Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
Changrong Ge, … , Doreen Dobritzsch, Rikard Holmdahl
Changrong Ge, … , Doreen Dobritzsch, Rikard Holmdahl
Published July 6, 2017
Citation Information: JCI Insight. 2017;2(13):e93688. https://doi.org/10.1172/jci.insight.93688.
View: Text | PDF
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

×

Figure 8

Pathogenicity of ACC1 mediated by cross-reactivity.

Options: View larger image (or click on image) Download as PowerPoint
Pathogenicity of ACC1 mediated by cross-reactivity. CII exists in a dyna...
CII exists in a dynamic state composed of both compact and relatively flexible conformations, which is essential for ensuring the mechanical resistance of collagen in joint cartilage. Under inflammatory conditions, this equilibrium state of triple-helical structure is disrupted. The citrullination resulting from dysregulation of PADs on some arginine residues further deteriorates triple-helical stability, leading to exposure of CII epitopes to immune systems. ACPAs, such as ACC1, attack CII via a shared structural motif, “RG-TG,” within all the epitopes, including the ones bearing a citrulline residue (e.g., C1-CIT365), to which the recognition is governed by electrostatic potential-controlled citrulline specificity. The triple-helical CII is shown as gray ribbon with the motif RG-TG marked in magenta. The arginine residue within this motif is colored in blue, while the corresponding citrulline is in yellow. CII, collagen type II; PADs, peptidylarginine deiminases.