Yanpeng Li1, Dongmei Tong2, Peibin Liang1, Erik Lönnblom2, Johan Viljanen3, Bingze Xu2, Kutty Selva Nandakumar1, Rikard Holmdahl4,5. 1. SMU-KI United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. 2. Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17177, Stockholm, Sweden. 3. Department of Chemistry Biomedical Center, Uppsala University, Box 576, SE-75123, Uppsala, Sweden. 4. SMU-KI United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. rikard.holmdahl@ki.se. 5. Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17177, Stockholm, Sweden. rikard.holmdahl@ki.se.
Abstract
BACKGROUND: Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage. METHODS: Purified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses. RESULTS: The new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice. CONCLUSIONS: The new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.
BACKGROUND: Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritispatients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage. METHODS: Purified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses. RESULTS:The new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice. CONCLUSIONS:The new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.
Authors: Lina M Olsson; Annika Nerstedt; Anna-Karin Lindqvist; Sa C M Johansson; Patrik Medstrand; Peter Olofsson; Rikard Holmdahl Journal: Antioxid Redox Signal Date: 2011-08-23 Impact factor: 8.401
Authors: Jian Zhao; Jianyang Ma; Yun Deng; Jennifer A Kelly; Kwangwoo Kim; So-Young Bang; Hye-Soon Lee; Quan-Zhen Li; Edward K Wakeland; Rong Qiu; Mengru Liu; Jianping Guo; Zhanguo Li; Wenfeng Tan; Astrid Rasmussen; Christopher J Lessard; Kathy L Sivils; Bevra H Hahn; Jennifer M Grossman; Diane L Kamen; Gary S Gilkeson; Sang-Cheol Bae; Patrick M Gaffney; Nan Shen; Betty P Tsao Journal: Nat Genet Date: 2017-01-30 Impact factor: 41.307
Authors: Alex Bersellini Farinotti; Gustaf Wigerblad; Diana Nascimento; Rikard Holmdahl; Camilla I Svensson; Duygu B Bas; Carlos Morado Urbina; Kutty Selva Nandakumar; Katalin Sandor; Bingze Xu; Sally Abdelmoaty; Matthew A Hunt; Kristina Ängeby Möller; Azar Baharpoor; Jon Sinclair; Kent Jardemark; Johanna T Lanner; Ia Khmaladze; Lars E Borm; Lu Zhang; Fredrik Wermeling; Mark S Cragg; Johan Lengqvist; Anne-Julie Chabot-Doré; Luda Diatchenko; Inna Belfer; Mattias Collin; Kim Kultima; Birgitta Heyman; Juan Miguel Jimenez-Andrade; Simone Codeluppi Journal: J Exp Med Date: 2019-06-13 Impact factor: 14.307