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Collagen type II is recognized by a pathogenic antibody through germline encoded structures

Boeiers, Ulrika; Lanig, Harald; Sehnert, Bettina; Holmdahl, Rikard LU and Burkhardt, Harald (2008) In European Journal of Immunology 38(10). p.2784-2795
Abstract
Collagen type II (CII) is a cartilage-specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen-induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single-chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. in silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII-binding sites in the CDR2 and CDR3... (More)
Collagen type II (CII) is a cartilage-specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen-induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single-chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. in silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII-binding sites in the CDR2 and CDR3 regions of both heavy and light chains. Since the conversion of the CIIC1scFv sequence into the respective germline at all 13 somatically mutated positions did not affect its CII binding, our data indicate that potentially harmful cartilage-specific humoral autoimmunity could be germline encoded. The molecular modeling further demonstrates that the rigid collagen triple helix restricts the likelihood of molecular interactions with the CDR regions of the antibody considerably compared with globular antigens. These sterical constraints provide an explanation as to why somatic mutations in the arthritogenic autoantibody have no obvious impact on CII recognition. (Less)
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author
organization
publishing date
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Contribution to journal
publication status
published
subject
keywords
Rheumatoid arthritis, dynamics simulations, Molecular, Comparative modeling, Autoantibody, Collagen type II
in
European Journal of Immunology
volume
38
issue
10
pages
2784 - 2795
publisher
John Wiley & Sons
external identifiers
  • wos:000260693500015
  • scopus:58149260526
ISSN
1521-4141
DOI
10.1002/eji.200838238
language
English
LU publication?
yes
id
0c2e11e1-872e-41dd-98b1-197e31ee2306 (old id 1283928)
date added to LUP
2009-02-09 10:51:41
date last changed
2017-03-12 03:36:21
@article{0c2e11e1-872e-41dd-98b1-197e31ee2306,
  abstract     = {Collagen type II (CII) is a cartilage-specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen-induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single-chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. in silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII-binding sites in the CDR2 and CDR3 regions of both heavy and light chains. Since the conversion of the CIIC1scFv sequence into the respective germline at all 13 somatically mutated positions did not affect its CII binding, our data indicate that potentially harmful cartilage-specific humoral autoimmunity could be germline encoded. The molecular modeling further demonstrates that the rigid collagen triple helix restricts the likelihood of molecular interactions with the CDR regions of the antibody considerably compared with globular antigens. These sterical constraints provide an explanation as to why somatic mutations in the arthritogenic autoantibody have no obvious impact on CII recognition.},
  author       = {Boeiers, Ulrika and Lanig, Harald and Sehnert, Bettina and Holmdahl, Rikard and Burkhardt, Harald},
  issn         = {1521-4141},
  keyword      = {Rheumatoid arthritis,dynamics simulations,Molecular,Comparative modeling,Autoantibody,Collagen type II},
  language     = {eng},
  number       = {10},
  pages        = {2784--2795},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Collagen type II is recognized by a pathogenic antibody through germline encoded structures},
  url          = {http://dx.doi.org/10.1002/eji.200838238},
  volume       = {38},
  year         = {2008},
}