria Ag-specific immune responses.…”

“…The accumulation of infected erythrocytes in the placenta may result in transplacental transport of infected erythrocytes or their soluble components, thereby exposing and sensitizing the fetal immune system to P. falciparum Ags (8)(9)(10)(11)(12). The reported frequency of malaria bloodstage-specific T and B cell responses in cord blood mononuclear cells (CBMC) ranges from ∼5% to .70% (13)(14)(15)(16)(17)(18). The consequences of this prenatal exposure of the infant to P. falciparum remain poorly understood.…”