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. 2014 May;82(5):1860-71.
doi: 10.1128/IAI.01514-13. Epub 2014 Feb 24.

B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 antigens in Ghanaian women naturally exposed to malaria parasites

Paulina Ampomah  1 , Liz Stevenson, Michael F Ofori, Lea Barfod, Lars Hviid
Affiliations

B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 antigens in Ghanaian women naturally exposed to malaria parasites

Paulina Ampomah et al. Infect Immun. 2014 May.

Abstract

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.

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Figures

FIG 1
FIG 1
Plasma levels of antigen-specific IgG in different groups of women. Levels of antigen-specific IgG in plasmas from P. falciparum-exposed nonpregnant (●; E) and parturient (▲; EP) women and from nonexposed, nonpregnant women (○; N) are shown. Individual plasma levels of IgG with specificity for the P. falciparum antigens FV2, FV6, and FV60 and the non-P. falciparum antigen tetanus toxoid (TT) are shown. Median levels (horizontal lines) and their 95% confidence intervals (error bars) are also indicated. Values are expressed as arbitrary units (AU) (see Materials and Methods for details). Significant intergroup differences are indicated by lines along the top of the diagram. The asterisks indicate the level of statistical significance (*, P < 0.05; **, P < 0.01; ***, P < 0.001). The x axis breaks indicate that levels of IgG specific for the different antigens are not directly comparable. Shaded areas indicate values below the negative cutoff.
FIG 2
FIG 2
Relationship between plasma IgG levels and age in nonpregnant Ghanaian women. Ages and IgG levels specific for FV2 (top), FV6 (center), and FV60 (bottom) in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoff (mean plus 2 SD of levels in negative-control donors) is indicated by shading. With respect to FV2, nonexposed donors (nulligravidae) are indicated with open symbols.
FIG 3
FIG 3
Relationship between plasma IgG levels and time since last pregnancy in nonpregnant Ghanaian women. Times since last pregnancy and IgG levels specific for FV2 (top), FV6 (center), and FV60 (bottom) in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoff (mean plus 2 SD of levels in negative-control donors) is indicated by shading. Note that nulligravidae were excluded from this graph. The proportions of women with FV2-specific IgG levels above the negative cutoff at different time points are shown in the inset (all time points where proportion is zero are indicated as 0.01 for visibility only).
FIG 4
FIG 4
Relationship between plasma IgG levels and parity in nonpregnant Ghanaian women. Parity and IgG levels specific for FV2 (top), FV6 (center), and FV60 (bottom) in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoff (mean plus 2 SD of levels in negative-control donors) is indicated by shading. With respect to FV2, nonexposed donors (nulligravidae) are indicated with open symbols.
FIG 5
FIG 5
Frequencies of antigen-specific IgG-secreting B cells in different groups of women. Frequencies of IgG-secreting B cells in peripheral blood from individual P. falciparum-exposed nonpregnant (●; E) and parturient (▲; EP) women and from nonexposed, nonpregnant women (○; N) are shown. Frequencies of B cells secreting IgG specific for the P. falciparum antigens FV2, FV6, and FV60 and the non-P. falciparum antigen tetanus toxoid (TT) are shown. The negative cutoff (1 antibody-secreting cell per 1 × 106 PBMC) is indicated by shading. Median levels (horizontal lines) are also indicated.
FIG 6
FIG 6
Relationship between frequency of IgG-secreting B cells and time since last pregnancy in nonpregnant Ghanaian women. Times since last pregnancy and frequencies of IgG antibody-secreting B cells specific for FV2 (top), FV6 (center), and FV60 (bottom) in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoff (1 antibody-secreting cell per 1 × 106 PBMC) is indicated by shading. Note that nulligravidae were excluded from this graph.
FIG 7
FIG 7
Relationship between frequency of IgG-secreting B cells and parity in nonpregnant Ghanaian women. Parity and frequencies of IgG antibody-secreting B cells specific for FV2 (top), FV6 (center), and FV60 (bottom) in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoff (1 antibody-secreting cell per 1 × 106 PBMC) is indicated by shading. With respect to FV2, nonexposed donors (nulligravidae) are indicated with open symbols.
FIG 8
FIG 8
Relationship between frequency of IgG-secreting B cells and plasma IgG levels in nonpregnant Ghanaian women. Frequencies of IgG antibody-secreting B cells specific for FV2 (top), FV6 (center), and FV60 (bottom) and plasma levels of the same IgG in individual donors are shown, as well as the linear regression lines and 95% confidence intervals for their relationship. The negative cutoffs are indicated by shading. With respect to FV2, nonexposed donors (nulligravidae) are indicated with open symbols. Note the scaling of the axes.
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