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

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Xu Z, Xu B, Lundström SL, Moreno-Giró À, Zhao D, Martin M, Lönnblom E, Li Q, Krämer A, Ge C, Cheng L, Liang B, Tong D, Stawikowska R, Blom AM, Fields GB, Zubarev RA, Holmdahl R

Nat Commun 14 (1) 5949 [2023-09-23; online 2023-09-23]

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.

Drug Discovery and Development (DDD) [Collaborative]

PubMed 37741824

DOI 10.1038/s41467-023-41561-7

Crossref 10.1038/s41467-023-41561-7

pmc: PMC10517938
pii: 10.1038/s41467-023-41561-7