The systemic lupus erythematosus (SLE) disease autoantigen—calreticulin can inhibit C1q association with immune complexes

Abstract

SUMMARYFollowing its release from cells during infection and inflammation, calreticulin (CRT) can act as an autoantigen in diseases such as SLE. Why CRT is a target of protective immunity and whether it may interfere with innate immunity once released from cells during inflammation is unclear. In the present study, we found that CRT was detected more frequently in SLE sera and in higher amounts than found in control sera. Approximately 40% of SLE sera tested contained autoantibodies against CRT as detected by ELISA and immunoblotting. CRT was found to be predominantly in the sera of SLE patients associated with immune complexes and C1q, and only bound to the surfaces of neutrophils in the presence of low levels of calcium and magnesium. In order to further investigate the C1q-CRT interaction, recombinant CRT and its discrete domains (N-, P-, and C-domains) were produced in Escherichia coli. CRT binds to globular head region of C1q primarily via its N-and P-domains. The N-domain was shown to be the most autoantigenic region of CRT, as the anti-CRT autoantibodies from most patients reacted against this region. CRT also altered C1q-mediated immune functions. The P-domain of CRT bound to C1q and reduced the binding of immune complexes in SLE sera to immobilized C1q. Full length CRT and its N-and P-domains were able to reduce the C1q-dependent binding of immune complexes to neutrophils and solid-phase bound C1q. We conclude that CRT, once released from leucocytes during inflammation, may not only induce an antigenic reaction, but also interfere with C1q-mediated inflammatory processes.

Calreticulin, a Potential Cell Surface Receptor Involved in Cell Penetration of Anti-DNA Antibodies

“…CRT has also been shown to be associated with the immune response in several ways (37,40). It may be a target for circulating autoantibodies and may contribute to the autoimmune process (37,41,42).…”

Pathophysiological Roles of Calreticulin in Autoimmune Disease

“…Both the collagen-like region [71] and globular heads of C1q [12] have been shown to bind in vitro to the N-terminal half of calreticulin containing the N-and P-domain. Calreticulin has been shown to compete with antibody for binding to C1q and ultimately classical complement activation [5], which may be of consequence in the aetiology of SLE, where immune complex formation and deposition are important. This competition implies that calreticulin and immunoglobulins may have similar binding sites recognized by C1q.…”

“…Over the past 10 years, several studies have identified autoantibodies directed against calreticulin in a number of autoimmune diseases, but predominantly in patients suffering from systemic lupus erythematosus (SLE) [2][3][4][5]. Such studies have highlighted a possible role for calreticulin in autoimmunity, especially in immune complex disorders such as SLE.…”

The pathophysiology of photosensitivity in lupus erythematosus

“…The identification of a dominant grp78 binding motif on Ro52 (178) and the coexistence of grp78, Ro52 and Ro60 in the surface membrane blebs of apoptotic cells (98) support this view. Interestingly, autoantibodies directed towards grp94/gp96 and calreticulin have also been detected in the sera of patients with SLE (133,179,180) and could perhaps be generated via a similar mechanism.…”