Germline polymorphisms in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire

TL;DR

This study shows that genetic variations in antibody light chain loci significantly influence the diversity of antibody repertoires, affecting immune responses and disease outcomes.

Contribution

The study identifies germline polymorphisms in immunoglobulin kappa and lambda loci as key determinants of antibody repertoire diversity.

Findings

Polymorphisms in IG loci contribute to inter-individual differences in >70% of light chain genes.

Variants in both intergenic and coding regions modulate gene usage through mechanisms like V(D)J recombination and gene pairing biases.

IGK exhibits more linkage disequilibrium and co-regulation compared to IGL, highlighting distinct regulatory features.

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 preclude functional Ab-mediated responses. Using long-read genomic sequencing of the IG kappa (IGK) and IG lambda (IGL) loci, we comprehensively resolved genetic variation, including novel structural variants, single nucleotide variants, and gene alleles. By integrating these genetic data with Ab repertoire profiling, we found that all forms of IG germline variation contributed 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, including complementarity determining region domains. The genomic locations of usage-associated variants in both intergenic and coding regions indicated 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 was characterized by more extensive linkage disequilibrium and genetic co-regulation of gene usage, illuminating differential regulatory and evolutionary features between the two light chain loci. 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.

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