Heritability of Antibody Isotype and Subclass Responses to Plasmodium falciparum Antigens

Abstract

BackgroundIt is important to understand the extent to which genetic factors regulate acquired immunity to common infections. A classical twin study design is useful to estimate the heritable component of variation in measurable immune parameters.Methodology/Principal FindingsThis study assessed the relative heritability of different plasma antibody isotypes and subclasses (IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE) naturally acquired to P. falciparum blood stage antigens AMA1, MSP1-19, MSP2 (two allelic types) and MSP3 (two allelic types). Separate analyses were performed on plasma from 213 pairs of Gambian adult twins, 199 child twin pairs sampled in a dry season when there was little malaria transmission, and another set of 107 child twin pairs sampled at the end of the annual wet season when malaria was common. There were significantly positive heritability (h 2) estimates for 48% (20/42) of the specific antibody assays (for the seven isotypes and subclasses to the six antigens tested) among the adults, 48% (20/42) among the children in the dry season and 31% (13/42) among the children in the wet season. In children, there were significant heritability estimates for IgG4 reactivity against each of the antigens, and this subclass had higher heritability than the other subclasses and isotypes. In adults, 75% (15/20) of the significantly heritable antigen-specific isotype responses were attributable to non-HLA class II genetic variation, whereas none showed a significant HLA contribution.SignificanceGenome-wide approaches are now warranted to map the major genetic determinants of variable antibody isotype and subclass responses to malaria, alongside evaluation of their impact on infection and disease. Although plasma levels of IgG4 to malaria antigens are generally low, the exceptionally high heritability of levels of this subclass in children deserves particular investigation.

Effect of transmission intensity and age on subclass antibody responses to Plasmodium falciparum pre-erythrocytic and blood-stage antigens

“…Interestingly, the Tanzanian study and several others (Dobano et al, 2012; Stanisic et al, 2009a) document a predominance of IgG1 over IgG3 for MSP-1 and AMA-1 in areas of moderate and high transmission, whereas we observed a clear IgG3 bias to these as well as to pre-erythrocytic antigens in the area of high, stable transmission. A number of other studies (Courtin et al, 2009; Dodoo et al, 2008; Duah et al, 2010; Duah et al, 2009; Kinyanjui et al, 2003; Richards et al, 2010), including our previous evaluations of CSP, TRAP and LSA-1 in another unstable transmission area of Kenya (John et al, 2003), have also shown an IgG3 bias over IgG1 to P. falciparum antigens. Such bias is somewhat unexpected, as IgG3 antibodies have a shorter half-life than other subclasses.…”

Human Interleukin 2 (IL-2) Promotion of Immune Regulation and ClinicalOutcomes: A Review

“…Allelic differences in these genes exhibited contradictory results among the various investigated endemic areas, including Brazil; therefore, it seems unlikely that they are the only mechanism responsible for deviations of the immune response [49][50][51].…”

Genome-wide genetic investigation of serological measures of common infections

“…There is evidence that host genetic factors influence antibody responses to both vaccines (eg varicella and rubella) 1,2 and to naturally occurring infections such as malaria, Chagas, and Epstein-Barr virus. [3][4][5] We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable for a number of common infectious pathogens. 6 Here we attempt to localize the genetic factors influencing serological phenotypes of these pathogens using genome-wide statistical gene-mapping approaches.…”