A systematic investigation into the non-genetic and genetic factors affecting the human anti-viral antibody repertoire

Abstract

SummaryImmunoglobulins are among the most important anti-viral effectors of the human immune system. The biological mechanisms underlying antibody production and maintenance are relatively well understood. However, a broader model of how host intrinsic factors and external processes influence humoral responses to viral infections is lacking. Here, we investigate how age, sex, genetics, health-related habits, and immune factors relate to the anti-viral antibody repertoire of healthy humans. We used VirScan, a high-throughput technology based on phage-display immunoprecipitation sequencing (PhIP-seq), to characterize antibody reactivity against more than 90,000 viral epitopes in 1,212 healthy adults of European and African descent. By comparing VirScan with various serological assays, we first show that PhIP-seq-based antibody repertoires recapitulate expected serostatuses and uncover considerable variation in epitope-specific reactivity. In addition to age and sex effects, we find that the antibody repertoire is strongly associated with active smoking, which results in increased antibody levels against rhinoviruses. We provide evidence that individuals born in Central Africa and Europe differ in antigenic reactivity to common herpesviruses by targeting different viral proteins. By comparing antibody repertoires to 169 immune cell parameters, we find that HLA-DR expression in circulating dendritic cells is associated with increased reactivity against EBV. Finally, we conducted a GWAS of antibody binding against more than 2,600 viral peptides. We confirmed a strong effect ofHLAandIGHloci and theFUT2gene and identified new associations between variants in these genes and antibodies against adenoviruses and saliviruses. These findings highlight the determinants of human variation in the humoral response to viruses and broaden perspectives on how the antibody repertoire is generated and maintained.

Investigation of the sero-epidemiology of vaccine preventable diseases and common viral infections in French populations using a multiplex serological assay

“…Complementary antigen-specific serological tests were conducted to measure IgG levels within samples of the MI cohort, following the manufacturer’s guidelines. This validation was performed for a subset of ten antigens 22 .…”