Abstract
Autoantibodies to ribosomal P (ribo P) are found in 15–30% of systemic lupus erythematosus (SLE) patients and are highly specific for SLE. The goal of this study is to assess the temporal association of anti-ribosomal P (anti-P) responses with SLE disease onset, as well as to characterize select humoral ribo P epitopes targeted in early, pre-diagnostic SLE samples. Patients with stored serial serum samples available prior to SLE diagnosis were identified from a military cohort. Each sample was tested for antibodies against ribo P utilizing standard C terminus ribo P enzyme-linked immunosorbent assays (ELISA) and a solid phase, bead-based assay with affinity-purified ribo P proteins. In this study, antibodies to ribo P were more common in African American SLE patients (p = 0.026), and anti-P-positive patients comprised a group with more measured autoantibody specificities than did other SLE patients (3.5 vs 2.2, p < 0.05). Antibodies against ribo P were present on average 1.7 years before SLE diagnosis and were detected an average of 1.08 years earlier in pre-diagnostic SLE samples using affinity-purified whole protein rather than C-terminal peptide alone (p = 0.0019). Furthermore, 61% of anti-P-positive patients initially had antibodies to aa 99–113, a known ribosomal P0 antigenic target, at a time point when no antibodies to the clinically used C terminus were detected. Our findings provide evidence that antibodies against ribosomal P frequently develop before clinical SLE diagnosis and are more broadly reactive than previously thought by targeting regions outside of the C terminus.
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Ghirardello A, Doria A, Zampieri S, Gerli R, Rapizzi E, Gambari PF (2000) Anti-ribosomal P protein antibodies detected by immunoblotting in patients with connective tissue diseases: their specificity for SLE and association with IgG anticardiolipin antibodies. Ann Rheum Dis 59:975–981
Hanly JG, Urowitz MB, Siannis F, Farewell V, Gordon C, Bae SC, Isenberg D, Dooley MA, Clarke A, Bernatsky S, Gladman D, Fortin PR, Manzi S, Steinsson K, Bruce IN, Ginzler E, Aranow C, Wallace DJ, Ramsey-Goldman R, van Vollenhoven R, Sturfelt G, Nived O, Sanchez-Guerrero J, Alarcon GS, Petri M, Khamashta M, Zoma A, Font J, Kalunian K, Douglas J, Qi Q, Thompson K, Merrill JT (2008) Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum 58:843–853
Bonfa E, Golombek SJ, Kaufman LD, Skelly S, Weissbach H, Brot N, Elkon KB (1987) Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 317:265–271
Briani C, Lucchetta M, Ghirardello A, Toffanin E, Zampieri S, Ruggero S, Scarlato M, Quattrini A, Bassi N, Ermani M, Battistin L, Doria A (2009) Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study. J Autoimmun 32:79–84
Abdel-Nasser AM, Ghaleb RM, Mahmoud JA, Khairy W, Mahmoud RM (2008) Association of anti-ribosomal P protein antibodies with neuropsychiatric and other manifestations of systemic lupus erythematosus. Clin Rheumatol 27:1377–1385
Karassa FB, Afeltra A, Ambrozic A, Chang DM, De Keyser F, Doria A, Galeazzi M, Hirohata S, Hoffman IE, Inanc M, Massardo L, Mathieu A, Mok CC, Morozzi G, Sanna G, Spindler AJ, Tzioufas AG, Yoshio T, Ioannidis JP (2006) Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. Arthritis Rheum 54:312–324
Chindalore V, Neas B, Reichlin M (1998) The association between anti-ribosomal P antibodies and active nephritis in systemic lupus erythematosus. Clin Immunol Immunopathol 87:292–296
Gerli R, Caponi L, Tincani A, Scorza R, Sabbadini MG, Danieli MG, De Angelis V, Cesarotti M, Piccirilli M, Quartesan R, Moretti P, Cantoni C, Franceschini F, Cavazzana I, Origgi L, Vanoli M, Bozzolo E, Ferrario L, Padovani A, Gambini O, Vanzulli L, Croce D, Bombardieri S (2002) Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients. Rheumatology (Oxford) 41:1357–1366
Arnett FC, Reichlin M (1995) Lupus hepatitis: an under-recognized disease feature associated with autoantibodies to ribosomal P. Am J Med 99:465–472
Gerli R, Caponi L (2005) Anti-ribosomal P protein antibodies. Autoimmunity 38:85–92
Arnett FC, Reveille JD, Moutsopoulos HM, Georgescu L, Elkon KB (1996) Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations. Arthritis and rheumatism 39:1833–1839
Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH (2002) Autoantibodies in neuropsychiatric lupus. Autoimmunity 35:79–86
Isenberg DA, Garton M, Reichlin MW, Reichlin M (1997) Long-term follow-up of autoantibody profiles in black female lupus patients and clinical comparison with Caucasian and Asian patients. Br J Rheumatol 36:229–233
Mahler M, Kessenbrock K, Raats J, Williams R, Fritzler MJ, Bluthner M (2003) Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins. J Mol Med 81:194–204
Sato T, Uchiumi T, Ozawa T, Kikuchi M, Nakano M, Kominami R, Arakawa M (1991) Autoantibodies against ribosomal proteins found with high frequency in patients with systemic lupus erythematosus with active disease. J Rheumatol 18:1681–1684
Teh LS, Lee MK, Wang F, Manivasagar M, Charles PJ, Nicholson GD, Hay EM, Isenberg DA, Amos N, Williams BD (1993) Antiribosomal P protein antibodies in different populations of patients with systemic lupus erythematosus. Br J Rheumatol 32:663–665
Reichlin M, Broyles TF, Hubscher O, James J, Lehman TA, Palermo R, Stafford HA, Taylor-Albert E, Wolfson-Reichlin M (1999) Prevalence of autoantibodies to ribosomal P proteins in juvenile-onset systemic lupus erythematosus compared with the adult disease. Arthritis Rheum 42:69–75
Hoffman IE, Lauwerys BR, De Keyser F, Huizinga TW, Isenberg D, Cebecauer L, Dehoorne J, Joos R, Hendrickx G, Houssiau F, Elewaut D (2009) Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis 68:412–415
Hasler P, Brot N, Weissbach H, Parnassa AP, Elkon KB (1991) Ribosomal proteins P0, P1, and P2 are phosphorylated by casein kinase II at their conserved carboxyl termini. J Biol Chem 266:13815–13820
Elkon K, Skelly S, Parnassa A, Moller W, Danho W, Weissbach H, Brot N (1986) Identification and chemical synthesis of a ribosomal protein antigenic determinant in systemic lupus erythematosus. Proc Natl Acad Sci USA 83:7419–7423
Hasler P, Brot N, Weissbach H, Danho W, Blount Y, Zhou JL, Elkon KB (1994) The effect of phosphorylation and site-specific mutations in the immunodominant epitope of the human ribosomal P proteins. Clin Immunol Immunopathol 72:273–279
Caponi L, Pegoraro S, Di Bartolo V, Rovero P, Revoltella R, Bombardieri S (1995) Autoantibodies directed against ribosomal P proteins: use of a multiple antigen peptide as the coating agent in ELISA. J Immunol Methods 179:193–202
Bruner BF, Wynn DM, Reichlin M, Harley JB, James JA (2005) Humoral antigenic targets of the ribosomal P0 lupus autoantigen are not limited to the carboxyl region. Ann N Y Acad Sci 1051:390–403
Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533
Heinlen LD, McClain MT, Merrill J, Akbarali YW, Edgerton CC, Harley JB, James JA (2007) Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum 56:2344–2351
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725
Binder SR, Goodrich JL, Safarian Z (2006) FXIII detection for verifying serum sample and sample size and for detecting dilution. In: Office USPaT. Bio-Rad Laboratories, US.
DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845
Arbuckle MR, James JA, Dennis GJ, Rubertone MV, McClain MT, Kim XR, Harley JB (2003) Rapid clinical progression to diagnosis among African-American men with systemic lupus erythematosus. Lupus 12:99–106
Mahler M, Kessenbrock K, Szmyrka M, Takasaki Y, Garcia-De La Torre I, Shoenfeld Y, Hiepe F, Shun-le C, von Muhlen CA, Locht H, Hopfl P, Wiik A, Reeves W, Fritzler MJ (2006) International multicenter evaluation of autoantibodies to ribosomal P proteins. Clin Vaccine Immunol 13:77–83. doi:13/1/77 [pii] 10.1128/CVI.13.1.77-83.2006
James JA, Gross T, Scofield RH, Harley JB (1995) Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med 181:453–461
McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA (2005) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11:85–89
Acknowledgments
The authors would like to thank Yasmin Akbarali MS, Roy Rindler MD, Tara Bruner PA-C, and Gabriel Vidal for their technical assistance and Scott Stewart MS for his statistical analysis assistance. This work has been supported by the National Institutes of Health (AI82714, AI31584, AR58554, AR45451, AI47575, AR53483, AR48045, AR45084, AR45231, AR42460, AR48940, AI24717, RR20143, RR15577, and RR14467), the Presbyterian Health Foundation, the Lou Kerr Chair in Biomedical Research, the Kirkland Foundation, and the US Department of Veteran Affairs. The opinions and assertions contained herein are private views of the authors and are not to be construed as official or as reflecting the views of the Army, Navy, or the Department of Defense.
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John B. Harley serves as a consultant to Bio Rad Laboratories and as a consultant and member of the Board of Directors of IVAX Diagnostics.
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Latisha D. Heinlen and Lauren L. Ritterhouse contributed equally to this work.
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Heinlen, L.D., Ritterhouse, L.L., McClain, M.T. et al. Ribosomal P autoantibodies are present before SLE onset and are directed against non-C-terminal peptides. J Mol Med 88, 719–727 (2010). https://doi.org/10.1007/s00109-010-0618-1
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DOI: https://doi.org/10.1007/s00109-010-0618-1