Elsevier

Autoimmunity Reviews

Volume 6, Issue 4, March 2007, Pages 232-236
Autoimmunity Reviews

Anti-RNP immunity: Implications for tissue injury and the pathogenesis of connective tissue disease

https://doi.org/10.1016/j.autrev.2006.08.007Get rights and content

Abstract

Certain autoantibodies are characteristic of autoimmune disease manifestations and contribute to organ pathology. The presence of high-titer antibodies to U1-RNP are associated with mixed connective tissue disease, although these antibodies may also be present in systemic lupus erythematosus and systemic sclerosis. However, the role of antibodies to U1-RNP in the pathogenesis of connective tissue disease remains unclear. Data from recent experimental studies promote the hypothesis that U1-RNP antibodies participate in both innate and adaptive immune responses, implicating them in the pathogenesis of connective tissue disease.

Introduction

Autoantibodies are the hallmark of many autoimmune diseases. Antibodies to U1-ribonuclear protein (U1-RNP) in high-titer are associated with mixed connective tissue disease (MCTD) [1]. These antibodies are not disease specific, however, and sometimes are present in systemic lupus erythematosus (SLE) and less commonly systemic sclerosis (SSc). Compared to the pathogenic role of dsDNA antibodies in lupus nephritis [2], the role of antibodies to U1-RNP in disease pathogenesis is less certain.

Despite the fact that anti-U1-RNP antibodies are present in patients with SLE and MCTD, the clinical features in these two diseases may differ. For example, severe pulmonary vascular disease occurs more frequently in MCTD compared to SLE [3]. It is possible that anti-U1-RNP antibody participates in disease pathogenesis through different, yet uncharacterized, mechanisms in MCTD and SLE.

To facilitate the discussion, a brief review of the U1-RNP antigens is in order. U1-RNP is a nuclear protein–RNA complex that is important in the processing of mRNA [4]. It is composed of U1-RNA, containing a partially double-stranded secondary structure, and proteins that are specific to the U1-RNP complex including U1-A, U1-C, and U1-70kDa [4]. Other proteins may be associated with U1-RNP, such Sm, but these are not specific to the U1-RNP complex [4].

The 70kDa protein is one of the major determinants in the antibody response to U1-RNP. Anti-70kDa antibodies often develop early in the U1-RNP antibody response and contribute to the development of antibodies against other proteins of the U1-RNP complex through the so-called epitope spreading [5]. Cellular events such as apoptosis or oxidation may lead to the development of modified autoantigens and distinct antibodies to modified forms of U1-70kDa have been described and are clinically relevant [6]. It is not currently known, however, if antibodies to U1-RNP antigens are directly involved in disease pathogenesis.

Herein we briefly review aspects of U1-RNP immunity likely to be involved in disease pathogenesis. Proposals for future research are discussed in the context of complement-mediated tissue injury.

Section snippets

Clinical associations of anti-U1-RNP antibodies

The U1-70kDa antigen appears to drive the immune response leading to the onset of SLE and MCTD. U1-70kDa has been shown to be a common initial target of the anti-U1-RNP response with subsequent epitope spreading resulting in the production of antibodies to other protein targets within the U1RNP complex [5]. Moreover, antibodies to U1-RNP were found in 26% of a cohort of SLE patients prior to the onset of clinical illness and this antibody frequently appeared within 1 year of disease onset [7].

Cellular effects of U1-RNP antibodies

Antibodies to U1-RNP interact with both mononuclear and endothelial cells. These interactions provide multiple putative pathways for the mediation of tissue injury by U1-RNP antibodies in connective tissue disease.

Anti-U1-RNP antibodies up-regulate inflammatory cytokine production by mononuclear cells. Supernatants of monocytes from MCTD patients show increased basal levels of IL-1 and IL-6 compared to monocytes from healthy individuals [14]. Exposure of these cells to purified U1-RNP antibody

Toll-like receptors (TLR) and lymphocyte epitopes in animal models of U1-70kDa disease

The study of U1-RNP immunity in animal models has produced important insights on pathogenic mechanisms in U1-RNP antibody-mediated disease. Components of the innate and adaptive immune systems interact with epitopes of the U1-RNP complex. The study of these interactions has given insight into pathogenic mechanisms of human connective tissue diseases.

TLR serve as pattern-recognition receptors in mammals and when activated up-regulate the production of inflammatory cytokines and co-stimulatory

Future directions

Both U1-RNA and antibodies to U1-RNP have multiple effects on the innate and adaptive immune responses, implicating them in the pathogenesis of connective tissue disease. The complement system is another pathway through which these antibodies could potentially mediate tissue injury with resultant expression of disease. Studies of mesenteric ischemia–reperfusion (I/R) injury have yielded insights into how complement may participate in tissue injury in autoimmune diseases.

In mesenteric I/R

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