Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
Changrong Ge, Dongmei Tong, Bibo Liang, Erik Lönnblom, Nadine Schneider, Cecilia Hagert, Johan Viljanen, Burcu Ayoglu, Roma Stawikowska, Peter Nilsson, Gregg B. Fields, Thomas Skogh, Alf Kastbom, Jan Kihlberg, Harald Burkhardt, Doreen Dobritzsch, Rikard Holmdahl
Changrong Ge, Dongmei Tong, Bibo Liang, Erik Lönnblom, Nadine Schneider, Cecilia Hagert, Johan Viljanen, Burcu Ayoglu, Roma Stawikowska, Peter Nilsson, Gregg B. Fields, Thomas Skogh, Alf Kastbom, Jan Kihlberg, Harald Burkhardt, Doreen Dobritzsch, Rikard Holmdahl
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Research Article Immunology

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

Abstract

Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif “RG-TG” within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

Authors

Changrong Ge, Dongmei Tong, Bibo Liang, Erik Lönnblom, Nadine Schneider, Cecilia Hagert, Johan Viljanen, Burcu Ayoglu, Roma Stawikowska, Peter Nilsson, Gregg B. Fields, Thomas Skogh, Alf Kastbom, Jan Kihlberg, Harald Burkhardt, Doreen Dobritzsch, Rikard Holmdahl

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Figure 7

Comparison of CDR loop conformation and peptide binding by ACC1, ACC4, CIIC1, and M2139.

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Comparison of CDR loop conformation and peptide binding by ACC1, ACC4, C...
(A) All 5 ACC1Fab peptide complexes reported here were superimposed based on the Cα atom coordinates of their respective VH domains. The backbone of the ACC1Fab in the complex with CII616-639-CIT is shown in stereo view, with heavy and light chains colored white and blue, respectively, except for the hypervariable CDR loop regions. The superimposed CDR loops and peptides of the respective ACC1Fab-peptide complexes are shown in yellow for the C1-CIT365-L complex, bright orange for C1-CIT365-T, mauve for CII538-591 in space group P1, magenta for CII538-591 in space group P212121, and green for the CII616-639-CIT complex. (B) Stereo view of the superimposed ACC1Fab-C1-CIT365-L (white) and ACC4Fab-C1Cit1 (gray) (PDB ID: 2W65) structures. The CDR loops of the ACC1 heavy chain are colored yellow (H1), orange (H2), and red (H3); those of the light chain are colored cyan (L1), marine (L2), and dark blue (L3). The cartoon representation of the C1-CIT365-L peptide bound to the ACC1Fab is shown in dark green, and that of the C1Cit1 peptide bound to ACC4Fab is shown in magenta. (C) Stereo view of the superimposed ACC1Fab-C1-CIT365-L (white), CIIC1Fab-C1 (dark grey) (PDB ID: 2Y5T), and M2139Fab-J1 (light gray) (PDB ID: 4BKL) structures. The CDR loops of the ACC1 heavy chain are colored as in B. The cartoon representation of the C1-CIT365-L peptide bound to the ACC1Fab is shown in dark green, and those of the triple-helical C1 and J1 peptides bound to CIIC1Fab and M2139Fab are shown in magenta and pink, respectively. CDR, complementarity-determining region; VH, heavy-chain-variable.