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Non-germ-line encoded residues are critical for effective antibody recognition of a poorly immunogenic neutralization epitope on glycoprotein B of human cytomegalovirus.

Lantto, Johan LU ; Lindroth, Ylva and Ohlin, Mats LU (2002) In European Journal of Immunology 32(6). p.1659-1669
Abstract
The capability of the antibody (Ab) repertoire to mount a response to appropriate epitopes on infectious agents will strongly affect the ability of the immune system to provide protection against disease. Certain epitopes may be poor inducers of immunity but are nevertheless able to promote biologically important protection when recognized by the immune repertoire. We have investigated the recognition by Ab of one such poorly immunogenic target, antigenic domain 2 (AD-2) on human cytomegalovirus glycoprotein B. To date, only two well-characterized human monoclonal Ab reactive with this epitope are known. To define parameters important for establishment of a human paratope recognizing this epitope, we created variants of the variable genes... (More)
The capability of the antibody (Ab) repertoire to mount a response to appropriate epitopes on infectious agents will strongly affect the ability of the immune system to provide protection against disease. Certain epitopes may be poor inducers of immunity but are nevertheless able to promote biologically important protection when recognized by the immune repertoire. We have investigated the recognition by Ab of one such poorly immunogenic target, antigenic domain 2 (AD-2) on human cytomegalovirus glycoprotein B. To date, only two well-characterized human monoclonal Ab reactive with this epitope are known. To define parameters important for establishment of a human paratope recognizing this epitope, we created variants of the variable genes utilized by one of these Ab and used phage display technology to select Ab fragments with retained antigen specificity. We show here that residues in the first complementarity determining region of both the heavy and the light chain are involved in determining the AD-2 specificity and, in addition, that key mutations in the germ-line sequence are required for effective interaction with this epitope. Thus, the products of the human germ-line IGHV3-30 and IGKV3-11 genes, the only V genes that have been demonstrated to participate in an AD-2 specific Ab response, do not have the intrinsic features required for high-affinity recognition of this epitope. We propose that the inability of the human germ-line gene-encoded Ab repertoire to directly recognize this and possibly other antigenic determinants results in their poor immunogenicity in vivo. This may favor responses to other epitopes, which have a high-affinity imprint in the human germ-line Ab repertoire. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Complementarity Determining Regions, Cytomegalovirus : immunology, Epitopes, Human, Immunoglobulin Variable Region : chemistry, Immunoglobulins, Heavy-Chain : chemistry, Molecular Sequence Data, Support, Non-U.S. Gov't, Viral Envelope Proteins : immunology, Base Sequence, Amino Acid Sequence, Antibodies, Viral : chemistry, Viral : immunology, Antibody Affinity
in
European Journal of Immunology
volume
32
issue
6
pages
1659 - 1669
publisher
John Wiley & Sons
external identifiers
  • wos:000176269000017
  • pmid:12115649
  • scopus:0036080381
ISSN
1521-4141
DOI
10.1002/1521-4141(200206)32:6<1659::AID-IMMU1659>3.0.CO;2-9
language
English
LU publication?
yes
id
a6c5cc92-2aa3-42c9-be32-fa2f76246242 (old id 109272)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12115649&dopt=Abstract
date added to LUP
2007-07-09 09:44:39
date last changed
2017-01-01 07:34:08
@article{a6c5cc92-2aa3-42c9-be32-fa2f76246242,
  abstract     = {The capability of the antibody (Ab) repertoire to mount a response to appropriate epitopes on infectious agents will strongly affect the ability of the immune system to provide protection against disease. Certain epitopes may be poor inducers of immunity but are nevertheless able to promote biologically important protection when recognized by the immune repertoire. We have investigated the recognition by Ab of one such poorly immunogenic target, antigenic domain 2 (AD-2) on human cytomegalovirus glycoprotein B. To date, only two well-characterized human monoclonal Ab reactive with this epitope are known. To define parameters important for establishment of a human paratope recognizing this epitope, we created variants of the variable genes utilized by one of these Ab and used phage display technology to select Ab fragments with retained antigen specificity. We show here that residues in the first complementarity determining region of both the heavy and the light chain are involved in determining the AD-2 specificity and, in addition, that key mutations in the germ-line sequence are required for effective interaction with this epitope. Thus, the products of the human germ-line IGHV3-30 and IGKV3-11 genes, the only V genes that have been demonstrated to participate in an AD-2 specific Ab response, do not have the intrinsic features required for high-affinity recognition of this epitope. We propose that the inability of the human germ-line gene-encoded Ab repertoire to directly recognize this and possibly other antigenic determinants results in their poor immunogenicity in vivo. This may favor responses to other epitopes, which have a high-affinity imprint in the human germ-line Ab repertoire.},
  author       = {Lantto, Johan and Lindroth, Ylva and Ohlin, Mats},
  issn         = {1521-4141},
  keyword      = {Complementarity Determining Regions,Cytomegalovirus : immunology,Epitopes,Human,Immunoglobulin Variable Region : chemistry,Immunoglobulins,Heavy-Chain : chemistry,Molecular Sequence Data,Support,Non-U.S. Gov't,Viral Envelope Proteins : immunology,Base Sequence,Amino Acid Sequence,Antibodies,Viral : chemistry,Viral : immunology,Antibody Affinity},
  language     = {eng},
  number       = {6},
  pages        = {1659--1669},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Non-germ-line encoded residues are critical for effective antibody recognition of a poorly immunogenic neutralization epitope on glycoprotein B of human cytomegalovirus.},
  url          = {http://dx.doi.org/10.1002/1521-4141(200206)32:6<1659::AID-IMMU1659>3.0.CO;2-9},
  volume       = {32},
  year         = {2002},
}