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Two monoclonal antibodies to precisely the same epitope of type II collagen select non-crossreactive phage clones by phage display: implications for autoimmunity and molecular mimicry

Xu, YK; Ramsland, PA; Davies, JM; Scealy, M; Nandakumar, K S; Holmdahl, Rikard LU and Rowley, MJ (2004) In Molecular Immunology 41(4). p.411-419
Abstract
Two monoclonal antibodies (mAb) CB268 and CII-C1 to type 11 collagen (CII) react with precisely the same conformational epitope constituted by the residues ARGLT on the three chains of the CII triple helix. The antibodies share structural similarity, with most differences in the complementarity determining region 3 of the heavy chain (HCDR3). The fine reactivity of these mAbs was investigated by screening two nonameric phage-displayed random peptide libraries. For each mAb, there were phage clones (phagotopes) that reacted strongly by ELISA only with the selecting mAb, and inhibited binding to CII only for that mAb, not the alternate mAb. Nonetheless, a synthetic peptide RRLPFGSQM corresponding to an insert from a highly reactive... (More)
Two monoclonal antibodies (mAb) CB268 and CII-C1 to type 11 collagen (CII) react with precisely the same conformational epitope constituted by the residues ARGLT on the three chains of the CII triple helix. The antibodies share structural similarity, with most differences in the complementarity determining region 3 of the heavy chain (HCDR3). The fine reactivity of these mAbs was investigated by screening two nonameric phage-displayed random peptide libraries. For each mAb, there were phage clones (phagotopes) that reacted strongly by ELISA only with the selecting mAb, and inhibited binding to CII only for that mAb, not the alternate mAb. Nonetheless, a synthetic peptide RRLPFGSQM corresponding to an insert from a highly reactive CII-C1-selected phagotope, which was unreactive (and non-inhibitory) with CB268, inhibited the reactivity of CB268 with CII. Most phage-displayed peptides contained a motif in the first part of the molecule that consisted of two basic residues adjacent to at least one hydrophobic residue (e.g. RRL or LRR), but the second portion of the peptides differed for the two mAbs. We predict that conserved CDR sequences interact with the basic-basic-hydrophobic motif, whereas non-conserved amino acids in the binding sites (especially HCDR3) interact with unique peptide sequences and limit cross-reactivity. The observation that two mAbs can react identically with a single epitope on one antigen (CII), but show no cross-reactivity when tested against a second (phagotope) indicates that microorganisms could exhibit mimics capable of initiating autoimmunity without this being evident from conventional assays. (C) 2004 Elsevier Ltd. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
phage display, collagen-induced arthritis, autoimmune disease, Cl, epitope
in
Molecular Immunology
volume
41
issue
4
pages
411 - 419
publisher
Pergamon
external identifiers
  • pmid:15163538
  • wos:000222147400007
  • scopus:2442538040
ISSN
1872-9142
DOI
10.1016/j.molimm.2004.03.025
language
English
LU publication?
yes
id
e95e8fd1-82f6-41eb-9305-b208f7cc3ce0 (old id 274480)
date added to LUP
2007-11-05 16:24:50
date last changed
2017-01-01 07:20:25
@article{e95e8fd1-82f6-41eb-9305-b208f7cc3ce0,
  abstract     = {Two monoclonal antibodies (mAb) CB268 and CII-C1 to type 11 collagen (CII) react with precisely the same conformational epitope constituted by the residues ARGLT on the three chains of the CII triple helix. The antibodies share structural similarity, with most differences in the complementarity determining region 3 of the heavy chain (HCDR3). The fine reactivity of these mAbs was investigated by screening two nonameric phage-displayed random peptide libraries. For each mAb, there were phage clones (phagotopes) that reacted strongly by ELISA only with the selecting mAb, and inhibited binding to CII only for that mAb, not the alternate mAb. Nonetheless, a synthetic peptide RRLPFGSQM corresponding to an insert from a highly reactive CII-C1-selected phagotope, which was unreactive (and non-inhibitory) with CB268, inhibited the reactivity of CB268 with CII. Most phage-displayed peptides contained a motif in the first part of the molecule that consisted of two basic residues adjacent to at least one hydrophobic residue (e.g. RRL or LRR), but the second portion of the peptides differed for the two mAbs. We predict that conserved CDR sequences interact with the basic-basic-hydrophobic motif, whereas non-conserved amino acids in the binding sites (especially HCDR3) interact with unique peptide sequences and limit cross-reactivity. The observation that two mAbs can react identically with a single epitope on one antigen (CII), but show no cross-reactivity when tested against a second (phagotope) indicates that microorganisms could exhibit mimics capable of initiating autoimmunity without this being evident from conventional assays. (C) 2004 Elsevier Ltd. All rights reserved.},
  author       = {Xu, YK and Ramsland, PA and Davies, JM and Scealy, M and Nandakumar, K S and Holmdahl, Rikard and Rowley, MJ},
  issn         = {1872-9142},
  keyword      = {phage display,collagen-induced arthritis,autoimmune disease,Cl,epitope},
  language     = {eng},
  number       = {4},
  pages        = {411--419},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Two monoclonal antibodies to precisely the same epitope of type II collagen select non-crossreactive phage clones by phage display: implications for autoimmunity and molecular mimicry},
  url          = {http://dx.doi.org/10.1016/j.molimm.2004.03.025},
  volume       = {41},
  year         = {2004},
}