Hepatitis B surface antigen presentation and HLA-DRB1*– lessons from twins and peptide binding studies

Abstract

SummaryThe aim of this study was to investigate the underlying mechanisms of the genetic association between certain HLA-DRB1* alleles and the immune response to HBsAg vaccination. Therefore, HBsAg peptide binding to HLA-DR molecules was measured in vitro by peptide binding ELISAs. Additionally, HBsAg-specific T cell reaction and cytokine profile of immune response were analysed ex vivo in ELISPOT assays and DR-restriction of T-cell proliferative responses was investigated with HBsAg specific T cell clones. In addition, we compared HBsAg specific T cell responses of 24 monozygotic and 3 dizygotic twin pairs after HBsAg vaccination. Our results showed that the peptide binding assays did not reflect antigen presentation in vivo . DR alleles associated with vaccination failure like DRB1*0301 and 0701 efficiently presented HBsAg peptides. In 11 of 24 investigated monozygotic twin pairs we observed pronounced differences in the recognition of HBsAg peptides. This study indicates that HLA-DR associations with HBsAg vaccination response are not caused by differences in peptide binding or by a shift in the Th1/Th2 profile. Our findings strongly argue for differences in the T cell recognition of peptide/MHC complexes as the critical event in T cell responsiveness to HBsAg.

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics

“…Immune responses induced by vaccination are in part under genetic control, and the degree of heritability varies by vaccine between 35 and 90%, as shown by family and twin studies both within African settings Marchant et al 2006;Newport et al 2004bNewport et al , 2005 and across the rest of the world (Alper 1995;De et al 2001;Hohler et al 2002;Konradsen et al 1993Konradsen et al , 1994Kruger et al 2005;Lin et al 1989;Musher et al 2000, Musher et al 1997 and reviewed by Kimman et al 2007). Additionally, we know that diVerences in vaccine eYcacy exist between diVerent ethnic groups, also indicating a putative role for genetic factors (Kimman et al 2007).…”

Genetic Variation in the Response to Vaccination

“…Model-fitting analyses were done to dissect genetic and environmental components of vaccine responses, revealing that the HLA-DRB1* alleles 01, 11 and 25 were associated with good HbsAg vaccine responses. Further studies by this group suggested that differences in the T cell recognition of peptide/MHC complexes are a critical event in T cell responsiveness to HBsAg [16]. The heritability of the HBsAg vaccine response accounted for by the HLA-DRB1* locus was subsequently estimated to be 25% (as estimated by comparison of intraclass correlations of dizygotic twin pairs who had an identical genotype at the HLA-DRB1* locus with those of dizygotic twin pairs who had a different genotype), leaving the remaining heritability of 36% to other gene loci.…”

Searching for the human genetic factors standing in the way of universally effective vaccines

“…These differences have been explored experimentally in detail. Multiple groups have found that antigen-presenting cells (APCs) from peripheral blood mononuclear cells of non-responders are able to stimulate DR-matched helper T cells from responders as effectively as APCs from high responding individuals making a deficit in antigen processing and presentation less likely [25,[73][74][75]. Conversely, these studies found that the T-cells from non-responders could not be activated by either their non-responding APC counterpart or DR-matched APCs from responders.…”