Immune response and lack of immune response to Plasmodium falciparum P126 antigen and its amino-terminal repeat in malaria-infected humans.

Abstract

Abstract. A parasitophorous vacuole protein of Plasmodium falciparum, p126, is a potential candidate for a malaria vaccine. Its N-terminal region, composed of six repeats of eight amino acids, appears to be involved in the induction of protective immunity against P. falciparum challenge in monkeys. This study evaluated the immune response to p126 and to its N-terminal region (Nt47) in patients (n ϭ 45) living in a malaria-endemic area of Brazil (Colina, Porto Velho, Rondonia). Cellular proliferative responses against Nt47 were low and infrequent. The study of the humoral immune response demonstrated that 95% of the patients had detectable anti-p126 antibodies and 77% had anti-Nt47 antibodies. Analysis of the antibody isotypes specific for Nt47 revealed that all four IgG subclasses were present and individuals with higher levels of anti-Nt47 cytophilic IgG antibody (IgG1 ϩ IgG3/IgG2 ϩ IgG4) had significantly lower parasitemia levels, suggesting that antibodies to the N-terminal region of the p126 protein may contribute to acquisition of immunity to P. falciparum malaria.The Plasmodium falciparum p126 antigen 1 is synthesized by the parasite between the 32nd and the 36th hr of a 42-hr erythrocytic cycle, then stored inside the parasitophorous vacuole. This antigen is processed into fragments of 50 and 73 kD, the latter one composed of two peptides of 47 and 18 kD linked by disulfide bridges. This processing is associated with the release of merozoites from mature schizonts. 2 The p126 protein, also known as serine-rich antigen 3 or serine-rich protein 4 based on the similarity of coding genes, ranks as a candidate antigen for inclusion in a subunit vaccine to control the asexual erythrocytic phase of P. falciparum malaria for the following reasons: 1) it is antigenically conserved among different strains of P. falciparum; 5 2) monoclonal and polyclonal antibodies specific for p126 inhibit the in vitro growth of the parasite; 6-9 and 3) it can induce partial protection against parasite challenge in various species of monkeys. 1,3,[10][11][12] Moreover, the N-terminal portion (located at the amino-terminal end of the 47-kD subfragment) is involved in the induction of this protective immunity. 13,14 In view of these encouraging results, we focused on the six repeats of eight amino acids at the N-terminal end of the molecule 15 (Nt47) since this domain 1) includes a B and T cell epitope recognized by infected humans 16 (Roussilhon C, unpublished data); and 2) is the only one of the C-and Nterminal regions of the processed fragments of p126 that is able to induce an antibody response in mice immunized with respective peptides. 17 However, mice did not develop antibodies against this domain of the molecule when immunized with schizont-infected erythrocytes. 16 It is therefore of great value for vaccine design to determine the degree of immunogenicity of the Nt47 domain in humans living in a malaria-endemic area and naturally exposed to plasmodial antigens. In this respect, we investigated the immune response to Nt47 an...

Human leukocyte antigen class II control of the immune response to p126-derived amino terminal peptide from Plasmodium falciparum.

“…Data on humoral responses to p126 and Nt47 are shown in Table 1. Antibodies against p126 protein were found in all malariaexposed donors (100% for Colina and Ribeirinha), confirming our earlier observation that this protein is a good immunogen 16,29 under natural conditions of exposure. Five percent (4 of 78) of the Porto Velho group presented antibodies against p126.…”

“…Nevertheless, in a previous study in which we examined the biologic activity of specific antibodies, we observed that anti-Nt47 cytophilic IgG of isotypes 1 and 3 could have an important role in the control of parasitemia loads in P. falciparum-infected humans. 16 The predominantly positive response to Nt47 observed in HLA-DR4 people was independent of the presence of any particular HLA allele. The small number of nonresponders carried the same alleles as their counterparts.…”

“…18 However, in preliminary studies of natural responses to the P. falciparum p126 protein, we observed that a percentage (23%) of the Colina population failed to develop antibody responses to its amino-terminal repetitive portion, the 49-amino-acid-long Nt47 peptide. 16 Thus, to understand the basis of naturally acquired immune responses to Nt47, we have expanded our investigation to include another population of Amazon Basin natives (Ribeirinha) to verify whether the responses could be under the influence of specific HLA class II molecules.…”

“…16 We have also reported that 77% of malaria-infected people from the same endemic area presented detectable anti-Nt47 antibodies 16 and that the lack of response in the remaining 23% could not be explained by the polymorphism present in some isolates that contained 5-instead of 6-octamer repeats. 16 By use of congenic mice, we have shown that immune response to p126 protein is H-2 b and H-2 d restricted. 17 This restriction can be overcome in cases where special constructs are employed.…”

“…16 Analysis of the isotypic profile of the anti-Nt47 response has revealed that people with higher levels of specific cytophilic immunoglobulin (Ig) G antibodies had significantly lower parasitemia, suggesting that cellular effector mechanisms such as antibody-dependent cellular inhibition targeting the p126 antigen could play a primary role in the protection against malaria. 16 We have also reported that 77% of malaria-infected people from the same endemic area presented detectable anti-Nt47 antibodies 16 and that the lack of response in the remaining 23% could not be explained by the polymorphism present in some isolates that contained 5-instead of 6-octamer repeats. 16 By use of congenic mice, we have shown that immune response to p126 protein is H-2 b and H-2 d restricted.…”