Anti-RNP immunity: Implications for tissue injury and 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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Integrated Diagnosis Project for Inflammatory Myopathies: An association between autoantibodies and muscle pathology
2017, Autoimmunity ReviewsCitation Excerpt :Anti-U1RNP, anti-PM/Scl and anti-Ku antibodies are detectable in mixed connective tissue disease (MCTD) or overlap connective tissue disease syndrome [65,66]. The presence of antibodies against U1RNP is considered the serological hallmark of MCTD [67]. In animal models, the immunization with U1RNP led to MCTD-like features, suggesting that exposure to U1RNP in a susceptible background is the key factor to induce autoimmunity and target organ injury consistent with MCTD.
Anti-centromere protein A antibodies in systemic sclerosis: Significance and origin
2016, Autoimmunity ReviewsCitation Excerpt :Immune system activation in SSc is demonstrated by the increase of B-cell activation markers [10,11], by the ability of fibroblasts to trigger an oligoclonal T-cell response in the early stage of the disease [3,12], and by the expression of antinuclear antibodies (ANA) [2,13]. ANA are found in the sera of more than 95% of SSc patients, but their antigenic specificity varies with the clinical characteristics of the disease (Table 1) [13–84]. The most frequently targeted autoantigens are alpha-topoisomerase, in 15%–40% of patients, and the centromere proteins (CENPs) [14], mainly protein A (CENP-A) and protein B (CENP-B), in 20%–40% of patients.
Derailed B cell homeostasis in patients with mixed connective tissue disease
2013, Human ImmunologyAutoantibodies in systemic sclerosis
2013, Autoimmunity ReviewsCitation Excerpt :Anti-U1RNP antibodies bind to small ribonucleoprotein (snRNP), a ribonuclease-sensitive macromolecular complex that is involved in splicing heterogeneous nuclear RNA into mRNA [159]. Anti-U1RNP is found in ~ 90% of mixed connective tissue disease sera whereas the prevalence in SSc is approximately 6% (range 2–14%) [10,35,37,54,160,161]. Anti-U1RNP antibodies are generally associated with overlap syndromes and are much more frequent among lcSSc patients compared to those with dcSSc [162].
Pulmonary manifestations of Sjögren's syndrome
2011, Presse MedicaleCitation Excerpt :Interstitial lung disease is also more frequently found in pSS-associated PH (26 vs. 9% in patients without PH) [111]. Patients with pSS-associated PH have significantly more frequently antinuclear, anti-Ro/SSA and anti-RNP antibodies as well as positive rheumatoid factor and hypergammaglobulinemia than pSS patients without PH. These immunological findings could suggest both an activation of B cells and a role of autoantibodies, such as anti-RNP antibodies [139], or other antibodies, such as anti-endothelial cell antibodies [140] in the pathogenesis of pSS-associated PAH. In conclusion, PH is a rare but quite severe complication of pSS, which should be searched for in cases of unexplained dyspnea, and/or syncope.
Newborn Illnesses Caused by Transplacental Antibodies
2008, Advances in PediatricsCitation Excerpt :SSA/Ro (52 and 60 kD isotypes) and SSB/La (48 kD) form ribonucleoprotein complexes with various untranslated RNAs that regulate cellular growth [101]. U1-RNP antigens bind U1-RNA to form small nuclear ribonucleoprotein complexes that regulate nuclear mRNA splicing [93]. The U1-RNP, SSA/Ro, and SSB/La antigens are transported to keratinocyte cell surfaces after sublethal UV light exposure [102].
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