Germline polymorphisms in the immunoglobulin kappa and lambda loci underpinning antibody light chain repertoire variability

Abstract

Abstract Variation in antibody (Ab) responses contributes to variable disease outcomes and therapeutic responsiveness, the determinants of which are incompletely understood. This study demonstrates that polymorphisms in immunoglobulin (IG) light chain loci dictate the composition of the Ab repertoire, establishing fundamental baseline differences that influence functional Ab-mediated responses. Using long-read genomic sequencing of the IG kappa (IGK) and IG lambda (IGL) loci, we resolve genetic variation, including structural variants, single nucleotide variants, and gene alleles. By integrating these genetic data with Ab repertoire profiling, we find that all forms of IG germline variation contribute to inter-individual gene usage differences for >70% of light chain genes in the repertoire, directly impacting the amino acids of expressed light chain transcripts. The genomic locations of usage-associated variants in both intergenic and coding regions indicate that IG polymorphisms modulate gene usage via diverse mechanisms, likely including the modulation of V(D)J recombination, heavy and light chain pairing biases, and transcription/translation. Finally, relative to IGL, IGK is characterized by more extensive linkage disequilibrium and genetic co-regulation of gene usage. These results firmly establish the critical contribution of IG light chain polymorphism in Ab repertoire diversity, with important implications for investigating Ab responses in health and disease.