The Rheumatoid Arthritis Shared Epitope Triggers Innate Immune Signaling via Cell Surface Calreticulin

Abstract

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-DRβ 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.

Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

“…However, no single specific peptide has ever been identified. Ling at al (2007) have now shown that the shared epitope binds to cell surface calreticulin and subsequently triggers the innate immune response such as the production of NO. In individuals positive for HLA-DRβ smoking significantly increases the risk of developing RA (Klareskog et al, 2006).…”

“…Recently an interesting article was published presenting a novel concept considering the shared epitope, where it was reported to act as an endogenous ligand stimulating the innate immunity response (Ling et al, 2007). The shared epitope has long been known to be associated with the occurrence of RA (de Vries-Bouwstra et al, 2008).…”

Calreticulin molecular evolution: a strong purifying and episodic diversifying selection result

“…Ling et al (2010) findings indicated that the rheumatoid arthritis shared epitope -a five-residue motif from HLA-DRB1 alleles known as a risk factor for disease severity (Gregersen et al 1987) and to interact with cell surface CRT (Ling et al 2007) activated signalling maps to the 234-240 region of the (rabbit) CRT P-domain. This interaction depends primarily on Glu 234 and Glu 240 , and to a lesser extent on Asp 237 (Ling et al 2010).…”

Endoplasmic Reticulum Chaperones at the Tumor Cell Surface and in the Extracellular Space

“…U proteinu GRP78 bylo v blízkosti KDEL sekvence identifikováno potenciální glykosylační místo (Thr648) [24,25]. Současně byly popsány další odlišně lokalizované posttranslačně modifikované varianty kalretikulinu v buňce zahrnující arginylovanou formu na buněčné membráně a v cytozolu [26] a citrullinovanou formu související s imunitní aktivitou u revmatoidní artritidy [27,28].…”