Immunoglobulin G Reactivities to Rhoptry-Associated Protein-1 Associated with Decreased Levels of Plasmodium falciparum Parasitemia in Tanzanian Children

Jakobsen, Palle; Lemnge, Martha; Abu-Zeid, Yousif A.; Msangeni, H.A.; Salum, F.M.; Mhina, J; Akida, Juma A; Ruta, Anna; Rønn, Anita M.; Heegaard, Peter M. H.; Ridley, Robert G.; Bygbjerg, Ib Christian

doi:10.4269/ajtmh.1996.55.642

Cited by 16 publications

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“…The association between HLA-DQB1*0301 and DQB1*03032 and antibody levels to RAP1 in the 5-to 15-year age group is highly significant even after multiple regression in which all HLA alleles and age are included as independent variables. Such an influence could provide early protection for young children positive for HLA-DQB1*0301 and DQB1*03032 since Jakobsen and colleagues reported that young children (under 5 years) with high IgG reactivity to RAP1 have lower P. falciparum parasite densities compared to young children with low IgG (25). Unfortunately, the village of Etoa did not allow blood to be drawn from children under the age of 5 years, the age when immunity to clinical symptoms and blood-stage parasites is presumably acquired, nor did our study design allow correlation with protection in the individuals tested.…”

Section: Discussionmentioning

confidence: 99%

Interaction of HLA and Age on Levels of Antibody toPlasmodium falciparumRhoptry-Associated Proteins 1 and 2

Johnson¹,

Leke

Harun

et al. 2000

Infect Immun

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The Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) are candidate antigens for a subunit malaria vaccine. The design of the study, which looks at the acquisition of immunity to malaria from childhood to old age, has allowed us to document the interaction of HLA and age on levels of antibody to specific malarial antigens. Antibodies reach maximum levels to RAP1 after the age of 15 but to RAP2 only after the age of 30. The effect of HLA-DRB1 and -DQB1 and age on levels of antibody to rRAP1 and rRAP2 was analyzed with a multiple regression model in which all HLA alleles and age were independent variables. DQB1*0301 and -*03032 showed an age-dependent association with levels of antibody to rRAP1, being significant in children 5 to 15 years (P < 0.001) but not in individuals over 15 years of age. DRB1*03011 showed an age-dependent association with antibody levels to rRAP2; however, this association was in adults over the age of 30 years (P < 0.01) but not in individuals under the age of 30 years. No associations were detected between DRB1 alleles and RAP1 antibody levels or between DQB1 alleles and RAP2 antibody levels. Thus, not only the HLA allele but also the age at which an interaction is manifested varies for different malarial antigens. The interaction may influence either the rate of acquisition of antibody or the final level of antibody acquired by adults.The rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) form a low-molecular-mass complex located in the rhoptries of Plasmodium falciparum (5, 9). The rhoptries are a pair of organelles at the apical end of the parasite that are involved in the invasion of erythrocytes; thus, molecules in the rhoptries were among the first components identified as potential candidates for a subunit vaccine. Subsequent studies have borne out this potential. Monoclonal antibodies (MAbs) directed against rhoptry-associated proteins have been shown to provide substantial inhibition of parasite invasion in vitro (7,17,19,22,29,37). In addition, protein preparations containing both RAP1 and RAP2 have been used to immunize Saimiri monkeys. In these studies, the immunized monkeys developed a lower peak parasitemia than nonimmunized controls and were protected from subsequent lethal blood-stage challenge with P. falciparum (9,30,32,34) in a way similar to the protection acquired by immunization with whole merozoite (27,39,46). Two rhoptry-associated proteins, RAP1 and RAP2, have been sequenced (20,36). Unlike many other P. falciparum antigens, RAP1 and RAP2 exhibit a high degree of sequence similarity among P. falciparum isolates. Isolates from Honduras,

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Section: Discussionmentioning

confidence: 99%

Interaction of HLA and Age on Levels of Antibody toPlasmodium falciparumRhoptry-Associated Proteins 1 and 2

Johnson¹,

Leke

Harun

et al. 2000

Infect Immun

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“…Published studies correlate high levels of antibodies to MSA2 (1,49), MSP1 (2, 5, 9, 38, 52), RAP1 and RAP2 (21,45), and RESA (39) with low parasite densities or lower prevalences of anemia and/or fewer clinical episodes of malaria. Definitive conclusions about the role of high levels of antibodies to AMA1 are not available.…”

Section: Discussionmentioning

confidence: 99%

Human Leukocyte Antigen Class II Alleles Influence Levels of Antibodies to thePlasmodium falciparumAsexual-Stage Apical Membrane Antigen 1 but Not to Merozoite Surface Antigen 2 and Merozoite Surface Protein 1

Johnson¹,

Leke

Mendell

et al. 2004

Infect Immun

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The apical membrane antigen 1 (AMA1), merozoite surface antigen 2 (MSA2), and merozoite surface protein 1 (MSP1) are asexual-stage proteins currently being evaluated for inclusion in a vaccine for Plasmodium falciparum. Accordingly, it is important to understand factors that control antibody responses to these antigens. Antibody levels in plasma from residents of Etoa, Cameroon, between the ages of 5 and 70 years, were determined using recombinant AMA1, MSA2, and the N-terminal region of MSP1 (MSP1-190L). In addition, antibody responses to four variants of the C-terminal region of MSP1 (MSP1 19 ) were assessed. Results showed that all individuals produced antibodies to AMA1, MSA2, and MSP1-190L; however, a proportion of individuals never produced antibodies to the MSP1 19 variants, although the percentage of nonresponders decreased with age. The influence of age and human leukocyte antigen (HLA)-DRB1/DQB1 alleles on antibody levels was evaluated using two-way analysis of variance. Age was correlated with levels of antibodies to AMA1 and MSP1 19 but not with levels of antibodies to MSA2 and MSP1-190L. No association was found between a single HLA allele and levels of antibodies to MSA2, MSP1-190L, or any of the MSP1 19 variants. However, individuals positive for DRB1*1201 had higher levels of antibodies to the variant of recombinant AMA1 tested than did individuals of all other HLA types. Since the effect was seen across all age groups, HLA influenced the level but not the rate of antibody acquisition. This association for AMA1, combined with the previously reported association between HLA class II alleles and levels of antibodies to rhoptry-associated protein 1 (RAP1) and RAP2, indicates that HLA influences the levels of antibodies to three of the five vaccine candidate antigens that we have evaluated.

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“…More importantly, we observed significantly higher levels of cytophilic IgG3-type antibodies in the protected group, as well as higher ratios of cytophilic to noncytophilic and of IgG3 to IgG1 isotypes. Previously, a number of studies had indicated an association between IgG-type antibody responses to the rhoptry protein RAP1 and lower parasitemia rates or protection from P. falciparum infection (1,11,13). The predominance of cytophilic isotypes, and more specifically the IgG3 class, rather than a total antibody level have been shown to be associated with antimalarial protection (3).…”

Section: Discussionmentioning

confidence: 99%

Associations between Responses to the Rhoptry-Associated Membrane Antigen of Plasmodium falciparum and Immunity to Malaria Infection

et al. 2004

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Rhoptry proteins participate in the invasion of red blood cells by merozoites during the malaria parasite's asexual-stage cycle. Interference with the rhoptry protein function has been shown to prevent invasion, and three rhoptry proteins have been suggested as potential components of a vaccine against malaria. Rhoptryassociated membrane antigen (RAMA) is a 170-kDa protein of Plasmodium falciparum which is processed to a 60-kDa mature form in the rhoptries. p60/RAMA is discharged from rhoptries of free merozoites and binds to the red-cell membrane before being internalized to form part of the parasitophorous vacuole of the newly developing ring. We examined the range of anti-RAMA responses in individuals living in an area of endemicity for malaria and determined its association with clinical immunity. RAMA is immunogenic during infections, and at least three epitopes within RAMA are recognized by hyperimmune sera in immunoblots. Sera from individuals living in a region of Vietnam where malaria is endemic possessed strong antibody responses toward two C-terminal regions of RAMA. Cytophilic antibody isotypes (immunoglobulin G1 [IgG1] and IgG3) predominated in humoral responses to both C-terminal epitopes. Acute episodes of P. falciparum infection result in significant boosting of levels of antibody to an epitope at the extreme C terminus of RAMA that harbors the red-cell-binding domain. Immunity to P. falciparum infection was linked to elevated levels of IgG3 responses to this functional domain of RAMA, suggesting that the region may contain a protective epitope useful for inclusion in a multiepitope vaccine against malaria.Plasmodium falciparum malaria is responsible for Ͼ2 million deaths each year. With the increasing resistance of Plasmodium parasites to antimalarial drugs and of the Anopheles mosquito vector to commonly available insecticides, an effective vaccine that would protect nonimmune individuals from death would be valuable. The life cycle of malaria parasites is quite complex and provides a number of potential vaccine targets. Several proteins expressed by P. falciparum during the erythrocytic stages are being investigated as candidates for a subunit vaccine, among them rhoptry-associated proteins. The most important immune response for immunity to asexual-stage infection is believed to be humoral, although cell-mediated responses may also contribute to immunity.Rhoptries are intracellular organelles of malaria parasites involved in the invasion of red blood cells (RBCs) by Plasmodium merozoites. Although their contents are only transiently accessible to antibodies, seroepidemiological studies have demonstrated the development of antibody responses to the rhoptry proteins RhopH3, RAP1, and RAP2 following infection (8,12,20,23). In vitro growth inhibition assays have indicated that antibodies directed against the RAP1 and RAP2 proteins have inhibitory effects on P. falciparum growth in in vitro culture (6,9,14,18). Moreover, immunization of Saimiri monkeys with RAP1 protected the animals from a lethal...

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Immunoglobulin G Reactivities to Rhoptry-Associated Protein-1 Associated with Decreased Levels of Plasmodium falciparum Parasitemia in Tanzanian Children

Cited by 16 publications

References 0 publications

Interaction of HLA and Age on Levels of Antibody toPlasmodium falciparumRhoptry-Associated Proteins 1 and 2

Interaction of HLA and Age on Levels of Antibody toPlasmodium falciparumRhoptry-Associated Proteins 1 and 2

Human Leukocyte Antigen Class II Alleles Influence Levels of Antibodies to thePlasmodium falciparumAsexual-Stage Apical Membrane Antigen 1 but Not to Merozoite Surface Antigen 2 and Merozoite Surface Protein 1

Associations between Responses to the Rhoptry-Associated Membrane Antigen of Plasmodium falciparum and Immunity to Malaria Infection

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