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.
Highlights
IntroductionThe predominant usage of the L-allele group in generation of non-neutralizing anti-gp[41] Abs was recently demonstrated in a HIV-1 vaccination study[11]
Immunology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA. 5Division of Biostatistics and Bioinformatics Sidney Kimmel Comprehensive Cancer
When hemagglutination inhibition titers (HAI) and microneutralization titers (MN) titers were compared within individuals, there was a trend toward lower HAI/MN ratios for the F/F and F/L groups compared to the L/L individuals (Supplementary Fig. 2c)
Summary
The predominant usage of the L-allele group in generation of non-neutralizing anti-gp[41] Abs was recently demonstrated in a HIV-1 vaccination study[11] These recent findings highlight the need to better understand how this genetic variability at the IGHV1-69 locus can modulate B cell repertoires as well as the extent to which this polymorphism varies across diverse human populations[3,5,6,12]. To address these two questions we analyzed Ab repertoires from an NIH H5N1 vaccinee cohort and samples from the 1000 Genomes Project (1KG)[13], respectively. We discovered marked variance in IGHV1-69 gene duplication and CN among the different ethnic populations that will affect HV1-69-sBnAb responses to influenza vaccines and natural infections
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