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 3

Characterization of the cross-reactivity of ACC1.

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Characterization of the cross-reactivity of ACC1. (A) Responses of ACC1,...
(A) Responses of ACC1, ACC3, ACC4, CIIC1, and GB8 toward cyclic CII peptides and triple-helical CII peptides determined in the Luminex assay (Supplemental Table 2). A total of 127 peptides was used in the assay, and each dot represents a unique peptide. The median fluorescence intensity (MFI) was used to quantify the interaction of antibody with given peptides. (B) Reactivity of ACC1 toward triple-helical CII peptides (107 triple-helical peptides from Supplemental Table 1) measured by surface plasmon resonance (SPR). Sensograms were processed using an automatic correction for nonspecific bulk-refractive index effects. Data processing and analysis were performed using Biacore T200 evaluation software in a heterogenous binding model (GE Healthcare). 13, CII121-144; 21, CII241-264; 43, CII571-591; 66, CII916-939; 67, CII931-954; ptm15/ptm16, C1-T-CIT365; ptm35/36, F4-T-CIT933. (C) Preference of ACC1 for citrullinated CCP1 compared with the corresponding unmodified CCP1. Data are representative of results from triplicate assays. (D) Reactivity of ACC1, ACC3, ACC4, and 15A toward peptides from the CCP2 kit. The peptides from the Immunoscan CCPlus Kit (Euro Diagnostica) were used to measure the binding of ACC1, ACC3, ACC4, and 15A (COMP-specific antibody). The absorbance value at 405 nm was used to quantify the binding capacity. Data are representative of results from two assays performed using duplicate technical replicates. SPR, surface plasmon resonance; CII, collagen type II.