Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point of care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

For more information, click below.


Subscribers log in here


The anti-Ro/SSA and anti-La/SSB antigen-antibody systems

INTRODUCTION

Autoantibodies directed against Ro/SSA and La/SSB autoantigens were originally identified in patients with Sjögren’s syndrome and systemic lupus erythematosus (SLE). Subsequent studies showed that anti-Ro/SSA antibodies may be present in patients with other autoimmune diseases, including systemic sclerosis, idiopathic inflammatory myopathies (IIM), primary biliary cirrhosis (PBC), and rheumatoid arthritis (RA). Additionally, anti-Ro/SSA antibodies (with or without anti-La/SSB antibodies) identify pregnant women who are at increased risk of having a child with neonatal lupus syndrome. Anti-Ro/SSA antibodies may also be the only autoantibodies present in a subset of patients with “ANA-negative” SLE. (See "Neonatal lupus".)

The anti-Ro/SSA and anti-La/SSB antibody system and the clinical significance of these antibodies are reviewed here. An overview of the antinuclear antibodies important in SLE and in related autoimmune diseases and the clinical significance of autoantibodies directed against double-stranded deoxyribonucleic acid (dsDNA), U1 ribonucleoprotein (RNP), Sm, and ribosomal P proteins are reviewed separately. (See "Measurement and clinical significance of antinuclear antibodies" and "Miscellaneous antinuclear antibodies" and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP" and "Antiribosomal P protein antibodies".)

Ro/SSA ANTIGENS

Serum containing autoantibodies directed against the Ro/SSA antigens may recognize one or both of two cellular proteins with molecular weights of approximately 52 and 60 kD [1-4]. These autoantigens are referred to as “Ro52” and “Ro60,” respectively. The two autoantigens were originally thought to interact with each other, but subsequent studies have shown that the two proteins reside in distinct cellular compartments, with Ro60 localized to the nucleus and nucleolus and with Ro52 localized to the cytoplasm.

Ro60 — The amino acid sequence of the Ro60 autoantigen was described in the late 1980s [1,2]; Ro60 was shown to bind small, non-coding ribonucleic acids (RNAs) termed “Y RNAs.” Although the function of Y RNAs is unknown, one report suggests that Y RNAs may be a source of micro (mi)RNA molecules, which have a role in the regulation of messenger (m)RNA stability and translation [5]. The crystal structure of Ro60 suggests that the protein can bind to both single- and double-stranded RNA. The protein may function as a “RNA chaperone” that binds to misfolded pre-5S ribosomal RNA and may hasten the degradation of the defective molecule. Ro60 may also bind to other cellular and viral RNAs in the cell, including Epstein-Barr virus (EBV) early RNA 1 (EBER1) [6]. Mice that lack the functional gene encoding Ro60 develop an autoimmune syndrome characterized by antiribosome and antichromatin antibodies, as well as glomerulonephritis [7], suggesting that Ro60 may have an important role in preventing systemic autoimmune disease.

Ro52 — The amino acid sequence of the Ro52 autoantigen was reported in 1991 [3]. Ro52 is an interferon-inducible protein that belongs to the “tripartite motif” family of proteins. Ro52 contains an amino (N)-terminal RING finger domain, followed by B-box and coiled-coil domains and by a carboxy (C)-terminal B30.2 or “PRYPRY” domain. The protein localizes to the cytoplasm and functions as an E3 ubiquitin ligase, an enzyme that adds ubiquitin molecules to target proteins [4].

                

Subscribers log in here

To continue reading this article you must have access through your hospital or your group practice, log in to your personal subscription, or purchase a personal subscription. For more information, click below.
Literature review current through: Apr 2013. | This topic last updated: Jan 25, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2013 UpToDate, Inc.
References
Top
  1. Deutscher SL, Harley JB, Keene JD. Molecular analysis of the 60-kDa human Ro ribonucleoprotein. Proc Natl Acad Sci U S A 1988; 85:9479.
  2. Ben-Chetrit E, Gandy BJ, Tan EM, Sullivan KF. Isolation and characterization of a cDNA clone encoding the 60-kD component of the human SS-A/Ro ribonucleoprotein autoantigen. J Clin Invest 1989; 83:1284.
  3. Chan EK, Hamel JC, Buyon JP, Tan EM. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J Clin Invest 1991; 87:68.
  4. Wada K, Kamitani T. Autoantigen Ro52 is an E3 ubiquitin ligase. Biochem Biophys Res Commun 2006; 339:415.
  5. Verhagen AP, Pruijn GJ. Are the Ro RNP-associated Y RNAs concealing microRNAs? Y RNA-derived miRNAs may be involved in autoimmunity. Bioessays 2011; 33:674.
  6. Fuchs G, Stein AJ, Fu C, et al. Structural and biochemical basis for misfolded RNA recognition by the Ro autoantigen. Nat Struct Mol Biol 2006; 13:1002.
  7. Xue D, Shi H, Smith JD, et al. A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen. Proc Natl Acad Sci U S A 2003; 100:7503.
  8. Keeble AH, Khan Z, Forster A, James LC. TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc Natl Acad Sci U S A 2008; 105:6045.
  9. Takahata M, Bohgaki M, Tsukiyama T, et al. Ro52 functionally interacts with IgG1 and regulates its quality control via the ERAD system. Mol Immunol 2008; 45:2045.
  10. Yamochi T, Ohnuma K, Hosono O, et al. SSA/Ro52 autoantigen interacts with Dcp2 to enhance its decapping activity. Biochem Biophys Res Commun 2008; 370:195.
  11. Wada K, Niida M, Tanaka M, Kamitani T. Ro52-mediated monoubiquitination of IKK{beta} down-regulates NF-{kappa}B signalling. J Biochem 2009; 146:821.
  12. Higgs R, Ní Gabhann J, Ben Larbi N, et al. The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol 2008; 181:1780.
  13. Higgs R, Lazzari E, Wynne C, et al. Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One 2010; 5:e11776.
  14. Espinosa A, Dardalhon V, Brauner S, et al. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med 2009; 206:1661.
  15. Bolland S, Garcia-Sastre A. Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice. J Exp Med 2009; 206:1647.
  16. Fok V, Friend K, Steitz JA. Epstein-Barr virus noncoding RNAs are confined to the nucleus, whereas their partner, the human La protein, undergoes nucleocytoplasmic shuttling. J Cell Biol 2006; 173:319.
  17. Chambers JC, Kenan D, Martin BJ, Keene JD. Genomic structure and amino acid sequence domains of the human La autoantigen. J Biol Chem 1988; 263:18043.
  18. Alfano C, Sanfelice D, Babon J, et al. Structural analysis of cooperative RNA binding by the La motif and central RRM domain of human La protein. Nat Struct Mol Biol 2004; 11:323.
  19. Teplova M, Yuan YR, Phan AT, et al. Structural basis for recognition and sequestration of UUU(OH) 3' temini of nascent RNA polymerase III transcripts by La, a rheumatic disease autoantigen. Mol Cell 2006; 21:75.
  20. Bitko V, Musiyenko A, Bayfield MA, et al. Cellular La protein shields nonsegmented negative-strand RNA viral leader RNA from RIG-I and enhances virus growth by diverse mechanisms. J Virol 2008; 82:7977.
  21. Honda M, Shimazaki T, Kaneko S. La protein is a potent regulator of replication of hepatitis C virus in patients with chronic hepatitis C through internal ribosomal entry site-directed translation. Gastroenterology 2005; 128:449.
  22. Pudi R, Abhiman S, Srinivasan N, Das S. Hepatitis C virus internal ribosome entry site-mediated translation is stimulated by specific interaction of independent regions of human La autoantigen. J Biol Chem 2003; 278:12231.
  23. Cordes S, Kusov Y, Heise T, Gauss-Müller V. La autoantigen suppresses IRES-dependent translation of the hepatitis A virus. Biochem Biophys Res Commun 2008; 368:1014.
  24. Inoue Y, Sato H, Fujita K, et al. Selective translation of the measles virus nucleocapsid mRNA by la protein. Front Microbiol 2011; 2:173.
  25. Liu Y, Tan H, Tian H, et al. Autoantigen La promotes efficient RNAi, antiviral response, and transposon silencing by facilitating multiple-turnover RISC catalysis. Mol Cell 2011; 44:502.
  26. Pollock W, Toh BH. Routine immunofluorescence detection of Ro/SS-A autoantibody using HEp-2 cells transfected with human 60 kDa Ro/SS-A. J Clin Pathol 1999; 52:684.
  27. Fritzler MJ, Hanson C, Miller J, Eystathioy T. Specificity of autoantibodies to SS-A/Ro on a transfected and overexpressed human 60 kDa Ro autoantigen substrate. J Clin Lab Anal 2002; 16:103.
  28. Reveille JD, Solomon DH, Schur PH, Kavanaugh A. Evidence based guidelines for the use of immunologic laboratory tests: Anti-Ro (SS-A) and La (SS-B). Arthritis Care Res 2013; in press.
  29. Franceschini F, Cavazzana I. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity 2005; 38:55.
  30. Izmirly PM, Kim MY, Llanos C, et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 2010; 69:1827.
  31. Llanos C, Izmirly PM, Katholi M, et al. Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis Rheum 2009; 60:3091.
  32. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61:554.
  33. Schulte-Pelkum J, Fritzler M, Mahler M. Latest update on the Ro/SS-A autoantibody system. Autoimmun Rev 2009; 8:632.
  34. Marie I, Hatron PY, Dominique S, et al. Short-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 antibody. Semin Arthritis Rheum 2012; 41:890.
  35. Peene I, Meheus L, De Keyser S, et al. Anti-Ro52 reactivity is an independent and additional serum marker in connective tissue disease. Ann Rheum Dis 2002; 61:929.
  36. Dugar M, Cox S, Limaye V, et al. Diagnostic utility of anti-Ro52 detection in systemic autoimmunity. Postgrad Med J 2010; 86:79.
  37. Langguth DM, Morris S, Clifford L, et al. Specific testing for "isolated" anti-52 kDa SSA/Ro antibodies during standard anti-extractable nuclear antigen testing is of limited clinical value. J Clin Pathol 2007; 60:670.
  38. Pourmand N, Blomberg S, Rönnblom L, et al. Ro 52kD autoantibodies are detected in a subset of ANA-negative sera. Scand J Rheumatol 2000; 29:116.
  39. Friedman DM, Rupel A, Buyon JP. Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus. Curr Rheumatol Rep 2007; 9:101.
  40. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349:1526.
  41. Biazar C, Sigges J, Patsinakidis N, et al. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev 2013; 12:444.
  42. Paz ML, González Maglio DH, Pino M, et al. Anti-ribonucleoproteins autoantibodies in patients with systemic autoimmune diseases. Relation with cutaneous photosensitivity. Clin Rheumatol 2011; 30:209.
  43. Muratori L, Granito A, Muratori P, et al. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis 2008; 12:261.
  44. Stinton LM, Swain M, Myers RP, et al. Autoantibodies to GW bodies and other autoantigens in primary biliary cirrhosis. Clin Exp Immunol 2011; 163:147.
  45. Granito A, Muratori P, Muratori L, et al. Antibodies to SS-A/Ro-52kD and centromere in autoimmune liver disease: a clue to diagnosis and prognosis of primary biliary cirrhosis. Aliment Pharmacol Ther 2007; 26:831.
  46. Cavazzana I, Franceschini F, Quinzanini M, et al. Anti-Ro/SSA antibodies in rheumatoid arthritis: clinical and immunologic associations. Clin Exp Rheumatol 2006; 24:59.
  47. Schneeberger E, Citera G, Heredia M, Maldonado Cocco J. Clinical significance of anti-Ro antibodies in rheumatoid arthritis. Clin Rheumatol 2008; 27:517.
  48. Matsudaira R, Tamura N, Sekiya F, et al. Anti-Ro/SSA antibodies are an independent factor associated with an insufficient response to tumor necrosis factor inhibitors in patients with rheumatoid arthritis. J Rheumatol 2011; 38:2346.
  49. Nardi N, Brito-Zerón P, Ramos-Casals M, et al. Circulating auto-antibodies against nuclear and non-nuclear antigens in primary Sjögren's syndrome: prevalence and clinical significance in 335 patients. Clin Rheumatol 2006; 25:341.
  50. Takada K, Suzuki K, Matsumoto M, et al. Primary biliary cirrhosis in female subjects with sicca-associated antibodies. Mod Rheumatol 2007; 17:486.