Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis

Fc, Arnett; Jd, Reveille; Goldstein, Rose; Pollard, K. Michael; Leaird, K; Ea, Smith; Ec, LeRoy; Mj, Fritzler

doi:10.1002/art.1780390712

Cited by 168 publications

(161 citation statements)

References 47 publications

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“…Nucleolar staining has been observed in 8-48% of SSc patient sera (6-10), 12-52% of which have been positive for anti-U3 RNP antibodies (6,9,12,13,27,29). Anti-U3 RNP antibodies have been detected in 5-8% of all SSc patients (7,9,(12)(13)(14). Positivity for these antibodies should be suspected in SSc patients with a nucleolar-only staining pattern.…”

Section: Discussionmentioning

confidence: 99%

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Anti–U3 RNP autoantibodies in systemic sclerosis

Aggarwal

Lucas

Fertig

et al. 2009

Arthritis & Rheumatism

134

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Objective. To describe the classification, demographic and clinical features, and survival in anti-U3 RNP autoantibody-positive patients with systemic sclerosis (SSc).Methods. Results. The anti-U3 RNP-positive group had a higher proportion of African American patients (27% versus 5%; P < 0.001) and male patients (29% versus 19%; P ‫؍‬ 0.021), and was younger at the time of first physician diagnosis (mean age 42.8 years versus 47.4 years; P ‫؍‬ 0.001). The 2 groups had similar proportions of patients with diffuse cutaneous involvement (47% and 45% in those with and those without anti-U3 RNP, respectively). However, among patients with diffuse cutaneous involvement, the mean maximum modified Rodnan skin score was significantly lower in the anti-U3 RNP group (22.3 versus 27.9; P < 0.001). Skeletal muscle involvement was more frequent in anti-U3 RNP-positive patients (25% versus 14%; P ‫؍‬ 0.002), as was "intrinsic" pulmonary arterial hypertension (PAH) (31% versus 13%; P < 0.001). The frequency of gastrointestinal involvement, cardiac involvement, pulmonary fibrosis, and "renal crisis" did not differ significantly between the 2 groups. Survival was worse in the anti-U3 RNP-positive group (hazard ratio 1.38 [95% confidence interval 1.05-1.82]). PAH was the most common known cause of death in patients with anti-U3 RNP (30%, versus 10% in the anti-U3 RNP-negative group; P < 0.001).Conclusion. The present findings demonstrate that the frequencies of African American race and male sex are greater among SSc patients with anti-U3 RNP antibody than those without, and the former group is younger at SSc diagnosis. Anti-U3 RNP-positive patients have more frequent skeletal muscle involvement and PAH, the latter being the most common cause of death.

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Section: Discussionmentioning

confidence: 99%

“…Antinucleolar antibodies have been detected in 10-15% of SSc patients in different studies (6)(7)(8)(9)(10), and anti-U3 RNP antibody (11) has been previously reported to occur in 5-8% of patients (7,9,(12)(13)(14). Clinical features and prognosis associated with anti-U3 RNP antibodies are not well characterized.…”

mentioning

confidence: 99%

Anti–U3 RNP autoantibodies in systemic sclerosis

Aggarwal

Lucas

Fertig

et al. 2009

Arthritis & Rheumatism

134

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“…Other putative autoantigens that elicit autoantibody responses in patients with SSc include fibrillarin (142), centromere (121), RNA polymerases I, II, and III (1,120), and other nucleolar autoantigens (143). Antifibrillarin antibodies are found in 33% of men with SSc and in 14% of women with SSc and are associated with the HLA-DQB1*0604 and DRB1*1302 haplotypes (142).…”

Section: Putative T Cell Antigens In Sscmentioning

confidence: 99%

Is systemic sclerosis an antigen‐driven T cell disease?

Sakkas¹,

Platsoucas²

2004

Arthritis & Rheumatism

112

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Section: Introductionmentioning

confidence: 99%

“…The factors triggering the formation of autoreactive B cells against nuclear proteins are still unknown, but genetic, hormonal, and environmental components are involved. A valuable model to study molecular mechanisms of systemic autoimmune responses is mercuryinduced autoimmunity: Chronic administration of mercuric chloride (HgCl 2 ) to susceptible H-2 s mice generates a specific immune response against the nucleolar protein fibrillarin (Hultman et al, 1989;Reuter et al, 1989), which is also a target of antinuclear autoantibodies (ANA) produced by a subset of patients with systemic sclerosis (Arnett et al, 1996).Fibrillarin is a 34-kDa protein that derives its name from its localization to both the fibrillar center (FC) and dense fibrillar component (DFC) of the nucleolus (Ochs et al, 1985). The nucleolus constitutes a highly dynamic substructure of the nucleus that forms around ribosome production (Scheer and Hock, 1999;Lewis and Tollervey, 2000;Carmo-Fonseca et al, 2001).…”

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confidence: 99%

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

Chen

Rockel

Steinweger

et al. 2002

MBoC

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A prerequisite for proteins to interact in a cell is that they are present in the same intracellular compartment. Although it is generally accepted that proteasomes occur in both, the cytoplasm and the nucleus, research has been focusing on cytoplasmic protein breakdown and antigen processing, respectively. Thus, little is known on the functional organization of the proteasome in the nucleus. Here we report that within the nucleus 20S and 26S proteasomes occur throughout the nucleoplasm and partially colocalize with splicing factor-containing speckles. Because proteasomes are absent from the nucleolus, a recruitment system was used to analyze the molecular fate of nucleolar protein fibrillarin: Subtoxic concentrations of mercuric chloride (HgCl 2 ) induce subcellular redistribution of fibrillarin and substantial colocalization (33%) with nucleoplasmic proteasomes in different cell lines and in primary cells isolated from mercury-treated mice. Accumulation of fibrillarin and fibrillarin-ubiquitin conjugates in lactacystin-treated cells suggests that proteasome-dependent processing of this autoantigen occurs upon mercury induction. The latter observation might constitute the cell biological basis of autoimmune responses that specifically target fibrillarin in mercury-mouse models and scleroderma. INTRODUCTIONThe bulk of nonlysosomal proteolysis is carried out by the ATP-powered 26S proteasome, which is involved in the regulation of major cellular processes such as progression of the cell cycle, transcription, flux of substrates through metabolic pathways, elimination of abnormal proteins, and antigen processing (Hershko and Ciechanover, 1998;Kloetzel, 2001). In most cultured mammalian cells 80 -90% of the protein breakdown occurs by the proteasome pathway (Lee and Goldberg, 1998). The 26S proteasome is composed of two distinct subcomplexes: the central 20S proteasome, in which proteins are degraded, and two flanking 19S complexes, which provide substrate specificity and regulation. The 20S proteasome forms the core subunit harboring multiple catalytic centers located within the hollow cavity of a cylinder (Finley, 2002). This topology sequesters the catalytic sites from potential substrates (Voges et al., 1999). Most of the substrates of the eukaryotic 26S proteasome must be marked by ubiquitination in order to be destroyed. This involves the covalent attachment of multiple ubiquitin molecules to the target protein (Ciechanover, 1998). However, exceptions to the rule such as ornithine decarboxylase (ODC), which is degraded by the 26S proteasome without ubiquitinylation are known, and more are currently under investigation (Murakami et al., 1992;Verma and Deshaies, 2000).Proteasomes generate oligopeptides, most of which are further degraded by distinct endopeptidases and aminopeptidases into amino acids. However, a fraction of these peptides escape complete destruction and are subjected to antigen presentation. The peptides are transported to the endoplasmic reticulum via the transporter associated with antigen pre...

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Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis

Cited by 168 publications

References 47 publications

Anti–U3 RNP autoantibodies in systemic sclerosis

Anti–U3 RNP autoantibodies in systemic sclerosis

Is systemic sclerosis an antigen‐driven T cell disease?

Subcellular Recruitment of Fibrillarin to Nucleoplasmic Proteasomes: Implications for Processing of a Nucleolar Autoantigen

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