9/12/2023 0 Comments Aive antibody repertoire![]() ![]() In addition, IGH is highly enriched for large structural variants (SVs), including insertions, deletions, and duplications of functional genes, many of which show considerable variability between human populations 25, 29. Akin to the extensive genetic diversity observed in the human leukocyte antigen (HLA) locus, >680 IGH alleles have been cataloged solely from limited surveys 30. The IGH locus is now understood to be among the most polymorphic and complex regions of the human genome 3, 25, 26, 27, 28, 29. The human IGH locus is located immediately adjacent to the telomere of chromosome 14, and harbors 129 variable (V), 27 diversity (D) and 9 joining (J) genes that are utilized during V(D)J recombination to produce the heavy chain of an Ab 24. With respect to genetic factors, the impact of variants in the immunoglobulin heavy (IGH) and light chain loci on the antibody response has not been determined. Delineating the mechanisms that drive variation in the functional Ab response is critical not only to understanding B cell-mediated immunity in disease, but also ultimately informing the design of improved vaccines and therapies 22, 23. The initial formation of the Ab repertoire is mediated by complex molecular processes, and can be influenced by factors such as prior vaccination and infection, health status, sex, age, and genetics 16, 17, 18, 19, 20, 21. The circulating Ab repertoire is composed of hundreds of millions of unique Abs 1, 2, and the composition of the repertoire varies considerably between individuals 1, 2, 3, potentially explaining the varied Ab responses observed in a variety of disease contexts, including infection 4, 5, 6, 7, 8, autoimmunity 9, 10, 11, 12, and cancer 13, 14, 15. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.Īntibodies (Abs) are critical to the function of the adaptive immune system and have evolved to be one of the most diverse protein families in the human body, providing essential protection against foreign pathogens. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. ![]()
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