TY - JOUR
T1 - A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis
AU - He, Yibo
AU - Ge, Changrong
AU - Moreno-Giró, Àlex
AU - Xu, Bingze
AU - Beusch, Christian M.
AU - Sandor, Katalin
AU - Su, Jie
AU - Cheng, Lei
AU - Lönnblom, Erik
AU - Lundqvist, Christina
AU - Slot, Linda M.
AU - Tong, Dongmei
AU - Urbonaviciute, Vilma
AU - Liang, Bibo
AU - Li, Taotao
AU - Lahore, Gonzalo Fernandez
AU - Aoun, Mike
AU - Malmström, Vivianne
AU - Rispens, Theo
AU - Ernfors, Patrik
AU - Svensson, Camilla I.
AU - Scherer, Hans Ulrich
AU - Toes, René E. M.
AU - Gjertsson, Inger
AU - Ekwall, Olov
AU - Zubarev, Roman A.
AU - Holmdahl, Rikard
N1 - Funding Information: The authors thank the staffs from the Histocore and Biomedicum Imaging Core (BIC) of Karolinska Institute (KI) for the assistance in histology and imaging, Comparative Medicine’s Annex (KM-A) of KI and Animal Facility in Lund for taking care of the mice, Protein Science Facility (PSF) of KI for protein synthesis, Redoxis AB and Zhongwei Xu for help in experiments. Especially, we also want to thank all the donors for the human samples used in this study. The work was supported by grants from The Knut and Alice Wallenberg Foundation (2019-0059), the Swedish Research Council (2019-01209), the China Scholarship Council (CSC), and the Natural Science Foundation of China No.32070913. Funding Information: The authors thank the staffs from the Histocore and Biomedicum Imaging Core (BIC) of Karolinska Institute (KI) for the assistance in histology and imaging, Comparative Medicine’s Annex (KM-A) of KI and Animal Facility in Lund for taking care of the mice, Protein Science Facility (PSF) of KI for protein synthesis, Redoxis AB and Zhongwei Xu for help in experiments. Especially, we also want to thank all the donors for the human samples used in this study. The work was supported by grants from The Knut and Alice Wallenberg Foundation (2019-0059), the Swedish Research Council (2019-01209), the China Scholarship Council (CSC), and the Natural Science Foundation of China No.32070913. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85147681186&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-36257-x
DO - https://doi.org/10.1038/s41467-023-36257-x
M3 - Article
C2 - 36754962
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 691
ER -