A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis

Yibo He, Changrong Ge, Àlex Moreno-Giró, Bingze Xu, Christian M. Beusch, Katalin Sandor, Jie Su, Lei Cheng, Erik Lönnblom, Christina Lundqvist, Linda M. Slot, Dongmei Tong, Vilma Urbonaviciute, Bibo Liang, Taotao Li, Gonzalo Fernandez Lahore, Mike Aoun, Vivianne Malmström, Theo Rispens, Patrik Ernfors, Camilla I. Svensson, Hans Ulrich Scherer, René E. M. Toes, Inger Gjertsson, Olov Ekwall, Roman A. Zubarev and Rikard Holmdahl ()
Additional contact information
Yibo He: Karolinska Institutet
Changrong Ge: Karolinska Institutet
Àlex Moreno-Giró: Karolinska Institutet
Bingze Xu: Karolinska Institutet
Christian M. Beusch: Karolinska Institutet
Katalin Sandor: Karolinska Institutet
Jie Su: Karolinska Institutet
Lei Cheng: Karolinska Institutet
Erik Lönnblom: Karolinska Institutet
Christina Lundqvist: University of Göteborg
Linda M. Slot: Leiden University Medical Center
Dongmei Tong: Karolinska Institutet
Vilma Urbonaviciute: Karolinska Institutet
Bibo Liang: Karolinska Institutet
Taotao Li: Karolinska Institutet
Gonzalo Fernandez Lahore: Karolinska Institutet
Mike Aoun: Karolinska Institutet
Vivianne Malmström: Karolinska Institutet, Karolinska University Hospital
Theo Rispens: University of Amsterdam
Patrik Ernfors: Karolinska Institutet
Camilla I. Svensson: Karolinska Institutet
Hans Ulrich Scherer: Leiden University Medical Center
René E. M. Toes: Leiden University Medical Center
Inger Gjertsson: University of Göteborg
Olov Ekwall: University of Göteborg
Roman A. Zubarev: Karolinska Institutet
Rikard Holmdahl: Karolinska Institutet

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certain RA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.

Date: 2023
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DOI: 10.1038/s41467-023-36257-x

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