Deciphering the genetic architecture of antibody repertoire development

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B725
Abstract ID: 5924

Presenting Author:
Oscar Rodriguez , postdoc at Univ. of Louisville Sch. of Med.

Abstract:

Unraveling the genetic complexities of the immunoglobulin loci (IG) has been a longstanding challenge in understanding variation in the human antibody (Ab) response. Employing long-read genomic sequencing and adaptive immune receptor repertoire sequencing in matched samples, our recent study demonstrated the significant impact of genetic variants within the IG heavy chain locus (IGH) on the circulating IgM and IgG antibody repertoires in human peripheral blood mononuclear cells (PBMCs). Expanding on these findings, our comprehensive analysis encompassed the heavy and light chain Ab repertoire across multiple stages of B cell development, including pro-B, pre-B, immature, and naive subsets. We uncovered strikingly high gene usage correlations (R² > 90%) between B cell stages. Intriguingly, our genetic analysis in pro-B cells replicated variants associated with inter-individual differences in peripheral Ab repertoire gene usage variation, further implicating a genetic effect on V(D)J recombination. Notably, we also establish associations between IGH genetic variants and distinct heavy and light chain gene usage profiles, proposing a model whereby the IGH locus exerts trans-effects on the light chain repertoire, potentially through constraints on heavy and light chain pairing. Our results underscore the importance of IG loci genomics in deciphering Ab-mediated responses and hold significant promise for advancing our understanding of human diseases and Ab functionality.