A role for calreticulin in the pathogenesis of rheumatoid arthritis

Abstract

Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217-223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8α(+) DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8α(-) DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. On the basis of these recent findings, we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE-activated Th17-polarizing signals.

Figure 1

CRT-SE interaction. A SE-positive HLA-DR4 molecule interacts with the SE-binding site in the CRT P-domain. The HLA-DRα chain is shown in green, HLA-DRβ chain is in yellow, the SE is in cyan, CRT P-domain is in pink, and the groove peptide is shown in orange.

Figure 2

T cell polarization by the SE. A. DCs were incubated overnight without (Medium) or with SE-positive (65-79*0401) or –negative (65-79*0402) 15mer peptides. Subsequently, naïve CD4 T cells were added and co-cultured in the presence of TGFβ and anti-CD3 antibodies. B. Mean ± SEM values of triplicate flow cytometry determinations of the experiment shown in A. C. Th17 polarization by the SE. DCs were co-cultured with naïve CD4 T cells in Th17-differentiating medium in the absence or presence of SE-positive (65-79*0401) or –negative (65-79*0402) peptides. D. DCs were incubated overnight with peptides or recombinant hepatitis B core (HBc) particles containing the SE motif QKRAA (SE+) or a non-SE sequence DERAA (SE-) and then co-cultured with naïve CD4 T cells as above. IL-17A concentrations in supernatants were determined by ELISA.

Figure 3

Proposed model. The SE is interacting with csCRT expressed on DCs. As a result of a combined effect of IDO inhibition on the one hand and production of Th17-polarizing cytokines on the other, an immune regulation shift occurs with reduced abundance of Tregs and enhanced Th17 differentiation.