skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Affinity maturation in a human humoral response to influenza hemagglutinin

Abstract

Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possiblemore » alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.« less

Authors:
 [1];  [2];  [3];  [4]; ORCiD logo [5]
  1. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
  2. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Broad Institute of MIT and Harvard, Cambridge, MA (United States)
  3. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  4. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Ragon Inst. of Massachusetts General Hospital, Massachusetts Inst. of Technology, and Harvard, Cambridge, MA (United States)
  5. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1581820
Grant/Contract Number:  
P01 AI089618; U19 AI117892
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 52; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; influenza virus; antibody; B cell; vaccine; X-ray crystallography

Citation Formats

McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., and Harrison, Stephen C. Affinity maturation in a human humoral response to influenza hemagglutinin. United States: N. p., 2019. Web. doi:10.1073/pnas.1915620116.
McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., & Harrison, Stephen C. Affinity maturation in a human humoral response to influenza hemagglutinin. United States. https://doi.org/10.1073/pnas.1915620116
McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., and Harrison, Stephen C. 2019. "Affinity maturation in a human humoral response to influenza hemagglutinin". United States. https://doi.org/10.1073/pnas.1915620116. https://www.osti.gov/servlets/purl/1581820.
@article{osti_1581820,
title = {Affinity maturation in a human humoral response to influenza hemagglutinin},
author = {McCarthy, Kevin R. and Raymond, Donald D. and Do, Khoi T. and Schmidt, Aaron G. and Harrison, Stephen C.},
abstractNote = {Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.},
doi = {10.1073/pnas.1915620116},
url = {https://www.osti.gov/biblio/1581820}, journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 52,
volume = 116,
place = {United States},
year = {Mon Dec 16 00:00:00 EST 2019},
month = {Mon Dec 16 00:00:00 EST 2019}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 12 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans
journal, December 2015


Complex Antigens Drive Permissive Clonal Selection in Germinal Centers
journal, March 2016


Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin.
journal, May 1984


Viral Receptor-Binding Site Antibodies with Diverse Germline Origins
journal, May 2015


Intraclonal generation of antibody mutants in germinal centres
journal, December 1991


Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody
journal, November 2012


Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site
journal, December 2015


B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study
journal, May 2012


Variations in Affinities of Antibodies during the Immune Response *
journal, July 1964


Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires
journal, January 2018


XDS
journal, January 2010


Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage: Key Mutations in Antibody Affinity Maturation
journal, February 2015


Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain
journal, November 2016


Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin
journal, August 2011


Phaser crystallographic software
journal, July 2007


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010


Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020


Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021


PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010


Viral Receptor-Binding Site Antibodies with Diverse Germline Origins
journal, May 2015


Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site
journal, December 2015


Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans
journal, December 2015


Taking the Broad View on B Cell Affinity Maturation
journal, March 2016


Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires
journal, January 2018


Variations in Affinities of Antibodies during the Immune Response *
journal, July 1964


Intraclonal generation of antibody mutants in germinal centres
journal, December 1991


B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study
journal, May 2012


Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain
journal, November 2016


Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin
journal, August 2011


Immunopaleontology reveals how affinity enhancement is achieved during affinity maturation of antibodies to influenza virus
journal, December 2012


Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin.
journal, May 1984


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009


PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010