The rheumatoid arthritis shared epitope triggers innate immune signaling via cell surface calreticulin.
The shared epitope (SE), carried by the vast majority of rheumatoid arthritis patients, is a 5-aa sequence motif in the third allelic hypervariable region of the HLA-DRbeta chain. We have recently demonstrated that the SE acts as an allele-specific ligand that triggers NO-mediated pro-oxidative signaling in opposite cells. The identity of the cell surface molecule that interacts with the SE is unknown. Using affinity chromatography purification, cell-binding assays, surface plasmon resonance, and time-resolved fluorescence resonance energy transfer techniques, we have identified cell surface calreticulin (CRT) as the SE-binding molecule. SE-triggered signaling could be blocked by anti-CRT Abs or Abs against CD91 and by CRT-specific antisense or small-interfering RNA oligonucleotides. Embryonic fibroblasts from crt(-/-) or CD91-deficient mice failed to transduce SE-triggered signals. Exogenously added soluble CRT attached to the cell surface and restored SE-triggered signaling responsiveness in crt(-/-) cells. These data indicate that cell surface CRT, a known innate immunity receptor, which has been previously proposed as a culprit in autoimmunity, plays a critical role in SE-triggered signal transduction.
Ling
Song
S
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Pi
Xiujun
X
Holoshitz
Joseph
J
D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D037282:Calreticulin / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D015398:Signal Transduction / Q000276:immunology*
D037282:Calreticulin; D000939:Epitopes