Is antiviral antibody epitope selection heritable?

Yes. In a VirScan PhIP-Seq study of 494 TwinsUK participants and 535 SNP-genotyped Vaccine Research Center volunteers, monozygotic twin pairs shared their immunodominant EBV reactivity profiles significantly more than dizygotic pairs (p = 4.2 x 10^-6) or random pairings (p = 3.6 x 10^-14), and 107 of 144 immunodominant EBV peptide reactivities reached estimated heritability of at least 20%.

Which genomic locus drives EBV epitope selection?

GWAS identified the MHC class II locus on chromosome 6 as significantly associated (p 0.8 for each pair) and antibody response increases linearly with the number of effect alleles.

How heritable is the breadth of the anti-EBV antibody response?

Structural Equation Modeling estimated additive genetic contribution at 39%, shared environmental at 27%, and unique environmental at 34%. Anti-EBV breadth correlated more tightly within monozygotic twin pairs (R^2 = 0.51) than dizygotic pairs (R^2 = 0.23).

Can antibody profiles predict EBV viral load?

Yes. A machine-learned 112-peptide serosignature predicted EBV viral load in peripheral blood mononuclear cells and mapped to the MHC class I locus, consistent with the established CD8+ T-cell role in controlling EBV-infected B cells.

Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait

Twin and GWAS evidence that the antiviral antibody reactome is an HLA-shaped, heritable phenotype.

Venkataraman T, Valencia C, Mangino M, Morgenlander W, Clipman SJ, Liechti T, Valencia A, Christofidou P, Spector T, Roederer M, Duggal P, Larman HB.

Immunity · 2022 Jan 11;55(1):174–184.e5 · DOI: 10.1016/j.immuni.2021.12.004

How to cite

AMA

Venkataraman T, Valencia C, Mangino M, et al. Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait. Immunity. 2022;55(1):174-184.e5. doi:10.1016/j.immuni.2021.12.004

APA

Venkataraman, T., Valencia, C., Mangino, M., Morgenlander, W., Clipman, S. J., Liechti, T., Valencia, A., Christofidou, P., Spector, T., Roederer, M., Duggal, P., & Larman, H. B. (2022). Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait. Immunity, 55(1), 174-184.e5. https://doi.org/10.1016/j.immuni.2021.12.004

BibTeX

@article{Venkataraman2022,
  author  = {Venkataraman, T. and Valencia, C. and Mangino, M. and Morgenlander, W. and Clipman, S. J. and Liechti, T. and Valencia, A. and Christofidou, P. and Spector, T. and Roederer, M. and Duggal, P. and Larman, H. B.},
  title   = {Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait},
  journal = {Immunity},
  volume  = {55},
  number  = {1},
  pages   = {174--184.e5},
  year    = {2022},
  doi     = {10.1016/j.immuni.2021.12.004}
}

VirScan PhIP-Seq across 494 TwinsUK participants (162 monozygotic, 332 dizygotic) and 535 SNP-genotyped Vaccine Research Center volunteers shows that antiviral antibody epitope selection — not just whether a person seroconverts — is heritable. The work uses Epstein-Barr virus as the focal model and combines twin-pair structural equation modeling with GWAS to map peptide-resolution antibody phenotypes onto the MHC class I and class II loci.

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In this publication:

107 EBV peptide reactivities cleared a heritability threshold of at least 20%, with monozygotic twins sharing immunodominant EBV reactivity profiles much more closely than dizygotic twins.
Four C-terminal EBNA-2 peptide reactivities reached genome-wide significance at the HLA class II locus on chromosome 6.
A 112-peptide machine-learned EBV serosignature predicted peripheral-blood viral load and mapped to the MHC class I locus.
Structural-equation modeling estimated additive genetic contribution at 39%, shared environment at 27%, and unique environment at 34% for EBV reactivity breadth.

Two people exposed to the same virus rarely make the exact same antibodies. They make antibodies of different fine specificity — different precise targets within the same viral protein — and at different breadths. This study asks a basic question that previous work has not directly resolved: is the choice of which antiviral epitopes get targeted itself a heritable trait?

To answer it, the authors ran VirScan, a Phage ImmunoPrecipitation Sequencing (PhIP-Seq) assay that displays 106,678 overlapping 56-amino-acid peptides spanning every human virus on bacteriophage. Sera from 494 twins in the TwinsUK cohort (162 monozygotic, 332 dizygotic pairs) and 535 SNP-genotyped Vaccine Research Center participants were profiled. Comparing the antibody reactivity profiles within twin pairs, then performing a genome-wide association study (GWAS) on heritable reactivities, lets them separate genetic from environmental drivers of epitope selection.

Epstein-Barr virus (EBV) was the focal model. EBV is a near-universal infection (about 94% seroprevalence here) and produced the most reactive peptides in the library — an average of 129 reactive peptides per individual. Monozygotic twins shared their immunodominant EBV reactivity profiles much more closely than dizygotic twins did, and 107 EBV peptide reactivities reached a heritability of at least 20%. GWAS then mapped four C-terminal EBNA-2 peptide reactivities to the MHC class II locus on chromosome 6, and a machine-learning serosignature built from 112 peptides predicted EBV viral load in peripheral blood and mapped to the MHC class I locus.

The bottom line: which antiviral epitopes a person targets is shaped by their inherited HLA repertoire, not just by exposure history. That has direct implications for vaccine design, for serology-based exposure attribution, and for any program reasoning about why antibody responses to the same antigen vary between people.

Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait

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