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 and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Anti-U1 RNP antibodies in mixed connective tissue disease

INTRODUCTION

Mixed connective tissue disease (MCTD) was originally defined as a connective tissue disorder characterized by the presence of high titers of a distinct autoantibody in combination with clinical features commonly seen in systemic lupus erythematosus (SLE), scleroderma, and polymyositis (referred to as overlap syndrome) [1]. The antigen recognized by these antibodies, originally called a ribonuclease-sensitive extractable nuclear antigen (RNAse sensitive ENA), is known to be a U1 ribonucleoprotein (RNP) complex. The presence of antibodies to U1 RNP remains a sine qua non for the diagnosis of this disorder; indeed, their emergence often precedes the onset of clinical disease [2,3].

The immunobiology of anti-U1 RNP antibodies in mixed connective tissue disease will be reviewed here. The clinical manifestations, diagnosis, prognosis, and treatment of this disorder, as well as a general discussion of anti-RNP autoantibodies, are discussed separately. (See "Clinical manifestations of mixed connective tissue disease" and "Definition and diagnosis of mixed connective tissue disease" and "Prognosis and treatment of mixed connective tissue disease" and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Anti-Sm and anti-U1 RNP antibodies'.)

GENERATION OF U1 RNP AUTOIMMUNITY

The antibody response in patients with mixed connective tissue disease (MCTD) is very vigorous and is characterized by a hypergammaglobulinemia that can amount to 30 percent of the total serum immunoglobulins (Ig) [4]. In the laboratory, this antibody response is first evident as a very high titer speckled antinuclear antibody (ANA) pattern [2]. The titer is often greater than 1:1000 and is sometimes greater than 1:10,000; this finding should prompt the measurement of antibodies to U1 ribonucleoprotein (RNP), Sm, Ro, and La.

The specificity of the antibodies most closely related to the clinical features of MCTD is for a 70 kD epitope on U1 RNP molecules [5]. This epitope has been further characterized as the RNA-binding domain on the peptide component of U1 RNP that spans residues 92 to 202 [6]. Anti-U1 RNP antibodies display Ig class switching from IgM to IgG, as evidenced by variable region mutations, a feature that is typical of a T-cell dependent B-cell maturation response [7].

The interaction of T-cell receptors and peptides presented by human leukocyte antigen (HLA) molecules is a critical event in the generation of autoimmunity. The 70 kD anti-U1 RNP antibody response is associated with CD4/Th1 T cells expressing a HLA-DR4 or -DR2 phenotype [8]. DNA sequencing of HLA-DB genes has revealed that DR2 and DR4-positive patients share a common set of amino acids in the beta chain at positions 26, 28, 30, 31, 32, 70, and 73 [9]. Such amino acids form a pocket for antigen binding (figure 1).

          

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jun 2014. | This topic last updated: Nov 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 ©2014 UpToDate, Inc.
References
Top
  1. Sharp GC, Irvin WS, Tan EM, et al. 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.
  2. Bennett RM. Scleroderma, inflammatory myopathies, and overlap syndromes. In: Textbook of Rheumatology, 8th, Harris ED Jr (Ed), WB Saunders, Philadelphia 2008. p.1381.
  3. 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.
  4. Maddison PJ, Reichlin M. Quantitation of precipitating antibodies to certain soluble nuclear antigens in SLE. Arthritis Rheum 1977; 20:819.
  5. Welin Henriksson E, Wahren-Herlenius M, Lundberg I, et al. Key residues revealed in a major conformational epitope of the U1-70K protein. Proc Natl Acad Sci U S A 1999; 96:14487.
  6. Degen WG, Pieffers M, Welin-Henriksson E, et al. Characterization of recombinant human autoantibody fragments directed toward the autoantigenic U1-70K protein. Eur J Immunol 2000; 30:3029.
  7. Hoffman RW, Maldonado ME. Immune pathogenesis of Mixed Connective Tissue Disease: a short analytical review. Clin Immunol 2008; 128:8.
  8. 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.
  9. Kaneoka H, Hsu KC, Takeda Y, et al. Molecular genetic analysis of HLA-DR and HLA-DQ genes among anti-U1-70-kd autoantibody positive connective tissue disease patients. Arthritis Rheum 1992; 35:83.
  10. Lanzavecchia A, Sallusto F. Toll-like receptors and innate immunity in B-cell activation and antibody responses. Curr Opin Immunol 2007; 19:268.
  11. Greidinger EL, Zang YJ, Jaimes K, et al. 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.
  12. Hoffman RW, Gazitt T, Foecking MF, et al. U1 RNA induces innate immunity signaling. Arthritis Rheum 2004; 50:2891.
  13. Decker P. Nucleosome autoantibodies. Clin Chim Acta 2006; 366:48.
  14. Radic M, Marion T, Monestier M. Nucleosomes are exposed at the cell surface in apoptosis. J Immunol 2004; 172:6692.
  15. Amoura Z, Koutouzov S, Chabre H, et al. Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus. Arthritis Rheum 2000; 43:76.
  16. Rivett AJ, Hearn AR. Proteasome function in antigen presentation: immunoproteasome complexes, Peptide production, and interactions with viral proteins. Curr Protein Pept Sci 2004; 5:153.
  17. Utz PJ, Anderson P. Posttranslational protein modifications, apoptosis, and the bypass of tolerance to autoantigens. Arthritis Rheum 1998; 41:1152.
  18. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity 2005; 38:47.
  19. Siapka S, Patrinou-Georgoula M, Vlachoyiannopoulos PG, Guialis A. Multiple specificities of autoantibodies against hnRNP A/B proteins in systemic rheumatic diseases and hnRNP L as an associated novel autoantigen. Autoimmunity 2007; 40:223.
  20. Skriner K, Sommergruber WH, Tremmel V, et al. Anti-A2/RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. Differential epitope recognition in rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. J Clin Invest 1997; 100:127.
  21. Deshmukh US, Bagavant H, Lewis J, et al. Epitope spreading within lupus-associated ribonucleoprotein antigens. Clin Immunol 2005; 117:112.
  22. Monneaux F, Muller S. Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins. Scand J Immunol 2001; 54:45.
  23. 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 U S A 1993; 90:12010.
  24. Steiner G, Shovman O, Skriner K, et al. Induction of anti-RA33 hnRNP autoantibodies and transient spread to U1-A snRNP complex of spliceosome by idiotypic manipulation with anti-RA33 antibody preparation in mice. Clin Exp Rheumatol 2002; 20:517.
  25. Tuohy VK, Kinkel RP. Epitope spreading: a mechanism for progression of autoimmune disease. Arch Immunol Ther Exp (Warsz) 2000; 48:347.
  26. 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.
  27. Mahoney JA, Rosen A. Apoptosis and autoimmunity. Curr Opin Immunol 2005; 17:583.
  28. Mihara S, Suzuki N, Takeba Y, et al. Combination of molecular mimicry and aberrant autoantigen expression is important for development of anti-Fas ligand autoantibodies in patients with systemic lupus erythematosus. Clin Exp Immunol 2002; 129:359.
  29. Rumore PM, Steinman CR. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest 1990; 86:69.
  30. 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.
  31. Hof D, Raats JM, Pruijn GJ. Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen. Autoimmun Rev 2005; 4:380.
  32. Graham KL, Utz PJ. Sources of autoantigens in systemic lupus erythematosus. Curr Opin Rheumatol 2005; 17:513.
  33. Greidinger EL, Foecking MF, Magee J, et al. A major B cell epitope present on the apoptotic but not the intact form of the U1-70-kDa ribonucleoprotein autoantigen. J Immunol 2004; 172:709.
  34. Hof D, Cheung K, de Rooij DJ, et al. Autoantibodies specific for apoptotic U1-70K are superior serological markers for mixed connective tissue disease. Arthritis Res Ther 2005; 7:R302.
  35. Davies JM. Molecular mimicry: can epitope mimicry induce autoimmune disease? Immunol Cell Biol 1997; 75:113.
  36. Wucherpfennig KW. Structural basis of molecular mimicry. J Autoimmun 2001; 16:293.
  37. Hemmer B, Kondo T, Gran B, et al. Minimal peptide length requirements for CD4(+) T cell clones--implications for molecular mimicry and T cell survival. Int Immunol 2000; 12:375.
  38. Oldstone MB. Molecular mimicry and immune-mediated diseases. FASEB J 1998; 12:1255.
  39. Prokop J, Jagodzinski PP. Identification of retroviral conserved pol sequences in serum of mixed connective tissue disease and systemic sclerosis patients. Biomed Pharmacother 2004; 58:61.
  40. Maul GG, Jimenez SA, Riggs E, Ziemnicka-Kotula D. Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis. Proc Natl Acad Sci U S A 1989; 86:8492.
  41. Douvas A, Takehana Y. Cross-reactivity between autoimmune anti-U1 snRNP antibodies and neutralizing epitopes of HIV-1 gp120/41. AIDS Res Hum Retroviruses 1994; 10:253.
  42. Ranki A, Kurki P, Riepponen S, Stephansson E. Antibodies to retroviral proteins in autoimmune connective tissue disease. Relation to clinical manifestations and ribonucleoprotein autoantibodies. Arthritis Rheum 1992; 35:1483.
  43. Poole BD, Gross T, Maier S, et al. Lupus-like autoantibody development in rabbits and mice after immunization with EBNA-1 fragments. J Autoimmun 2008; 31:362.