A role for calreticulin in the pathogenesis of rheumatoid arthritis.
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.
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA. jholo@umich.edu
Joseph
J
Holoshitz
Denise E
DE
De Almeida
Song
S
Ling
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000503:physiopathology*; D016827:CD8 Antigens / Q000276:immunology; D037282:Calreticulin / Q000502:physiology*; D002454:Cell Differentiation; D000939:Epitopes / Q000276:immunology; D006801:Humans; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
D016827:CD8 Antigens; D037282:Calreticulin; D000939:Epitopes