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Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies

Pushparaj, Pradeepa ; Nicoletto, Andrea ; Sheward, Daniel J. ; Das, Hrishikesh ; Castro Dopico, Xaquin ; Perez Vidakovics, Laura ; Hanke, Leo ; Chernyshev, Mark ; Narang, Sanjana and Kim, Sungyong , et al. (2023) In Immunity 56(1). p.7-206
Abstract

The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes. The IGHV1-69∗20-using CAB-I47 antibody and two similar antibodies isolated from an independent donor were critically dependent on allele usage. Neutralization was retained when reverting the V region to the germline... (More)

The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes. The IGHV1-69∗20-using CAB-I47 antibody and two similar antibodies isolated from an independent donor were critically dependent on allele usage. Neutralization was retained when reverting the V region to the germline IGHV1-69∗20 allele but lost when reverting to other IGHV1-69 alleles. Structural data confirmed that two germline-encoded polymorphisms, R50 and F55, in the IGHV1-69 gene were required for high-affinity receptor-binding domain interaction. These results demonstrate that polymorphisms in IGH genes can influence the function of SARS-CoV-2 neutralizing antibodies.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
copy-number variation, immunoglobulin allelic diversity, neutralizing antibody, SARS-CoV-2, single-nucleotide polymorphism
in
Immunity
volume
56
issue
1
pages
7 - 206
publisher
Cell Press
external identifiers
  • scopus:85146043995
  • pmid:36574772
ISSN
1074-7613
DOI
10.1016/j.immuni.2022.12.005
language
English
LU publication?
yes
id
86c9c588-29d4-4c6b-a13c-6025b2dfd4b8
date added to LUP
2023-02-17 13:44:33
date last changed
2024-06-26 04:27:23
@article{86c9c588-29d4-4c6b-a13c-6025b2dfd4b8,
  abstract     = {{<p>The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes. The IGHV1-69<sup>∗</sup>20-using CAB-I47 antibody and two similar antibodies isolated from an independent donor were critically dependent on allele usage. Neutralization was retained when reverting the V region to the germline IGHV1-69<sup>∗</sup>20 allele but lost when reverting to other IGHV1-69 alleles. Structural data confirmed that two germline-encoded polymorphisms, R50 and F55, in the IGHV1-69 gene were required for high-affinity receptor-binding domain interaction. These results demonstrate that polymorphisms in IGH genes can influence the function of SARS-CoV-2 neutralizing antibodies.</p>}},
  author       = {{Pushparaj, Pradeepa and Nicoletto, Andrea and Sheward, Daniel J. and Das, Hrishikesh and Castro Dopico, Xaquin and Perez Vidakovics, Laura and Hanke, Leo and Chernyshev, Mark and Narang, Sanjana and Kim, Sungyong and Fischbach, Julian and Ekström, Simon and McInerney, Gerald and Hällberg, B. Martin and Murrell, Ben and Corcoran, Martin and Karlsson Hedestam, Gunilla B.}},
  issn         = {{1074-7613}},
  keywords     = {{copy-number variation; immunoglobulin allelic diversity; neutralizing antibody; SARS-CoV-2; single-nucleotide polymorphism}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{7--206}},
  publisher    = {{Cell Press}},
  series       = {{Immunity}},
  title        = {{Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies}},
  url          = {{http://dx.doi.org/10.1016/j.immuni.2022.12.005}},
  doi          = {{10.1016/j.immuni.2022.12.005}},
  volume       = {{56}},
  year         = {{2023}},
}