title: 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.
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Avnir
authors.affiliation: 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.
authors.forename: Corey T
authors.initials: CT
authors.lastname: Watson
authors.affiliation: Program in Computational and Systems Immunology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Glanville
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peterson
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Tallarico
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bennett
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Qin
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Division of Biostatistics and Bioinformatics Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University 550 N. Broadway, Room 1103-A Baltimore, Maryland 21205-2013, USA.
authors.forename: Chiung-Yu
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Beigel
authors.affiliation: Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Breden
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Cancer Immunology &AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
mesh_terms: D000483:Alleles; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology; D000914:Antibodies, Viral / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018628:Gene Dosage; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007143:Immunoglobulin Heavy Chains; D007252:Influenza Vaccines