Functional IGH V polymorphism is frequent in humans: implications for immunity and vaccination (HUM8P.349)

Abstract

Abstract Antibody heavy chain variable region genes (VH) are important for antigen binding, as evidenced by the dominant usage of particular VHs, such as the VH3b subfamily, in the immune responses to the capsular polysaccharide of H. influenza b. The presence or absence of particular VH alleles may be important for immunity. To screen for polymorphic VH alleles in humans, we sequenced functionally rearranged VH from 500K circulating B cells in each of 100 healthy young adults. We focused on the naïve repertoire (0-1 mutations compared to the closest known germline allele), and analyzed the proportion of rearrangements that were in-frame without stop codons (IF). In mice, low IF VHs have not undergone robust selection and are often pseudogenes. We confirmed several polymorphically functional VH genes with variable IF fractions, including V3-20, V5-a, V3-f, V1-8, and V3-9. We also identified homozygous individuals carrying novel, non-functional alleles at V7-4-1, V6-1, V3-66 and V2-70. Comparison of VH usage patterns between individuals revealed significant variation in the number of functional VH contributing to the naïve repertoire, with between 36 and 43 functional VH segments observed in each individual. These data demonstrate a significant level of functional allelic diversity and VH copy number variation between individuals, which could contribute to differential disease susceptibility, as well as influence vaccine efficacy.