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 6

Hydrogen-bonding network formed upon peptide binding to ACC1, with emphasis on conserved interactions.

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Hydrogen-bonding network formed upon peptide binding to ACC1, with empha...
The chosen orientation focuses on the conserved interactions between the threonine of the conserved peptide motif and the H3 CDR loop (see Supplemental Figure 5 for another orientation). The heavy and light chains of the ACC1Fab are shown in white and blue, respectively. Fab residues forming hydrogen bonds to the peptide are shown as sticks, with carbon atoms colored according to their chain of origin and labeled in black. To improve clarity, residues lying behind the peptide are not labeled. Hydrogen bonds are indicated as black dotted lines, water molecules are indicated as red spheres. The peptides are shown as thicker sticks, with carbon atoms in yellow (C1-CIT365-L), mauve (CII538-591 in space group p1), and green (CII616-639-CIT), respectively. All peptide residues other than glycine, proline (except the proline occurring in CII538-591 and CII616-639-CIT at the same position as the citrulline in C1-CIT365-L and C1-CIT365-T), and 4-hydroxyproline are labeled in bold and according color. (A) ACC1Fab-C1-CIT365-L. (B) ACC1Fab-CII538-591 as in P1 space group. (C) ACC1Fab-CII616-639-CIT. (The hydrogen bonding networks of the complexes ACC1Fab-C1-CIT365-T and ACC1Fab-CII538-591 in P212121 are shown in Supplemental Figure 4). CDR, complementarity-determining region; Fab, antigen-binding fragment.