THE SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE) DISEASE AUTOANTIGEN - CALRETICULIN INHIBIT C1Q ASSOCIATION WITH IMMUNE-COMPLEXES

Following its release from cells during infection and inflammation, ca lreticulin (CRT) can act as an autoantigen in diseases such as SLE. Wh y CRT is a target of protective immunity and whether it may interfere with innate immunity once released from cells during inflammation is u nclear. In the present study, we found that CRT was detected more freq uently in SLE sera and in higher amounts than found in control sera. A pproximately 40% of SLE sera tested contained autoantibodies against C RT as detected by ELISA and immunoblotting. CRT was found to be predom inantly in the sera of SLE patients associated with immune complexes a nd C1q, and only bound to the surfaces of neutrophils in the presence of low levels of calcium and magnesium. In order to further investigat e the Clq-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 an ti-CRT autoantibodies from most patients reacted against this region. CRT also altered C1q-mediated immune functions. The P-domain of CRT bo und 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 Clq-dependent binding of immune complexes to neutrophils a nd solid-phase bound C1q. We conclude that CRT, once released from leu cocytes during inflammation, may not only induce an antigenic reaction , but also interfere with Clq-mediated inflammatory processes.