Abstract
Introduction Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.
Methods We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age‐ and sex-stratified cohort of 1,000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.
Results and discussion We identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.
Conclusions Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
Footnotes
The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Kalla Astrom (Lund University), Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Darragh Duffy, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Magnus Fontes, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Cochin), Antonio Raussel (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Marie-Noëlle Ungeheuer, Lluis Quintana-Murci§, Matthew L. Albert§
Additional information can be found at: http://www.pasteur.fr/labex/milieu-interieur
§ Co-coordinators of the Milieu Intérieur Consortium