Dr. Harley has received consulting fees, speaking fees, and/or honoraria from Bio-Rad Laboratories, ImmunoVision, Inc., and IVAX Diagnostics (more than $10,000 each) and owns stock or stock options in IVAX Diagnostics.
Systemic Lupus Erythematosus
Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus
Article first published online: 26 FEB 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 3, pages 848–859, March 2009
How to Cite
Poole, B. D., Schneider, R. I., Guthridge, J. M., Velte, C. A., Reichlin, M., Harley, J. B. and James, J. A. (2009), Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus. Arthritis & Rheumatism, 60: 848–859. doi: 10.1002/art.24306
- Issue published online: 26 FEB 2009
- Article first published online: 26 FEB 2009
- Manuscript Accepted: 7 NOV 2008
- Manuscript Received: 18 APR 2008
- NIH. Grant Numbers: AR-48940, AR-045084, RR-15577, AR-053483, T32-AI-007633, RR-020143
- Lou Kerr Chair in Biomedical Research at the Oklahoma Medical Research Foundation
The U1 small nuclear RNPs are common targets of autoantibodies in lupus and other autoimmune diseases. However, the etiology and progression of autoimmune responses directed against these antigens are not well understood. The aim of this study was to use a unique collection of serial samples obtained from patients before and after the development of nuclear RNP (nRNP) antibodies to investigate early humoral events in the development of anti-nRNP autoimmunity.
Lupus patients with sera available from both before and after the development of nRNP antibody precipitin were identified from the Oklahoma Clinical Immunology Serum Repository. Antibodies in the serial samples were analyzed by enzyme-linked immunosorbent assay, Western blotting, solid-phase epitope mapping, and competition assays.
The first-detected nRNP antibodies targeted 6 common initial epitopes in nRNP A, 2 in nRNP C, and 9 in nRNP 70K. The initial epitopes of nRNP A and nRNP C were significantly enriched for proline and shared up to 95% sequence homology. The initial nRNP 70K humoral epitopes differed from those of nRNP A and nRNP C. The initial antibodies to nRNP A and nRNP C were cross-reactive with the SmB′-derived peptide PPPGMRPP. Antibody binding against all 3 nRNP subunits diversified significantly over time.
Autoantibodies to nRNP A and nRNP C initially targeted restricted, proline-rich motifs. Antibody binding subsequently spread to other epitopes. The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.