Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies

Harris, Michelle L.; Rosen, Antony

doi:10.1097/00002281-200311000-00016

Cited by 80 publications

(66 citation statements)

References 48 publications

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“…T lymphocytes have been shown to affect the synthesis of anti-DNA topoisomerase antibodies, other autoantibodies and accumulation of B lymphocytes in skin lesions. This confirms the hypothesis that interactions between T and B lymphocytes are likely to play a significant role in the pathogenesis of systemic sclerosis (7,27). The cause of lymphocyte activation in systemic sclerosis is not known.…”

Section: The Role Of T Lymphocytes In Sscsupporting

confidence: 84%

Apoptosis of T Lymphocytes in Systemic Sclerosis

Szymanek¹,

Chodorowska²,

Pietrzak³

et al. 2012

Systemic Sclerosis - An Update on the Aberrant Immune System and Clinical Features

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Section: The Role Of T Lymphocytes In Sscsupporting

confidence: 84%

Apoptosis of T Lymphocytes in Systemic Sclerosis

Szymanek¹,

Chodorowska²,

Pietrzak³

et al. 2012

Systemic Sclerosis - An Update on the Aberrant Immune System and Clinical Features

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“…They are present in up to 90% of SSc patient sera and are generally associated with specific SSc subtypes (35)(36)(37). However, their role in the pathogenesis of SSc is still unclear, and few studies have directly addressed this subject (for review, see ref.…”

Section: Discussionmentioning

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

106

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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: S Ystemic Sclerosis (Ssc)mentioning

confidence: 99%

“…The type of autoantibody found in the patient's serum clearly correlates with the disease phenotype and is often used as a diagnostic tool to differentiate SSc from other connective tissue diseases (3,4,7,22). For example, patients with diffuse SSc tend to have Abs against topoisomerase I, RNA-polymerases, or U3 RNPs including fibrillarin (3,4,7,22). Anti-topoisomerase I Abs are the most frequently observed autoantibodies in these patients and are associated with pulmonary fibrosis and cardiac involvement (3,4,7,(22)(23)(24)(25)(26).…”

Section: S Ystemic Sclerosis (Ssc)mentioning

confidence: 99%

Demonstration of Autoimmunity in the Tight Skin-2 Mouse: A Model for Scleroderma

Gentiletti

McCloskey

Artlett

et al. 2005

The Journal of Immunology

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The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of systemic sclerosis (SSc) because this animal exhibits increased collagen synthesis and accumulation in the dermis. The Tsk2/+ mouse also has been reported to have a mononuclear cell infiltrate in the dermis; however, to date no evidence of autoimmunity has been described in this animal model. We report here that Tsk2/+ mice harbor numerous autoantibodies in their plasma including some, which are similar to those, present in SSc patients. Immunofluorescence with HEp-2 cells revealed the presence of anti-nuclear Abs (ANAs) in the plasma of 92% of the Tsk2/+ mice. In contrast, <5% of cage-mated CAST/ei mice had a positive ANA and none of the C3H/HeJ age-matched controls were positive. Homogenous, speckled, rim, nucleolar, centromere as well as combinations of these patterns were observed. The proportion of Tsk2/+ animals with a positive ANA increased slightly with age. ELISAs showed that 93% of the Tsk2/+ animals were positive for anti-Scl70, 82% for anti-centromere, 5% for anti-RNP/Sm, and none were positive for anti-RNA-polymerase II Abs. Indirect immunofluorescence with Crithidia luciliae and ELISA for anti-dsDNA Abs showed that 76% of Tsk2/+ mice were positive for this autoantibody. The high frequency of anti-Scl70 and anti-centromere autoantibodies indicates that Tsk2/+ mice display some humoral immune alterations which are similar to those found in patients with SSc. However, the Tsk2/+ mice also develop autoantibodies to dsDNA and a majority of the mice develop multiple autoantibody specificities (anti-Scl70, anti-CENP-B, and anti-dsDNA) indicating that the mouse may be a useful model to study autoimmunity in a wider spectrum of connective tissue diseases.

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Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies

Cited by 80 publications

References 48 publications

Apoptosis of T Lymphocytes in Systemic Sclerosis

Apoptosis of T Lymphocytes in Systemic Sclerosis

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

Demonstration of Autoimmunity in the Tight Skin-2 Mouse: A Model for Scleroderma

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