Engelbrecht Eric, Rodriguez Oscar L, Lees William, Vanwinkle Zach, Shields Kaitlyn, Schultze Steven, Gibson William S, Smith David R, Jana Uddalok, Saha Swati, Peres Ayelet, Yaari Gur, Smith Melissa L, Watson Corey T
Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
bioRxiv. 2025 Jun 1:2025.05.28.656470. doi: 10.1101/2025.05.28.656470.
Variation in antibody (Ab) responses contributes to disease outcomes and therapeutic responsiveness, the determinants of which remain incompletely understood. This study demonstrates that polymorphisms in immunoglobulin kappa (IGK) and lambda (IGL) loci influence baseline differences in the Ab repertoire that preclude antigen-driven responses. We pair IGK/IGL genomic sequencing with Ab repertoire profiling to comprehensively resolve coding and non-coding single nucleotide and structural variants that explain gene usage variation at >70% of light chain genes, with direct impacts on the amino acid composition of complementarity determining regions. The identification of both intergenic and coding repertoire-associated variants indicates genetic modulation of gene usage via diverse mechanisms. Relative to IGL, IGK is characterized by extensive linkage disequilibrium and genetic co-regulation of gene usage, highlighting differential regulatory and evolutionary features. These results establish the contribution of IG polymorphism in the formation of the Ab repertoire, shedding light on our understanding of Ab-mediated immunity.
抗体（Ab）反应的差异会影响疾病结局和治疗反应性，但其决定因素仍未完全明确。本研究表明，免疫球蛋白κ（IGK）和λ（IGL）基因座的多态性会影响抗体库的基线差异，从而妨碍抗原驱动的反应。我们将IGK/IGL基因组测序与抗体库分析相结合，以全面解析编码和非编码单核苷酸及结构变异，这些变异解释了超过70%的轻链基因的基因使用差异，并直接影响互补决定区的氨基酸组成。基因间和编码库相关变异的鉴定表明，基因使用通过多种机制受到遗传调控。相对于IGL，IGK的特点是广泛的连锁不平衡和基因使用的遗传共调控，突出了不同的调控和进化特征。这些结果确定了IG多态性在抗体库形成中的作用，为我们理解抗体介导的免疫提供了新的线索。
