Genetic regulation of human anti-malarial antibodies in twins.

Abstract

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...

Quantifying genetic and nongenetic contributions to malarial infection in a Sri Lankan population

“…Such effects would be consistent with the known presence in South Asian populations of inherited blood disorders that give partial protection against clinical illness from P. falciparum such as sickle cell trait (hemoglobin S), hemoglobin E, the thalassemias, and glucose 6-phosphate dehydrogenase deficiency (40). Degrees of genetic protection against P. falciparum infection could also occur through immunological mechanisms such as the postulated HLA-controlled blocking of parasite development in the liver (7,41) or through other immune response genes (16,17,28). The effects are also consistent with the existence of genes affecting parasite density during blood infections of P. falciparum such as the single locus genetic effect on parasite density during P. falciparum infection, which has been reported in populations of West Africa (8,(11)(12)(13)(14).…”

“…The latter, therefore, remains largely undefined. A further feature of these genetic studies is that they have used a broad spectrum of possible measures of resistance, including parasite density (8)(9)(10)(18)(19)(20)(21), severity of symptoms (7,15,(22)(23)(24)(25)(26)(27), and immune responsiveness (16,17,28). As there is no real consensus as to which measures are good indicators of protection from disease, it can be argued that the importance of host genetics is most meaningfully assessed by observing the frequency and severity of clinical disease, as reported by the patient, in the field.…”

IgE elevation and IgE anti-malarial antibodies in Plasmodium falciparum malaria; association of high IgE levels with cerebral malaria

“…The children were not matched for area of residence or ethnic group, but the patients in the two hospitals were recruited from overlapping areas and their ethnic composition was similar, reflecting the proportion of the various groups in the areas [15]. Blood was also obtained from 54 residents (aged 2-35 years) of three villages in the central highlands of Madagascar [12,16] where F. falciparum malaria had recently (1986) reappeared and is currently hyperendemic [17]. Blood was taken at the beginning of the transmission season.…”

Genetic regulation of immune responses to vaccines in early life

“…Furthermore, although HLA has been associated with variation in immune responses in adults, non-HLA genes also influence susceptibility to pathogens. 24,25 The unique twin study presented here also provided an opportunity to quantify for the first time the relative contribution of HLA to the genetic control of immune responses in infancy.…”