Effects of pregnancy and intensity of Plasmodium falciparum transmission on immunoglobulin G subclass responses to variant surface antigens

Abstract

Placenta-sequestering Plasmodium falciparum involved in the pathogenesis of pregnancy-associated malaria (PAM) in otherwise clinically immune women expresses particular variant surface antigens (VSA(PAM)) on the surface of infected erythrocytes that differ from VSA found in parasitized nonpregnant individuals (non-PAM type VSA). We studied levels of immunoglobulin G (IgG) and IgG subclasses with specificity for VSA(PAM) and for non-PAM type VSA in pregnant and nonpregnant women from two sites with different endemicities in Cameroon. We found that VSA(PAM)-specific responses depended on the pregnancy status, parity, gestational age, and parasite transmission intensity, whereas only the parasite transmission intensity influenced the levels of IgG specific for non-PAM type VSA. For both types of VSA, the responses were dominated by the cytophilic subclass IgG1, followed by IgG3. In pregnant women, the levels of VSA(PAM)-specific antibodies either were very low or negative or were very high, whereas the levels of the antibodies specific for non-PAM type VSA were uniformly high. Interestingly, the levels of VSA(PAM)-specific IgG1 increased with increasing gestational age, while the levels of the corresponding IgG3 tended to decrease with increasing gestational age. The IgG subclass responses with specificity for non-PAM type VSA did not vary significantly with gestational age. Taken together, our data indicate that IgG1 and to a lesser extent IgG3 are the main subclasses involved in acquired VSA(PAM)-specific immunity to pregnancy-associated malaria.

FIG. 1.

Distribution of plasma levels of VSA-specific IgG in Cameroonian women. The levels of IgG with specificity for VSA expressed by parasites infecting nonpregnant individuals (non-PAM type VSA) (a to c) and by parasites infecting the placentas of pregnant women (VSA_PAM) (d to f) in nonpregnant (a and d) and pregnant (b and e) women from Yaounde and in pregnant women from Etoa (c and f) are shown. Levels were measured by flow cytometry and are expressed in MFI units. The negative cutoff levels (means plus two standard deviations of MFI values) obtained with plasma from nonexposed control donors (vertical dashed lines) and with plasma from sympatric nonpregnant nulligravidae (vertical solid lines) are shown for reference.

FIG. 2.

Relationship between plasma levels of VSA-specific IgG and parity in Cameroonian pregnant women. Individual levels of IgG with specificity for VSA expressed by parasites infecting nonpregnant individuals (non-PAM type VSA) (a and b) and by parasites capable of sequestering in the placenta (VSA_PAM) (c and d) in pregnant women from Yaounde (a and c) and Etoa (b and d) are shown. The negative cutoff levels (means plus two standard deviations of MFI values) obtained with plasma from nonexposed control donors (horizontal dashed lines) and with plasma from sympatric nonpregnant nulligravidae (horizontal solid lines) are shown for reference.