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Sci Rep. 2016 Feb 16;6:20842. doi: 10.1038/srep20842.

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

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Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Program in Computational and Systems Immunology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.
Division of Biostatistics and Bioinformatics Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University 550 N. Broadway, Room 1103-A Baltimore, Maryland 21205-2013, USA.
Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA.


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.

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