A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
(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.
(Less)
- author
- organization
- publishing date
- 2023-12
- 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
- 2024-07-06 11:08:16
@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}}, }