Is Anti-Topoisomerase I a Serum Marker of Pulmonary Involvement in Systemic Sclerosis?

Diot, Élisabeth; Giraudeau, Bruno; Diot, Patrice; Degenne, Danielle; Ritz, Laurence; Guilmot, J.-L.; Lemarié, É.

doi:10.1378/chest.116.3.715

Cited by 48 publications

(34 citation statements)

References 26 publications

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“…First, anti-topo I autoantibodies are associated with a more severe SSc phenotype, notably, pulmonary fibrosis (8,(41)(42)(43)(44). Second, in patients with anti-topo I, these antibodies are almost invariably present very early in the disease course (43).…”

Section: Discussionmentioning

confidence: 99%

“…For example, anti-topo I are usually associated with more diffuse cutaneous SSc (4,5), whereas anti-CENP-B are detected predominantly in patients with limited cutaneous SSc (4,6,7). Also, anti-topo I are strongly associated with pulmonary fibrosis in SSc (6,8), while pulmo-nary arterial hypertension is more common in patients with anti-CENP-B (9). In spite of the prevalence of ANAs and their association with different SSc subsets and selective visceral involvement, their direct or indirect role in the pathophysiology of SSc is still unclear.…”

Section: Second Topo I-anti-topo I Complex Binding Can Then Trigger mentioning

confidence: 99%

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DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients

Hénault¹,

Robitaille²,

Senécal³

et al. 2006

Arthritis & Rheumatism

109

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Objective. Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis due to excessive and dysregulated collagen production by fibroblasts. Previously, we reported that anti-DNA topoisomerase I (anti-topo I) antibodies bound specifically to fibroblast surfaces; however, we had not identified their antigenic target. We undertook this study to characterize the target of anti-topo I antibodies on fibroblasts and the effects of their binding.Methods. Purified topo I or topo I released from apoptotic cells was tested for surface binding to a number of human cell types by cell-based enzyme-linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. Antibodies purified from SSc patient and normal control sera were used to detect topo I binding. The consequences of topo I and anti-topo I binding to fibroblasts were assessed by coculture with THP-1 monocytes.Results. The autoantigen topo I itself was found to bind specifically to fibroblasts in a dose-dependent and saturable manner, where it was recognized by anti-topo I from SSc patients. The binding of anti-topo I subsequently stimulated adhesion and activation of cocultured monocytes. Topo I released from apoptotic endothelial cells was also found to bind specifically to fibroblasts.Conclusion. The findings of this study thus confirm and extend the findings of our previous study by showing that topo I binding to fibroblast surfaces is both necessary and sufficient for anti-topo I binding. Second, topo I-anti-topo I complex binding can then trigger the adhesion and activation of monocytes, thus providing a plausible model for the amplification of the fibrogenic cascade in anti-topo I-positive SSc patients.

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Section: Discussionmentioning

confidence: 99%

Section: Second Topo I-anti-topo I Complex Binding Can Then Trigger mentioning

confidence: 99%

DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients

Hénault¹,

Robitaille²,

Senécal³

et al. 2006

Arthritis & Rheumatism

109

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“…Studies suggest that more severe interstitial lung disease is a feature of diffuse scleroderma that is associated with antibodies against topoisomerase I (8,32). In contrast, limited scleroderma is associated with ACA and a higher prevalence of isolated pulmonary hypertension (8).…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension

Ulanet

Wigley

Gelber

et al. 2003

Arthritis & Rheumatism

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Objective. To determine whether the abundant nucleolar phosphoprotein B23 is a target of autoantibodies in scleroderma, and to examine the clinical phenotype associated with these antibodies. Methods. Ninety-two randomly selected scleroderma sera were screened by enzyme-linked immunosorbent assay against recombinant human B23. Demographic, clinical, and serologic parameters associated with B23 autoantibody status were examined. Results. We demonstrated that autoantibodies against B23 occur in ϳ11% of sera obtained from patients with scleroderma. B23 seropositivity was related to pulmonary hypertension, antifibrillarin antibody, anti-RNP antibody, and decreased lung capacity. In multivariate analysis, B23 autoantibodies remained strongly associated with moderate-tosevere pulmonary hypertension and antifibrillarin antibodies. Conclusion. These data unite B23 with the group of nucleolar autoantigens targeted in scleroderma and thus focus attention on changes in the nucleolus that render its components immunogenic in this disease. The demonstration that antibodies to B23 are associated with an increased prevalence of pulmonary hypertension points to anti-B23 antibodies as a possible marker of a specific phenotype in scleroderma.

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“…Autoantibodies to topoisomerase I are specific for SSc patients and are associated with diffuse skin involvement and pulmonary fibrosis (16,17).…”

Section: Discussionmentioning

confidence: 99%

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Zhou

Tan

Xiong

et al. 2001

The Journal of Immunology

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The pathogenesis of systemic sclerosis (SSc) involves complex interactions between activated fibroblasts eventually leading to fibrosis, and impaired immune tolerance characterized by a variety of circulating SSc-specific autoantibodies. The expression of autoantigens in fibroblasts, a key target tissue in SSc, may play an important role in this process. To obtain a global view of this process, we examined gene expression profiles of SSc dermal fibroblasts using cDNA microarrays. The results show that dermal fibroblasts from SSc patients obtained from either affected or unaffected skin displayed a characteristic pattern of increased SSc autoantigen gene expression compared with that from normal controls. In particular, fibrillarin (p = 0.028), centromeric protein B (p = 0.01), centromeric autoantigen P27 (p = 0.042), and RNA polymerase II (220 kDa; p = 0.02) were significantly overexpressed in SSc fibroblasts. Quantitative RT-PCR confirmed overexpression of these autoantigens and also revealed increased levels of DNA topoisomerase I transcripts in SSc fibroblasts compared with normal control fibroblasts (p = 0.0318). The polymyositis/scleroderma autoantigen gene was overexpressed in some SSc patients (p = 0.09). To examine the specificity of these overexpressed autoantigen genes for SSc and its tissue specificity for fibroblasts, cDNA microarrays of dermal fibroblasts from patients with eosinophilic fasciitis and scleromyxedema were studied as well as PBMC and muscle biopsies from SSc patients. None of these tissues showed significant alterations in gene expression of SSc-specific autoantigens. Therefore, SSc-associated autoantigen genes are selectively overexpressed in SSc dermal fibroblasts, a major tissue involved in disease pathogenesis.

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Is Anti-Topoisomerase I a Serum Marker of Pulmonary Involvement in Systemic Sclerosis?

Cited by 48 publications

References 26 publications

DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients

DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients

Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension

Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

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