Nature Communications (Feb 2023)
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,
- Rikard Holmdahl
Affiliations
- Yibo He
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Changrong Ge
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Àlex Moreno-Giró
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Bingze Xu
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Christian M. Beusch
- Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Katalin Sandor
- Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet
- Jie Su
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Lei Cheng
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Erik Lönnblom
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Christina Lundqvist
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Göteborg
- Linda M. Slot
- Department of Rheumatology C1-R, Leiden University Medical Center
- Dongmei Tong
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Vilma Urbonaviciute
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Bibo Liang
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Taotao Li
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Gonzalo Fernandez Lahore
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Mike Aoun
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Vivianne Malmström
- Department of Medicine, Division of Rheumatology, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital
- Theo Rispens
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam
- Patrik Ernfors
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Camilla I. Svensson
- Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet
- Hans Ulrich Scherer
- Department of Rheumatology C1-R, Leiden University Medical Center
- René E. M. Toes
- Department of Rheumatology C1-R, Leiden University Medical Center
- Inger Gjertsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Göteborg
- Olov Ekwall
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Göteborg
- Roman A. Zubarev
- Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Rikard Holmdahl
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- DOI
- https://doi.org/10.1038/s41467-023-36257-x
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
