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A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils

Xu, Zhongwei ; Xu, Bingze ; Lundström, Susanna L. ; Moreno-Giró, Àlex ; Zhao, Danxia ; Martin, Myriam LU ; Lönnblom, Erik ; Li, Qixing ; Krämer, Alexander and Ge, Changrong , et al. (2023) In Nature Communications 14(1).
Abstract

Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed... (More)

Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.

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type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
5949
publisher
Nature Publishing Group
external identifiers
  • scopus:85171896560
  • pmid:37741824
ISSN
2041-1723
DOI
10.1038/s41467-023-41561-7
language
English
LU publication?
yes
id
a86c9d9e-cf58-4242-acd3-b641965d9e3a
date added to LUP
2024-01-12 09:57:59
date last changed
2024-04-27 05:23:23
@article{a86c9d9e-cf58-4242-acd3-b641965d9e3a,
  abstract     = {{<p>Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.</p>}},
  author       = {{Xu, Zhongwei and Xu, Bingze and Lundström, Susanna L. and Moreno-Giró, Àlex and Zhao, Danxia and Martin, Myriam and Lönnblom, Erik and Li, Qixing and Krämer, Alexander and Ge, Changrong and Cheng, Lei and Liang, Bibo and Tong, Dongmei and Stawikowska, Roma and Blom, Anna M. and Fields, Gregg B. and Zubarev, Roman A. and Holmdahl, Rikard}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-41561-7}},
  doi          = {{10.1038/s41467-023-41561-7}},
  volume       = {{14}},
  year         = {{2023}},
}