IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity

Abstract

IGHV polymorphism provides a rich source of humoral immune system diversity. One important example is the IGHV1-69 germline gene where the biased use of alleles that encode the critical CDR-H2 Phe54 (F-alleles) to make broadly neutralizing antibodies (HV1-69-sBnAb) to the influenza A hemagglutinin stem domain has been clearly established. However, whether IGHV1-69 polymorphism can also modulate B cell function and Ab repertoire expression through promoter and copy number (CN) variations has not been reported, nor has whether IGHV1-69 allelic distribution is impacted by ethnicity. Here we studied a cohort of NIH H5N1 vaccinees and demonstrate for the first time the influence of IGHV1-69 polymorphism on V-segment usage, somatic hypermutation and B cell expansion that elucidates the dominance of F-alleles in HV1-69-sBnAbs. We provide evidence that Phe54/Leu54 (F/L) polymorphism correlates with shifted repertoire usage of other IGHV germline genes. In addition, we analyzed ethnically diverse individuals within the 1000 genomes project and discovered marked variations in F- and L- genotypes and CN among the various ethnic groups that may impact HV1-69-sBnAb responses. These results have immediate implications for understanding HV1-69-sBnAb responses at the individual and population level and for the design and implementation of “universal” influenza vaccine.

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

“…The critical difference between these alleles is whether they encode a Phe or Ile at position 54 of CDR H2 (Table 1) (Avnir et al, 2014; Avnir et al, 2016; Pappas et al, 2014). Many antibodies derived from Phe54-encoding alleles of the V H 1-69 germline (mainly the *01, *03, *06, *12 alleles) have been found to have heterosubtypic activity against influenza viruses, and likely target the conserved HA stem (Avnir et al, 2014; Pappas et al, 2014).…”

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains

“…Nevertheless, the partial documentation of the IGH loci reported here and the strain differences seen are sufficient to raise the possibility that the IGHV locus may contribute to strain‐related differences in mouse models of human disease. Allelic variants have been associated with differences in disease susceptibility of rats and humans . IGHV sequence variability might also contribute to the differences that have been reported in the susceptibility of inbred mouse strains to both infectious and autoimmune diseases …”

“…There was a sharp decline in the reporting of new sequences once the complete human IGH locus was published in 1998, but the advent of high‐throughput sequencing of human antibody genes reawakened interest in the documentation of allelic variants . A surprising level of immunoglobulin gene variation, including structural variation of the IGH locus, has since been shown within the human population, and such variation can have important consequences for the development of a suitable protective antibody repertoire . A similar exploration of immunoglobulin gene variation is now beginning in the mouse.…”

iReceptor: A platform for querying and analyzing antibody/B‐cell and T‐cell receptor repertoire data across federated repositories

“…(17)), and cancer immunotherapy ((18) (19). Here we review some of the latest applications of this type of data, emphasizing studies that would benefit from performing analyses across federated repositories covering many studies, labs and institutions.…”