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Anti-U1 RNP antibodies in mixed connective tissue disease

Robert M Bennett, MD, FRCP, MACR
Section Editor
Robert H Shmerling, MD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


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'.)


The development of an autoantibody-mediated disease is the result of a complex interaction between genetic and environmental factors. Because the cytosol and nucleoplasm need to be densely packed with a severe restriction on diffusion of macromolecules, partitioning of the eukaryote cell into functionally specialized compartments is essential for efficiency. This necessitates the association of RNA and protein into large ribonucleoprotein (RNP) complexes, including nucleosomes and spliceosomes [4]. There is compelling evidence that autoimmunity is often antigen-driven by these RNA-associated components of subcellular particles [5]. The U1-RNA component of U1 RNP is capable of activating toll-like receptors (TLRs); this early innate immune response may be a critical event in the initiation of autoimmunity to RNA protein complexes [6]. The innate immune response is often a mechanism whereby antigens are "focused" as a prelude to the T-cell recognition that is characteristic of adaptive immunity [7]. TLRs include molecules that recognize single-stranded DNA (TLR3) and double-stranded RNA (TLR7, TLR8). This may be of some relevance to U1 RNP autoimmunity, as U1-RNA 70 kD reactive T-cell clones preferentially recognize a residue within the RNA binding portion of the 70 kD peptide [8], and U1 RNA can induce an innate immune response [9].

Autoimmunity to nucleosomal components — Nucleosomes are the compact building blocks of chromatin and consist of an octamer of two copies of histones H2A, H2B, H3, and H4, wrapped around approximately 146 base pairs of DNA. During apoptosis, endonucleases cleave chromatin with the liberation of nucleosomal particles. Following the release into the cytoplasm, nucleosomes migrate to the surface of the dying cell [10] and thus become accessible to B-cell receptors. Nucleosomal antibodies are directed to antigenic determinants on the intact nucleosome rather than its individual components, DNA, and histones [4]. In a study of 496 patients with 13 different connective tissue diseases and of 100 patients with hepatitis C, antinucleosome antibodies were found only in the sera of patients with systemic lupus erythematosus (SLE), systemic sclerosis, and mixed connective tissue disease (MCTD) (72, 46, and 45 percent, respectively) [11].

Autoimmunity to spliceosomal components — Autoimmunity to specific components of the spliceosome is the immunological signature of MCTD. Spliceosomes are complex nuclear particles that are involved in the processing of pre-messenger RNA into mature "spliced RNA." The 26S proteasome is a large subcellular particle involved in the degradation of proteins that have been tagged with ubiquitin and the generation peptides for presentation by the major histocompatability complex (MHC) class I molecules [12]. Certain components of the spliceosome are common targets of autoimmunity in the diffuse connective tissue diseases (DCTDs). Furthermore, it appears that post-translational modifications of these molecules, as occur during apoptosis, are often associated with increased immunogenicity [13]. There are two major spliceosomal sub-units that are antigenic targets in autoimmunity: 1) small nuclear ribonucleoprotein protein particles (snRNPs); and 2) heterogeneous nuclear RNP particles (hnRNPs).

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Literature review current through: Nov 2017. | This topic last updated: Dec 04, 2017.
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