The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases
Nicole H. Kattah,
Michael G. Kattah,
Paul J. Utz,
Nicole H. Kattah
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorMichael G. Kattah
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorPaul J. Utz
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorNicole H. Kattah,
Michael G. Kattah,
Paul J. Utz,
Nicole H. Kattah
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorMichael G. Kattah
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorPaul J. Utz
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Search for more papers by this authorNicole H. Kattah
Division of Immunology and RheumatologyDepartment of MedicineStanford University269 Campus DriveCCSR 2250Stanford, CA 94305, USATel.: +1 650 723 7038Fax: +1 650 723 7509e-mail: [email protected]
Abstract
Summary: The U1 small nuclear ribonucleoprotein particle (snRNP) is a target of autoreactive B cells and T cells in several rheumatic diseases including systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). We propose that inherent structural properties of this autoantigen complex, including common RNA-binding motifs, B and T-cell epitopes, and a unique stimulatory RNA molecule, underlie its susceptibility as a target of the autoimmune response. Immune mechanisms that may contribute to overall U1-snRNP immunogenicity include epitope spreading through B and T-cell interactions, apoptosis-induced modifications, and Toll-like receptor (TLR) activation through stimulation by U1-snRNA. We conclude that understanding the interactions between U1-snRNP and the immune system will provide insights into why certain patients develop anti-U1-snRNP autoimmunity, and more importantly how to effectively target therapies against this autoimmune response.
References
- 1 Von Muhlen CA, Tan EM. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum 1995; 24: 323–358.
- 2 Holman H, Deicher HR. The reaction of the lupus erythematosus (L.E.) cell factor with deoxyribonucleoprotein of the cell nucleus. J Clin Invest 1959; 38: 2059–2072.
- 3 Tan EM, Kunkel HG. Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J Immunol 1966; 96: 464–471.
- 4 Sharp GC, et al. Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest 1971; 50: 350–359.
- 5 Van Venrooij WJ, Zendman AJ, Pruijn GJ. Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun Rev 2006; 6: 37–41.
- 6 Kidd BA, et al. Epitope spreading to citrullinated antigens in mouse models of autoimmune arthritis and demyelination. Arthritis Res Ther 2008; 10: R119.
- 7 Pomeranz Krummel DA, Oubridge C, Leung AK, Li J, Nagai K. Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution. Nature 2009; 458: 475–480.
- 8 Kramer A. The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem 1996; 65: 367–409.
- 9 Lutz CS, James J. Antibodies to Spliceosomal Components. Dubois’ Lupus Erythematosus. Lippincott: Williams & Wilkins, 2007.
- 10 Lerner MR, Steitz JA. Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Sci USA 1979; 76: 5495–5499.
- 11 Krol A, Westhof E, Bach M, Luhrmann R, Ebel JP, Carbon P. Solution structure of human U1 snRNA. Derivation of a possible three-dimensional model. Nucleic Acids Res 1990; 18: 3803–3811.
- 12 Kambach C, et al. Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs. Cell 1999; 96: 375–387.
- 13 Stark H, Dube P, Luhrmann R, Kastner B. Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle. Nature 2001; 409: 539–542.
- 14 Theissen H, et al. Cloning of the human cDNA for the U1 RNA-associated 70K protein. EMBO J 1986; 5: 3209–3217.
- 15 Nelissen RL, Will CL, Van Venrooij WJ, Luhrmann R. The association of the U1-specific 70K and C proteins with U1 snRNPs is mediated in part by common U snRNP proteins. EMBO J 1994; 13: 4113–4125.
- 16 Lutz CS, McClain MT, Harley JB, James JA. Anti-U1A monoclonal antibodies recognize unique epitope targets of U1A which are involved in the binding of U1 RNA. J Mol Recognit 2002; 15: 163–170.
- 17 Faig OZ, Lutz CS. Novel specificity of anti-U1A autoimmune patient sera. Scand J Immunol 2003; 57: 79–84.
- 18 Query CC, Bentley RC, Keene JD. A common RNA recognition motif identified within a defined U1 RNA binding domain of the 70K U1 snRNP protein. Cell 1989; 57: 89–101.
- 19 Query CC, Bentley RC, Keene JD. A specific 31-nucleotide domain of U1 RNA directly interacts with the 70K small nuclear ribonucleoprotein component. Mol Cell Biol 1989; 9: 4872–4881.
- 20 Scherly D, Boelens W, Van Venrooij WJ, Dathan NA, Hamm J, Mattaj IW. Identification of the RNA binding segment of human U1 A protein and definition of its binding site on U1 snRNA. EMBO J 1989; 8: 4163–4170.
- 21 Oubridge C, Ito N, Evans PR, Teo CH, Nagai K. Crystal structure at 1.92 A resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin. Nature 1994; 372: 432–438.
- 22 Kastner B, Kornstadt U, Bach M, Luhrmann R. Structure of the small nuclear RNP particle U1: identification of the two structural protuberances with RNP-antigens A and 70K. J Cell Biol 1992; 116: 839–849.
- 23 Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA. Are snRNPs involved in splicing? Nature 1980; 283: 220–224.
- 24 Staley JP, Guthrie C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell 1998; 92: 315–326.
- 25 Murray HL, Jarrell KA. Flipping the switch to an active spliceosome. Cell 1999; 96: 599–602.
- 26 Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell 2009; 136: 701–718.
- 27 Bessonov S, Anokhina M, Will CL, Urlaub H, Luhrmann R. Isolation of an active step I spliceosome and composition of its RNP core. Nature 2008; 452: 846–850.
- 28 Stark H, Luhrmann R. Cryo-electron microscopy of spliceosomal components. Annu Rev Biophys Biomol Struct 2006; 35: 435–457.
- 29 Luhrmann R, Stark H. Structural mapping of spliceosomes by electron microscopy. Curr Opin Struct Biol 2009; 19: 96–102.
- 30 Utz PJ, Hottelet M, Van Venrooij WJ, Anderson P. Association of phosphorylated serine/arginine (SR) splicing factors with the U1-small ribonucleoprotein (snRNP) autoantigen complex accompanies apoptotic cell death. J Exp Med 1998; 187: 547–560.
- 31 Zahler AM, Lane WS, Stolk JA, Roth MB. SR proteins: a conserved family of pre-mRNA splicing factors. Genes Dev 1992; 6: 837–847.
- 32 Wu JY, Maniatis T. Specific interactions between proteins implicated in splice site selection and regulated alternative splicing. Cell 1993; 75: 1061–1070.
- 33 Zahler AM, Neugebauer KM, Lane WS, Roth MB. Distinct functions of SR proteins in alternative pre-mRNA splicing. Science 1993; 260: 219–222.
- 34 Zahler AM, Roth MB. Distinct functions of SR proteins in recruitment of U1 small nuclear ribonucleoprotein to alternative 5′ splice sites. Proc Natl Acad Sci USA 1995; 92: 2642–2646.
- 35 Neugebauer KM, Merrill JT, Wener MH, Lahita RG, Roth MB. SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of phosphoepitopes. Arthritis Rheum 2000; 43: 1768–1778.
- 36 Mattioli M, Reichlin M. Characterization of a soluble nuclear ribonucleoprotein antigen reactive with SLE sera. J Immunol 1971; 107: 1281–1290.
- 37 Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972; 52: 148–159.
- 38 Sharp GC, et al. Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systematic lupus erythematosus and other rheumatic diseases. N Engl J Med 1976; 295: 1149–1154.
- 39 Venables PJ. Mixed connective tissue disease. Lupus 2006; 15: 132–137.
- 40 Hoffman RW, Maldonado ME. Immune pathogenesis of Mixed Connective Tissue Disease: a short analytical review. Clin Immunol 2008; 128: 8–17.
- 41 Pettersson I, Hinterberger M, Mimori T, Gottlieb E, Steitz JA. The structure of mammalian small nuclear ribonucleoproteins. Identification of multiple protein components reactive with anti-(U1)ribonucleoprotein and anti-Sm autoantibodies. J Biol Chem 1984; 259: 5907–5914.
- 42 Delpech A, Gilbert D, Daliphard S, Le Loet X, Godin M, Tron F. Antibodies to Sm, RNP and SSB detected by solid-phase ELISAs using recombinant antigens: a comparison study with counter immunoelectrophoresis and immunoblotting. J Clin Lab Anal 1993; 7: 197–202.
- 43 Maddison PJ, Skinner RP, Vlachoyiannopoulos P, Brennand DM, Hough D. Antibodies to nRNP, Sm, Ro(SSA) and La(SSB) detected by ELISA: their specificity and inter-relations in connective tissue disease sera. Clin Exp Immunol 1985; 62: 337–345.
- 44 Garcia Lerma JG, Mendoza AZ, Ramos MJ, Sequi J. Evaluation of recombinant Ro/SSA, La/SSB, Sm, and U1 RNP autoantigens in clinical diagnosis. J Clin Lab Anal 1995; 9: 52–58.
- 45 Benito-Garcia E, Schur PH, Lahita R. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-Sm and anti-RNP antibody tests. Arthritis Rheum 2004; 51: 1030–1044.
- 46 Takada K, et al. Clinical characteristics of patients with both anti-U1RNP and anti-centromere antibodies. Scand J Rheumatol 2008; 37: 360–364.
- 47 St Clair EW, et al. Expression of autoantibodies to recombinant (U1) RNP-associated 70K antigen in systemic lupus erythematosus. Clin Immunol Immunopathol 1990; 54: 266–280.
- 48 Faria AC, Barcellos KS, Andrade LE. Longitudinal fluctuation of antibodies to extractable nuclear antigens in systemic lupus erythematosus. J Rheumatol 2005; 32: 1267–1272.
- 49 Habets WJ, et al. Antibodies against distinct nuclear matrix proteins are characteristic for mixed connective tissue disease. Clin Exp Immunol 1983; 54: 265–276.
- 50 Van Venrooij WJ, Hoet R, Castrop J, Hageman B, Mattaj IW, Van De Putte LB. Anti-(U1) small nuclear RNA antibodies in anti-small nuclear ribonucleoprotein sera from patients with connective tissue diseases. J Clin Invest 1990; 86: 2154–2160.
- 51 Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 1999; 42: 899–909.
- 52 Ho KT, Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003; 5: 80–93.
- 53 Chung L, Utz PJ. Antibodies in scleroderma: direct pathogenicity and phenotypic associations. Curr Rheumatol Rep 2004; 6: 156–163.
- 54 Coppo P, Clauvel JP, Bengoufa D, Oksenhendler E, Lacroix C, Lassoued K. Inflammatory myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies: a subset of myositis associated with a favourable outcome. Rheumatology (Oxford) 2002; 41: 1040–1046.
- 55 Dayal NA, Isenberg DA. SLE/myositis overlap: are the manifestations of SLE different in overlap disease? Lupus 2002; 11: 293–298.
- 56 Lundberg I, Nennesmo I, Hedfors E. A clinical, serological, and histopathological study of myositis patients with and without anti-RNP antibodies. Semin Arthritis Rheum 1992; 22: 127–138.
- 57 Arbuckle MR, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–1533.
- 58 Reichlin M, Van Venrooij WJ. Autoantibodies to the URNP particles: relationship to clinical diagnosis and nephritis. Clin Exp Immunol 1991; 83: 286–290.
- 59 Thompson D, Juby A, Davis P. The clinical significance of autoantibody profiles in patients with systemic lupus erythematosus. Lupus 1993; 2: 15–19.
- 60 Greidinger EL, Casciola-Rosen L, Morris SM, Hoffman RW, Rosen A. Autoantibody recognition of distinctly modified forms of the U1-70-kd antigen is associated with different clinical disease manifestations. Arthritis Rheum 2000; 43: 881–888.
- 61 Keith MP, et al. Anti-ribonucleoprotein antibodies mediate enhanced lung injury following mesenteric ischemia/reperfusion in Rag-1(−/−) mice. Autoimmunity 2007; 40: 208–216.
- 62 Query CC, Keene JD. A human autoimmune protein associated with U1 RNA contains a region of homology that is cross-reactive with retroviral p30gag antigen. Cell 1987; 51: 211–220.
- 63 Guldner HH, Netter HJ, Szostecki C, Lakomek HJ, Will H. Epitope mapping with a recombinant human 68-kDa (U1) ribonucleoprotein antigen reveals heterogeneous autoantibody profiles in human autoimmune sera. J Immunol 1988; 141: 469–475.
- 64 Cram DS, Fisicaro N, Coppel RL, Whittingham S, Harrison LC. Mapping of multiple B cell epitopes on the 70-kilodalton autoantigen of the U1 ribonucleoprotein complex. J Immunol 1990; 145: 630–635.
- 65 Netter HJ, Guldner HH, Szostecki C, Will H. Major autoantigenic sites of the (U1) small nuclear ribonucleoprotein-specific 68-kDa protein. Scand J Immunol 1990; 32: 163–176.
- 66 Nyman U, Lundberg I, Hedfors E, Pettersson I. Recombinant 70-kD protein used for determination of autoantigenic epitopes recognized by anti-RNP sera. Clin Exp Immunol 1990; 81: 52–58.
- 67 Monneaux F, Briand JP, Muller S. B and T cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) T cells recognize a T cell epitope located within the RNP80 motif of the 70K protein. Eur J Immunol 2000; 30: 2191–2200.
- 68 Monneaux F, Muller S. Epitope spreading in systemic lupus erythematosus: identification of triggering peptide sequences. Arthritis Rheum 2002; 46: 1430–1438.
- 69 Barakat S, Briand JP, Abuaf N, Van Regenmortel MH, Muller S. Mapping of epitopes on U1 snRNP polypeptide A with synthetic peptides and autoimmune sera. Clin Exp Immunol 1991; 86: 71–78.
- 70 James JA, Harley JB. Human lupus anti-spliceosome A protein autoantibodies bind contiguous surface structures and segregate into two sequential epitope binding patterns. J Immunol 1996; 156: 4018–4026.
- 71 Halimi H, Dumortier H, Briand JP, Muller S. Comparison of two different methods using overlapping synthetic peptides for localizing linear B cell epitopes in the U1 snRNP-C autoantigen. J Immunol Methods 1996; 199: 77–85.
- 72 Hoet RM, Kastner B, Luhrmann R, Van Venrooij WJ. Purification and characterization of human autoantibodies directed to specific regions on U1RNA; recognition of native U1RNP complexes. Nucleic Acids Res 1993; 21: 5130–5136.
- 73 Monneaux F, Muller S. Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins. Scand J Immunol 2001; 2: 45–54.
- 74 Freed JH, Marrs A, VanderWall J, Cohen PL, Eisenberg RA. MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus. J Immunol 2000; 164: 4697–4705.
- 75 O’Brien RM, Cram DS, Coppel RL, Harrison LC. T-cell epitopes on the 70-kDa protein of the (U1)RNP complex in autoimmune rheumatologic disorders. J Autoimmun 1990; 3: 747–757.
- 76 Monneaux F, Parietti V, Briand JP, Muller S. Intramolecular T cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151. Arthritis Rheum 2004; 50: 3232–3238.
- 77 Monneaux F, Dumortier H, Steiner G, Briand JP, Muller S. Murine models of systemic lupus erythematosus: B and T cell responses to spliceosomal ribonucleoproteins in MRL/Fas(lpr) and (NZB × NZW)F(1) lupus mice. Int Immunol 2001; 13: 1155–1163.
- 78 Kent SC, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005; 435: 224–228.
- 79 Hoffman RW, et al. Human T-cell clones reactive against U-small nuclear ribonucleoprotein autoantigens from connective tissue disease patients and healthy individuals. J Immunol 1993; 151: 6460–6469.
- 80 Talken BL, Lee DR, Caldwell CW, Quinn TP, Schafermeyer KR, Hoffman RW. Analysis of T cell receptors specific for U1-70kD small nuclear ribonucleoprotein autoantigen: the alpha chain complementarity determining region three is highly conserved among connective tissue disease patients. Hum Immunol 1999; 60: 200–208.
- 81 Talken BL, Bailey CW, Reardon SL, Caldwell CW, Hoffman RW. Structural analysis of TCRalpha and beta chains from human T-Cell clones specific for small nuclear ribonucleoprotein polypeptides Sm-D, Sm-B and U1-70 kDa: TCR complementarity determining region 3 usage appears highly conserved. Scand J Immunol 2001; 2: 204–210.
- 82 Greidinger EL, et al. T cell immunity in connective tissue disease patients targets the RNA binding domain of the U1-70kDa small nuclear ribonucleoprotein. J Immunol 2002; 169: 3429–3437.
- 83 Holyst MM, Hill DL, Hoch SO, Hoffman RW. Analysis of human T cell and B cell responses against U small nuclear ribonucleoprotein 70-kd, B, and D polypeptides among patients with systemic lupus erythematosus and mixed connective tissue disease. Arthritis Rheum 1997; 40: 1493–1503.
- 84 Yang MH, Suen JL, Li SL, Chiang BL. Identification of T-cell epitopes on U1A protein in MRL/lpr mice: double-negative T cells are the major responsive cells. Immunology 2005; 115: 279–286.
- 85 Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol 1991; 9: 243–269.
- 86 Suen JL, Chuang YH, Chiang BL. In vivo tolerance breakdown with dendritic cells pulsed with U1A protein in non-autoimmune mice: the induction of a high level of autoantibodies but not renal pathological changes. Immunology 2002; 106: 326–335.
- 87 Okubo M, et al. Detection and epitope analysis of autoantigen-reactive T cells to the U1-small nuclear ribonucleoprotein A protein in autoimmune disease patients. J Immunol 1993; 151: 1108–1115.
- 88 Greidinger EL, Zang YJ, Jaimes K, Martinez L, Nassiri M, Hoffman RW. CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease. J Immunol 2008; 180: 8444–8454.
- 89 Monneaux F, Parietti V, Briand JP, Muller S. Importance of spliceosomal RNP1 motif for intermolecular T-B cell spreading and tolerance restoration in lupus. Arthritis Res Ther 2007; 9: R111.
- 90 Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature 1985; 314: 537–539.
- 91 Mamula MJ, Fatenejad S, Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol 1994; 152: 1453–1461.
- 92 Peng SL, et al. alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. J Immunol 1997; 158: 2464–2470.
- 93 Greidinger EL, et al. Tissue targeting of anti-RNP autoimmunity: effects of T cells and myeloid dendritic cells in a murine model. Arthritis Rheum 2009; 60: 534–542.
- 94 Greidinger EL, Gazitt T, Jaimes KF, Hoffman RW. Human T-cell clones specific for heterogeneous nuclear ribonucleoprotein A2 autoantigen from connective tissue disease patients assist in autoantibody production. Arthritis Rheum 2004; 50: 2216–2222.
- 95 Takeno M, et al. Autoreactive T-cell clones from patients with systemic lupus erythematosus support polyclonal autoantibody production. J Immunol 1997; 158: 3529–3538.
- 96 Mamula MJ. Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol Rev 1998; 164: 231–239.
- 97 James JA, Harley JB. B-cell epitope spreading in autoimmunity. Immunol Rev 1998; 164: 185–200.
- 98 Deshmukh US, Bagavant H, Lewis J, Gaskin F, Fu SM. Epitope spreading within lupus-associated ribonucleoprotein antigens. Clin Immunol. 2005; 117: 112–120.
- 99 Fatenejad S, Mamula MJ, Craft J. Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles. Proc Natl Acad Sci USA 1993; 90: 12010–12014.
- 100 Deshmukh US, Kannapell CC, Fu SM. Immune responses to small nuclear ribonucleoproteins: antigen-dependent distinct B cell epitope spreading patterns in mice immunized with recombinant polypeptides of small nuclear ribonucleoproteins. J Immunol 2002; 168: 5326–5332.
- 101 Fatenejad S, Brooks W, Schwartz A, Craft J. Pattern of anti-small nuclear ribonucleoprotein antibodies in MRL/Mp-lpr/lpr mice suggests that the intact U1 snRNP particle is their autoimmunogenic target. J Immunol 1994; 152: 5523–5531.
- 102 Greidinger EL, Hoffman RW. The appearance of U1 RNP antibody specificities in sequential autoimmune human antisera follows a characteristic order that implicates the U1-70 kd and B’/B proteins as predominant U1 RNP immunogens. Arthritis Rheum 2001; 44: 368–375.
- 103 Utz PJ, Anderson P. Posttranslational protein modifications, apoptosis, and the bypass of tolerance to autoantigens. Arthritis Rheum 1998; 41: 1152–1160.
- 104 Utz PJ, Gensler TJ, Anderson P. Death, autoantigen modifications, and tolerance. Arthritis Res 2000; 2: 101–114.
- 105 Graham KL, Utz PJ. Sources of autoantigens in systemic lupus erythematosus. Curr Opin Rheumatol 2005; 17: 513–517.
- 106 Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994; 179: 1317–1330.
- 107 Dieker J, et al. Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K. Cell Death Differ 2008; 15: 793–804.
- 108 Utz PJ, Hottelet M, Schur PH, Anderson P. Proteins phosphorylated during stress-induced apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus. J Exp Med 1997; 185: 843–854.
- 109 Casciola-Rosen LA, Miller DK, Anhalt GJ, Rosen A. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J Biol Chem 1994; 269: 30757–30760.
- 110 Casciola-Rosen L, et al. Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death. J Exp Med 1996; 183: 1957–1964.
- 111 Degen WG, Aarssen Y, Pruijn GJ, Utz PJ, Van Venrooij WJ. The fate of U1 snRNP during anti-Fas induced apoptosis: specific cleavage of the U1 snRNA molecule. Cell Death Differ 2000; 7: 70–79.
- 112 Andrade F, Casciola-Rosen LA, Rosen A. Generation of novel covalent RNA-protein complexes in cells by ultraviolet B irradiation: implications for autoimmunity. Arthritis Rheum 2005; 52: 1160–1170.
- 113 Kuhn A, Beissert S. Photosensitivity in lupus erythematosus. Autoimmunity. 2005; 38: 519–529.
- 114
Degen WG,
Pieffers M,
Welin-Henriksson E,
Van Den Hoogen FH,
Van Venrooij WJ,
Raats JM.
Characterization of recombinant human autoantibody fragments directed toward the autoantigenic U1-70K protein.
Eur J Immunol
2000; 30: 3029–3038.
10.1002/1521-4141(200010)30:10<3029::AID-IMMU3029>3.0.CO;2-J CAS PubMed Web of Science® Google Scholar
- 115 Greidinger EL, Foecking MF, Ranatunga S, Hoffman RW. Apoptotic U1-70 kd is antigenically distinct from the intact form of the U1-70-kd molecule. Arthritis Rheum 2002; 46: 1264–1269.
- 116 Hof D, et al. Autoantibodies specific for apoptotic U1-70K are superior serological markers for mixed connective tissue disease. Arthritis Res Ther 2005; 7: R302–R309.
- 117 Kaplan MJ. Apoptosis in systemic lupus erythematosus. Clin Immunol 2004; 112: 210–218.
- 118 Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol 1994; 152: 3685–3692.
- 119 Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus 1998; 7: 113–118.
- 120 Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 2006; 6: 823–835.
- 121 Marshak-Rothstein A, Rifkin IR. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol 2007; 25: 419–441.
- 122 Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303: 1529–1531.
- 123 Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002; 416: 603–607.
- 124 Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005; 202: 321–331.
- 125 Lau CM, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 2005; 202: 1171–1177.
- 126 Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 1979; 301: 5–8.
- 127 Bennett L, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003; 197: 711–723.
- 128 Fu Q, et al. Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients. Arthritis Res Ther 2008; 10: R112.
- 129 Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005; 52: 1491–1503.
- 130 Zhuang H, et al. Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus. Clin Immunol 2005; 117: 238–250.
- 131 Hua J, Kirou K, Lee C, Crow MK. Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum 2006; 54: 1906–1916.
- 132 Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 2006; 25: 417–428.
- 133 Kattah MG, Alemi GR, Thibault DL, Balboni I, Utz PJ. A new two-color Fab labeling method for autoantigen protein microarrays. Nat Methods 2006; 3: 745–751.
- 134 Thibault DL, et al. IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice. J Clin Invest 2008; 118: 1417–1426.
- 135 Nacionales DC, et al. Deficiency of the type I interferon receptor protects mice from experimental lupus. Arthritis Rheum 2007; 56: 3770–3783.
- 136 Thibault DL, Graham KL, Lee LY, Balboni I, Hertzog PJ, Utz PJ. Type I IFN receptor controls B cell expression of nucleic acid sensing toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther 2009; 11: R112.
- 137 Kelly-Scumpia KM, et al. In vivo adjuvant activity of the RNA component of the Sm/RNP lupus autoantigen. Arthritis Rheum 2007; 56: 3379–3386.
- 138 Lovgren T, Eloranta ML, Kastner B, Wahren-Herlenius M, Alm GV, Ronnblom L. Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjogren’s syndrome autoantigen-associated RNA. Arthritis Rheum 2006; 54: 1917–1927.
- 139 Hoffman RW, et al. U1 RNA induces innate immunity signaling. Arthritis Rheum 2004; 50: 2891–2896.
- 140 Greidinger EL, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 2006; 54: 661–669.
- 141 Herlands RA, Christensen SR, Sweet RA, Hershberg U, Shlomchik MJ. T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 2008; 29: 249–260.
- 142 Seo SJ, et al. The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells. Immunity 2002; 16: 535–546.
- 143 Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity 2008; 28: 18–28.
- 144 Monneaux F, Lozano JM, Patarroyo ME, Briand JP, Muller S. T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice. Eur J Immunol 2003; 33: 287–296.
- 145 Page N, et al. The spliceosomal phosphopeptide P140 controls the lupus disease by interacting with the HSC70 protein and via a mechanism mediated by gammadelta T cells. PLoS ONE 2009; 4: e5273.
- 146 Monneaux F, et al. Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. J Immunol 2005; 175: 5839–5847.
- 147 Muller S, et al. Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial. Arthritis Rheum 2008; 58: 3873–3883.
- 148 Riemekasten G, et al. Intravenous injection of a D1 protein of the Smith proteins postpones murine lupus and induces type 1 regulatory T cells. J Immunol 2004; 173: 5835–5842.
- 149 Ferrera F, La Cava A, Rizzi M, Hahn BH, Indiveri F, Filaci G. Gene vaccination for the induction of immune tolerance. Ann N Y Acad Sci 2007; 1110: 99–111.
- 150 Newell EW, Klein LO, Yu W, Davis MM. Simultaneous detection of many T-cell specificities using combinatorial tetramer staining. Nat Methods 2009; 6: 497–499.
- 151
Joos T, et al.
A microarray enzyme-linked immunosorbent assay for autoimmune diagnostics.
Electrophoresis
2000; 21: 2641–2650.
10.1002/1522-2683(20000701)21:13<2641::AID-ELPS2641>3.0.CO;2-5 CAS PubMed Web of Science® Google Scholar
- 152 Robinson W, et al. Autoantigen microarrays for multiplex characterization of autoantibody responses. Nature Med. 2001; 8: 295–301.
- 153 Balboni I, Chan SM, Kattah M, Tenenbaum JD, Butte AJ, Utz PJ. Multiplexed protein array platforms for analysis of autoimmune diseases. Annu Rev Immunol 2006; 24: 391–418.
- 154 Chan SM, Utz PJ. The challenge of analyzing the proteome in humans with autoimmune diseases. Ann N Y Acad Sci 2005; 1062: 61–68.
- 155 Balboni I, Limb C, Tenenbaum JD, Utz PJ. Evaluation of microarray surfaces and arraying parameters for autoantibody profiling. Proteomics 2008; 8: 3443–3449.
- 156 Graham KL, Vaysberg M, Kuo A, Utz PJ. Autoantigen arrays for multiplex analysis of antibody isotypes. Proteomics 2006; 6: 5720–5724.
- 157 Rouquette AM, Desgruelles C, Laroche P. Evaluation of the new multiplexed immunoassay, FIDIS, for simultaneous quantitative determination of antinuclear antibodies and comparison with conventional methods. Am J Clin Pathol 2003; 120: 676–681.
- 158 Martins TB, Burlingame R, Von Muhlen CA, Jaskowski TD, Litwin CM, Hill HR. Evaluation of multiplexed fluorescent microsphere immunoassay for detection of autoantibodies to nuclear antigens. Clin Diagn Lab Immunol 2004; 11: 1054–1059.
- 159 Ray CA, et al. Development, validation, and implementation of a multiplex immunoassay for the simultaneous determination of five cytokines in human serum. J Pharm Biomed Anal 2005; 36: 1037–1044.
- 160 Poole BD, et al. Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus. Arthritis Rheum 2009; 60: 848–859.
- 161 Takeda Y, et al. Antigenic domains on the U1 small nuclear ribonucleoprotein-associated 70K polypeptide: a comparison of regions selectively recognized by human and mouse autoantibodies and by monoclonal antibodies. Clin Immunol Immunopathol 1991; 61: 55–68.
- 162 Welin Henriksson E, Wahren-Herlenius M, Lundberg I, Mellquist E, Pettersson I. Key residues revealed in a major conformational epitope of the U1-70K protein. Proc Natl Acad Sci USA 1999; 96: 14487–14492.
- 163 James JA, Scofield RH, Harley JB. Basic amino acids predominate in the sequential autoantigenic determinants of the small nuclear 70K ribonucleoprotein. Scand J Immunol 1994; 39: 557–566.
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