U1 RNA induces innate immunity signaling

Hoffman, Robert W.; Gazitt, Tal; Foecking, Mark F.; Ortmann, Robert A.; Misfeldt, Michael L.; Jorgenson, Rebecca L.; Young, Steven L.; Greidinger, Eric L.

doi:10.1002/art.20428

Cited by 66 publications

(54 citation statements)

References 16 publications

(16 reference statements)

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“…However, the 70K-immunized mice were much more likely to develop histologic evidence of MCTD-like lung disease, as determined by blinded histopathologic review, than the MaBP-immunized mice ( Based on prior findings that U1 RNA could potentially induce proimmune signals similarly to CFA (14), and given that U1 RNA would be expected to bind to both intact and apoptotic forms of 70K in vivo (21), we tested whether U1 RNA could substitute for CFA in our model. In parallel, 5 female mice between 8 and 12 weeks of age each were immunized with 50 g of the p205 form of 70K along with either 50 g of U1 RNA in (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…U1 RNA was produced by in vitro transcription of an Sp64 plasmid (Promega, Madison, WI) containing a 165-base insert corresponding to the sequence of human U1 RNA, as previously described (14). U1 RNA was tested with a Limulus assay (Cambrex BioScience, Baltimore, MD) to confirm the absence of endotoxin contamination.…”

Section: Methodsmentioning

confidence: 99%

“…The RNA component of the U1 snRNP particle, U1 RNA, which has previously been found to act as a Toll-like receptor 3 (TLR-3) agonist (14), was able to substitute for Freund's complete adjuvant (CFA) in the induction of MCTD-like autoimmunity. However, in mice deficient in TLR-3, U1 RNA exposure induced SLE-like GN rather than MCTD-like manifestations.…”

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confidence: 99%

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A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

Greidinger¹,

Zang²,

Jaimes³

et al. 2006

Arthritis & Rheumatism

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Objective. To test whether immunizing mice with autoantigens closely linked to mixed connective tissue disease (MCTD) could induce an MCTD-like clinical syndrome distinguishable from systemic lupus erythematosus (SLE).Methods. Transgenic and knockout C57BL/6-derived mice were immunized subcutaneously at age 8-12 weeks with U1-70-kd small nuclear RNP (70K) fusion protein along with either Freund's complete adjuvant (CFA) or U1 RNA. After 2 months, mice were killed and analyzed histologically and serologically. Mixed connective tissue disease (MCTD) is a systemic autoimmune syndrome characterized by antibodies to components of the U1 small nuclear RNP (U1 snRNP), whose clinical manifestations partly overlap those seen in systemic lupus erythematosus (SLE) (1). In contrast to lupus, though, major end organ manifestations, including glomerulonephritis (GN), are not typical features of MCTD. Rather, lung disease, an uncommon manifestation of SLE, is the leading cause of death in MCTD (2). While animal models involving anti-RNP autoantibodies have been previously described (3-7), these models have either demonstrated no clinical disease or manifested double-stranded DNA (dsDNA) antibodies and GN, and thus have not been models of the distinctive features of MCTD.Recent evidence has suggested that components of the U1 snRNP complex may participate directly in provoking the anti-RNP responses seen in MCTD. Autoantibodies in MCTD recognize intact and apoptotically modified forms of individual U1 snRNP proteins (8,9), and frequently also recognize structures composed of multiple subunits of the U1 snRNP macromolecule (10). Moreover, anti-RNP antibodies have been found to interact with lung tissue in ways that could mediate MCTD lung pathology (11). In a small series of mice, we have previously found that direct immunization of a Dr.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

Greidinger¹,

Zang²,

Jaimes³

et al. 2006

Arthritis & Rheumatism

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“…Consistent with the possibility that altered TLR-signalling promotes the generation of anti-nuclear antibodies in these mice, congenic B cells demonstrated hyper-responsiveness to poly(I:C), a dsRNA analogue and TLR3 ligand. These results are intriguing and suggest a novel mechanism for how inappropriate TLR signalling contributes to lupus autoimmunity.B cells normally proliferate and exhibit enhanced survival in response to signalling through the nucleic acid sensing TLRs [15,[17][18][19]. Recently it has been shown that TLR7 overexpression in mice bearing the Y autoimmune accelerator (Yaa) or a TLR7 Tg leads to increased B-cell proliferation in response to TLR7 ligands in vitro and promotes the differentiation of B cells into anti-RNA antibody-producing cells that augments lupus-like autoimmunity in vivo [20,21].…”

mentioning

confidence: 99%

“…SnRNP complexes are composed of RNPs and RNAs, including, U1-70kd RNP and its ligand, U1 RNA. Recently, U1 RNA has been shown to mimic the effects of poly(I:C), as it forms a double-stranded secondary structure that can elicit TLR3 activation [18]. Thus, autoreactive BCR recognition of this antigen could potentially stimulate TLR3 and specifically promote antiSm/RNP reactive B-cell survival and differentiation to antibodyproducing cells.…”

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An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

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Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including hightitre anti-chromatin antibody production, abnormal B-and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. Keywords: Autoimmunity . B cells . TLRs Supporting Information available online IntroductionSystemic lupus erythematosus is a chronic autoimmune disorder characterized by the production of antibodies directed against nuclear antigens (ANAs). Similar to human lupus, the New Zealand Black (NZB) mouse produces antibodies directed against nuclear antigens, develops Coomb's positive hemolytic anaemia, and exhibits a number of phenotypic and functional B-cell abnormalities (reviewed in [1]). Although glomerulonephritis is mild in these mice, severe nephritis develops when the NZB background is crossed onto a permissive MHC haplotype (H-2 bm12 ), indicating that this mouse possesses a full complement of non-MHC lupus susceptibility genes [2].Generation of congenic mice, by introgression of homozygous chromosomal intervals from the NZB mouse strain onto a normal mouse C57BL/6 (B6) background, has been a particularly useful technique for characterizing susceptibility loci and their role in disease genesis [3]. In our mapping study of (B6 Â NZB) F 2 mice, we identified a locus on NZB chromosome (c) 13 that was linked to increased B-cell activation and abnormal IgM production [4]. To further characterize this locus, we generated congenic mice with an NZB c13 interval (denoted B6.NZBc13). B6.NZBc13 mice spontaneously developed autoimmunity characterized by hightitre IgM and IgG anti-chromatin antibody production, increased 527T-cell activation, expansion of DCs, and the development of mild glomerulonephritis [5]. Moreover, as predicted from our mapping study, B6.NZBc13 mice closely recapitulated the abnormal polyclonal B-cell activation and B-cell subset distribution...

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RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via toll‐like receptor 3

Brentano

Schorr

Kyburz

2005

Arthritis & Rheumatism

324

291

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Objective. To assess the expression of Toll-like receptor 3 (TLR-3) protein in synovial tissues and cultured synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to investigate the consequences of stimulation of cultured synovial fibroblasts with TLR-3 ligands.Methods. TLR-3 expression in synovial tissues was determined by immunohistochemistry and immunofluorescence, and expression in cultured RA synovial fibroblasts (RASFs) was determined by fluorescenceactivated cell sorting and real-time polymerase chain reaction techniques. TLR-3 signaling was assessed by incubating RASFs with poly(I-C), lipopolysaccharide, palmitoyl-3-cysteine-serine-lysine-4, or necrotic synovial fluid cells from RA patients in the presence or absence of hydroxychloroquine or Benzonase. Subsequent determination of interferon-␤ (IFN␤), CXCL10, CCL5, and interleukin-6 (IL-6) protein production in the culture supernatants was performed by enzyme-linked immunosorbent assays.Results. TLR-3 protein expression was found to be higher in RA synovial tissues than in OA synovial tissues. TLR-3 expression was localized predominantly in the synovial lining, with a majority of the TLR-3-expressing cells coexpressing fibroblast markers.

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U1 RNA induces innate immunity signaling

Cited by 66 publications

References 16 publications

A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via toll‐like receptor 3

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