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

Zhongwei Xu, Bingze Xu, Susanna L. Lundström, Àlex Moreno-Giró, Danxia Zhao, Myriam Martin, Erik Lönnblom, Qixing Li, Alexander Krämer, Changrong Ge, Lei Cheng, Bibo Liang, Dongmei Tong, Roma Stawikowska, Anna M. Blom, Gregg B. Fields, Roman A. Zubarev and Rikard Holmdahl ()
Additional contact information
Zhongwei Xu: Karolinska Institute
Bingze Xu: Karolinska Institute
Susanna L. Lundström: Karolinska Institute
Àlex Moreno-Giró: Karolinska Institute
Danxia Zhao: Karolinska Institute
Myriam Martin: Lund University
Erik Lönnblom: Karolinska Institute
Qixing Li: Southern Medical University
Alexander Krämer: Karolinska Institute
Changrong Ge: Karolinska Institute
Lei Cheng: Karolinska Institute
Bibo Liang: Karolinska Institute
Dongmei Tong: Karolinska Institute
Roma Stawikowska: Florida Atlantic University
Anna M. Blom: Lund University
Gregg B. Fields: Florida Atlantic University
Roman A. Zubarev: Karolinska Institute
Rikard Holmdahl: Karolinska Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41467-023-41561-7

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