Immune responses to defined antigens may differ between individuals in a population as the reflection of differences in genetic regulation. In experimental animals, variation in responsiveness to a given epitope may be due to major histocompatibility complex (HLA, in hans) class II restrictions, implying serious limitations for the development of subunit vaccines. For human populations, knowledge of the relative importance of genetic as opposed to environmental factors affecting the immune response is scarce. We have compared antibody levels after immunization through repeated infections to a major malarial antigen (Pf155/RESA) in monozygotic twins with those in dizygotic twins, siblings, or unrelated controls. Antibody responses to the intact antigen and to some of its immunodominant epitopes were found to be more concordant within monozygotic twin pairs than in dizygotic pairs or age-and sex-matched siblings living under similar environmental conditions. The results support the conclusion that the antibody responses were genetically regulated. When the responses were assessed for possible associations with different HLA class II DRB, DQA, and DQB alleles and haplotypes, no associations were found. This suggests that the regulation of the Pf155/RESA antibody responses seen in this study reflects the impact of factors encoded by genes outside the HLA class II region.The occurrence and degree of an immune response to a given antigen following infection or vaccination are governed by both genetic and environmental factors. The effects of different genetic factors such as major histocompatibility complex (MHC) restriction or macrophage function (1) have to a large extent been clarified by studies of inbred animals (2). However, in human populations, immune responses to an infectious agent are strongly biased by environmental factors, including intensity of exposure to the pathogen and immune or health status or socioeconomic conditions of the hosts. Therefore, it may be difficult to decide whether different levels of responsiveness in individual human responders represent an intrinsic genetic regulation of the response or external factors.In this work, we have attempted to approach these questions for the humoral response in Plasmodium falciparum malaria, one of the most significant infectious diseases worldwide. The major antigen studied here was Pfl55/RESA (3-6), a polypeptide that the P. falciparum merozoite deposits in the membrane of erythrocytes at invasion. Of clinically immune adults living in villages of northern Liberia where malaria is holoendemic and perennial, -75% have antiPf155/RESA antibodies, as detected by a modified erythrocyte membrane immunofluorescence (EMIF) assay (3), although all have elevated antibodies to intracellular P. falciparum antigens. When assayed in ELISA with short synthetic peptides, concentrations of antibodies to different immunodominant epitopes of Pf155/RESA vary in different donors, resulting in individual antibody profiles that are characteristic for each donor, r...

Available evidence suggests that human T and B cell responses to a major Plasmodium falciparum malaria antigen (Pf155/RESA) in individuals primed by repeated infections are genetically regulated. In the present study we have attempted to establish whether these regulations reflect genetic restrictions imposed on the immune response by class II molecules of the donor's MHC system. T cell activation (proliferation and IFN-gamma release in vitro) and antibody activity (ELISA) were assayed with synthetic peptides corresponding to major Pf155/RESA epitopes. To associate T cell and antibody responses with the donors' MHC class II genotypes, leukocytes from 145 donors living in holo- or hyperendemic regions of Africa (Liberia, Gambia, Madagascar) were used for genomic HLA class II typing of their DRB-DQA and DQB genes by means of restriction fragment length analysis (RFLP). No associations between T cell responses and HLA-DR or -DQ alleles or DRB-DQA-DQB haplotypes were seen among the West Africans even when the donors were divided into high, medium or low responders. This was also true for a small group of HLA class II identical Malagasy donors including three pairs of twins. However, while the T cell responses between the twin pairs varied, those within the pairs were similar. Very similar findings were made with antibodies binding to Pf155/RESA peptides. Our data imply that the impact of MHC class II gene products on specific immune responses to Pf155/RESA epitopes is weak and hard to demonstrate in outbred human populations naturally primed by infection. This may be due to genetic regulations by other, non-HLA class II coded factors superimposed on possible HLA class II restrictions.

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ReFacto lacks the major part of the B-domain, except for 14 amino acid residues from the N-terminal and C-terminal ends, which are linked into a 14 amino acid SQ-peptide tail in the C-terminal end of the 90 kD heavy chain, thereby introducing a new peptide sequence in the factor VIII (FVIII) molecule. Therefore, samples from some of the patients enrolled in the ReFacto clinical trials were analyzed for the emergence of anti-SQ-peptide antibodies in addition to determinations for inhibitors by Bethesda assay and for anti-FVIII antibodies by enzyme-linked immunosorbent assay (ELISA). An anti-peptide ELISA was developed using six partially overlapping 15-16 mer peptides covering the SQ-linker region. Results from ReFacto-treated anti-FVIII antibody-positive or -negative patients were compared with those for normal healthy adults and patients treated with other FVIII products. The pattern was compared with that for SQ-peptide specific monoclonal antibodies, each recognizing three or four overlapping SQ-peptides. Antibodies recognizing mainly one of the SQ-peptides were found in samples in some individuals from all investigated groups. This means that the anti-SQ reactivity found in patients treated with ReFacto is not induced by the SQ-sequence of the molecule but rather by some other agent, giving rise to antibodies cross-reactive with SQ-peptides.

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