The systemic lupus erythematosus (SLE) disease autoantigen-calreticulin can inhibit C1q association with immune complexes.
Following 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.
Kishore
U
U
Department of Biochemistry, University of Oxford, UK.
Sontheimer
R D
RD
Sastry
K N
KN
Zappi
E G
EG
Hughes
G R
GR
Khamashta
M A
MA
Reid
K B
KB
Eggleton
P
P
D000328:Adult; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D037282:Calreticulin; D015922:Complement C1q / Q000037:antagonists & inhibitors* / Q000276:immunology*; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000187:drug effects / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D012261:Ribonucleoproteins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D003169:Complement Inactivator Proteins; D007074:Immunoglobulin G; D012261:Ribonucleoproteins; D015922:Complement C1q