J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/03/843/12 $2.00
Volume 185, Number 5, March 3, 1997 843-854

Proteins Phosphorylated during Stress-induced Apoptosis Are Common Targets for Autoantibody Production in Patients with Systemic Lupus Erythematosus

By Paul J. Utz,^* Maria Hottelet,^* Peter H. Schur, and Paul Anderson^*

From the ^* Division of  Tumor Immunology, the Dana Farber Cancer Institute; and the  Department of Medicine, Division of Rheumatology and Immunology, Brigham & Women's Hospital, Boston, Massachusetts 02115

Proteins cleaved by interleukin-1 converting enzyme family proteases during apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus (SLE). We have tested the possibility that proteins phosphorylated in cells undergoing apoptosis are also targets for autoantibody production in patients with autoimmune disease. Sera from 9/12 patients containing antinuclear antibodies (10/12 meeting diagnostic criteria for SLE or a lupus overlap syndrome), precipitated new phosphoproteins from lysates derived from Jurkat T cells treated with apoptotic stimuli (i.e., Fas-ligation, gamma irradiation, ultraviolet irradiation), but not with an activation (i.e., CD3-ligation) stimulus. Sera derived from individual patients precipitated different combinations of seven distinct serine-phosphorylated proteins. None of these phosphoproteins were included in precipitates prepared using sera from patients with diseases that are not associated with autoantibody production or using serum from rheumatoid arthritis patients. Protein phosphorylation precedes, or is coincident with, the induction of DNA fragmentation, and is not observed when apoptosis is inhibited by overexpression of bcl-2. Serum from four patients precipitated a serine/threonine kinase from apoptotic cell lysates that phosphorylates proteins of 23-, 34-, and 46-kD in in vitro kinase assays. Our results suggest that proteins phosphorylated during apoptosis may be preferred targets for autoantibody production in patients with SLE.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Doyle, H. A., Zhou, J., Wolff, M. J., Harvey, B. P., Roman, R. M., Gee, R. J., Koski, R. A., Mamula, M. J. (2006). Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity. J. Biol. Chem. 281: 32676-32683 [Abstract] [Full Text]  
• Bijl, M, Reefman, E, Horst, G, Limburg, P C, Kallenberg, C G M (2006). Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis 65: 57-63 [Abstract] [Full Text]  
• Suarez, A, Lopez, P, Mozo, L, Gutierrez, C (2005). Differential effect of IL10 and TNF{alpha} genotypes on determining susceptibility to discoid and systemic lupus erythematosus. Ann Rheum Dis 64: 1605-1610 [Abstract] [Full Text]  
• Miyazaki, K., Takeda, N., Ishimaru, N., Omotehara, F., Arakaki, R., Hayashi, Y. (2005). Analysis of in Vivo Role of {alpha}-Fodrin Autoantigen in Primary Sjogren's Syndrome. Am. J. Pathol. 167: 1051-1059 [Abstract] [Full Text]  
• Blank, M., Shoenfeld, Y. (2005). Experimental models of systemic lupus erythematosus: anti-dsDNA in murine lupus. Rheumatology (Oxford) 44: 1086-1089 [Full Text]  
• Hattori, N., Ikekubo, K., Nakaya, Y., Kitagawa, K., Inagaki, C. (2005). Immunoglobulin G Subclasses and Prolactin (PRL) Isoforms in Macroprolactinemia Due to Anti-PRL Autoantibodies. J. Clin. Endocrinol. Metab. 90: 3036-3044 [Abstract] [Full Text]  
• Graham, K. L., Gustin, K. E., Rivera, C., Kuyumcu-Martinez, N. M., Choe, S. S., Lloyd, R. E., Sarnow, P., Utz, P. J. (2004). Proteolytic Cleavage of the Catalytic Subunit of DNA-Dependent Protein Kinase during Poliovirus Infection. J. Virol. 78: 6313-6321 [Abstract] [Full Text]  
• Rosen, A., Casciola-Rosen, L. (2004). ALTERED AUTOANTIGEN STRUCTURE IN SJoGREN'S SYNDROME: IMPLICATIONS FOR THE PATHOGENESIS OF AUTOIMMUNE TISSUE DAMAGE. CROBM 15: 156-164 [Abstract] [Full Text]  
• Caricchio, R., McPhie, L., Cohen, P. L. (2003). Ultraviolet B Radiation-Induced Cell Death: Critical Role of Ultraviolet Dose in Inflammation and Lupus Autoantigen Redistribution. J. Immunol. 171: 5778-5786 [Abstract] [Full Text]  
• D'Agnillo, P., Levine, J. S., Subang, R., Rauch, J. (2003). Prothrombin Binds to the Surface of Apoptotic, But Not Viable, Cells and Serves as a Target of Lupus Anticoagulant Autoantibodies. J. Immunol. 170: 3408-3422 [Abstract] [Full Text]  
• van Nieuwenhuijze, A E M, van Lopik, T, Smeenk, R J T, Aarden, L A (2003). Time between onset of apoptosis and release of nucleosomes from apoptotic cells: putative implications for systemic lupus erythematosus. Ann Rheum Dis 62: 10-14 [Abstract] [Full Text]  
• Kamachi, M., Le, T. M., Kim, S. J., Geiger, M. E., Anderson, P., Utz, P. J. (2002). Human Autoimmune Sera as Molecular Probes for the Identification of an Autoantigen Kinase Signaling Pathway. JEM 0: 20021167-13 [Abstract] [Full Text]  
• Thebault, S., Gilbert, D., Hubert, M., Drouot, L., Machour, N., Lange, C., Charlionet, R., Tron, F. (2002). Orderly Pattern of Development of the Autoantibody Response in (New Zealand White x BXSB)F1 Lupus Mice: Characterization of Target Antigens and Antigen Spreading by Two-Dimensional Gel Electrophoresis and Mass Spectrometry. J. Immunol. 169: 4046-4053 [Abstract] [Full Text]  
• Chernysheva, A. D., Kirou, K. A., Crow, M. K. (2002). T Cell Proliferation Induced by Autologous Non-T Cells Is a Response to Apoptotic Cells Processed by Dendritic Cells. J. Immunol. 169: 1241-1250 [Abstract] [Full Text]  
• Saegusa, K., Ishimaru, N., Yanagi, K., Mishima, K., Arakaki, R., Suda, T., Saito, I., Hayashi, Y. (2002). Prevention and Induction of Autoimmune Exocrinopathy Is Dependent on Pathogenic Autoantigen Cleavage in Murine Sjogren's Syndrome. J. Immunol. 169: 1050-1057 [Abstract] [Full Text]  
• Davies, M. L., Young, S. P., Welsh, K., Bunce, M., Wordsworth, B. P., Davies, K. A., Wagenknecht, D. R., Taylor, E., Gordon, C., Jobson, S., Briggs, D., Bowman, S. J. (2002). Immune responses to native {beta}2-glycoprotein I in patients with systemic lupus erythematosus and the antiphospholipid syndrome. Rheumatology (Oxford) 41: 395-400 [Abstract] [Full Text]  
• Du, L., Fukushima, S., Sallmyr, A., Manthorpe, R., Bredberg, A. (2002). Exposure of HEp-2 Cells to Stress Conditions Influences Antinuclear Antibody Reactivity. CVI 9: 287-294 [Abstract] [Full Text]  
• Aringer, M, Feierl, E, Steiner, G, Stummvoll, G H, Hofler, E, Steiner, C W, Radda, I, Smolen, J S, Graninger, W B (2002). Increased bioactive TNF in human systemic lupus erythematosus: associations with cell death. Lupus 11: 102-108 [Abstract]  
• Lai, J.-H., Ho, L.-J., Lu, K.-C., Chang, D.-M., Shaio, M.-F., Han, S.-H. (2001). Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction. J. Immunol. 166: 6914-6924 [Abstract] [Full Text]  
• Oriss, T. B., Hu, P. Q., Wright, T. M. (2001). Distinct Autoreactive T Cell Responses to Native and Fragmented DNA Topoisomerase I: Influence of APC Type and IL-2. J. Immunol. 166: 5456-5463 [Abstract] [Full Text]  
• Masson-Bessiere, C., Sebbag, M., Girbal-Neuhauser, E., Nogueira, L., Vincent, C., Senshu, T., Serre, G. (2001). The Major Synovial Targets of the Rheumatoid Arthritis-Specific Antifilaggrin Autoantibodies Are Deiminated Forms of the {{alpha}}- and {{beta}}-Chains of Fibrin. J. Immunol. 166: 4177-4184 [Abstract] [Full Text]  
• Navratil, J. S., Watkins, S. C., Wisnieski, J. J., Ahearn, J. M. (2001). The Globular Heads of C1q Specifically Recognize Surface Blebs of Apoptotic Vascular Endothelial Cells. J. Immunol. 166: 3231-3239 [Abstract] [Full Text]  
• van der Linden, M W, van Lopik, T, Aarden, L A, Westendorp, R G J, Huizinga, T W J (2001). Soluble CD95 concentrations are increased in patients with severe systemic lupus erythematosus, but not in their first degree relatives. Ann Rheum Dis 60: 237-241 [Abstract] [Full Text]  
• Stummvoll, G. H., Aringer, M., Smolen, J. S., Koller, M., Kiener, H. P., Steiner, C. W., Bohle, B., Knobler, R., Graninger, W. B. (2000). Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis. Rheumatology (Oxford) 39: 1341-1350 [Abstract] [Full Text]  
• Lawley, W., Doherty, A., Denniss, S., Chauhan, D., Pruijn, G., van Venrooij, W. J., Lunec, J., Herbert, K. (2000). Rapid lupus autoantigen relocalization and reactive oxygen species accumulation following ultraviolet irradiation of human keratinocytes. Rheumatology (Oxford) 39: 253-261 [Abstract] [Full Text]  
• HUCK, S., DEVEAUD, E., NAMANE, A., ZOUALI, M. (1999). Abnormal DNA methylation and deoxycytosine-deoxyguanine content in nucleosomes from lymphocytes undergoing apoptosis. FASEB J. 13: 1415-1422 [Abstract] [Full Text]  
• Girbal-Neuhauser, E., Durieux, J.-J., Arnaud, M., Dalbon, P., Sebbag, M., Vincent, C., Simon, M., Senshu, T., Masson-Bessiere, C., Jolivet-Reynaud, C., Jolivet, M., Serre, G. (1999). The Epitopes Targeted by the Rheumatoid Arthritis-Associated Antifilaggrin Autoantibodies are Posttranslationally Generated on Various Sites of (Pro)Filaggrin by Deimination of Arginine Residues. J. Immunol. 162: 585-594 [Abstract] [Full Text]  
• Utz, P. J., Hottelet, M., Le, T. M., Kim, S. J., Geiger, M. E., van Venrooij, W. J., Anderson, P. (1998). The 72-kDa Component of Signal Recognition Particle Is Cleaved during Apoptosis. J. Biol. Chem. 273: 35362-35370 [Abstract] [Full Text]  
• von Muhlen, C A, Chan, E K., Angles-Cano, E, Mamula, M J, Garcia-De La Torre, I, Fritzler, M J (1998). Advances in autoantibodies in SLE. Lupus 7: 507-514  
• Jemmerson, R., Minnerath, J. M., Hedrick, S. M., Oehen, S. (1998). B Cell Tolerance to a Minor, But Not to a Major, Antigenic Surface of the Self Antigen, Cytochrome c. J. Immunol. 161: 2841-2847 [Abstract] [Full Text]  
• Utz, P. J., Hottelet, M., van Venrooij, W. J., Anderson, P. (1998). Association of Phosphorylated Serine/Arginine (SR) Splicing Factors With The U1-Small Ribonucleoprotein (snRNP) Autoantigen Complex Accompanies Apoptotic Cell Death. JEM 187: 547-560 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS