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Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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-DR
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 J.H. was supported by grants from the National Institutes of Health (AI47331, AR46468, AR20557, and AR48310) and by Basic Research Grants from the Arthritis Foundation and the American College of Rheumatology. X.P. was supported by Postdoctoral Training Grant AR07080 from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Joseph Holoshitz, University of Michigan, 5520D Medical Science Research Building 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0680. E-mail address: jholo{at}umich.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; SE, shared epitope; SPR, surface plasmon resonance; TR-FRET, time-resolved fluorescence resonance energy transfer; CRT, calreticulin; siRNA, small-interfering RNA; HSP, heat shock protein; MEF, murine embryonic fibroblast; RU, resonance unit.
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