Spontaneous Occurrence of Anti-Fibrillin-1 Autoantibodies in Tight-Skin Mice

Murai, Chihiro; Saito, Shinichiro; Kasturi, Kuppuswamy N.; Bona, Constantin A.

doi:10.3109/08916939808996283

Cited by 61 publications

(44 citation statements)

References 13 publications

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“…Although homozygous mice die in utero, heterozygous (TSK/ϩ) mice survive, but develop cutaneous fibrosis. TSK/ϩ mice produce autoantibodies against SSc-specific target autoantigens, including topoisomerase I, fibrillin 1, and RNA polymerase I (7)(8)(9). Although a tandem duplication within the fibrillin 1 gene and the production of a large fibrillin 1 protein are found in TSK/ϩ mice (10 -12), the role of the fibrillin 1 gene in the genesis of tissue hyperplasia and autoimmunity remains unsolved.…”

Section: S Ystemic Sclerosis (Ssc)mentioning

confidence: 99%

Intercellular Adhesion Molecule-1 Deficiency Attenuates the Development of Skin Fibrosis in Tight-Skin Mice

Matsushita

Hasegawa

Matsushita

et al. 2007

The Journal of Immunology

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The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis, develops cutaneous fibrosis. Although a fibrillin 1 gene mutation and immunological abnormalities have been demonstrated, the roles of adhesion molecules have not been investigated. To directly assess roles of adhesion molecules in skin fibrosis, TSK/+ mice lacking L-selectin and/or ICAM-1 were generated. The deficiency of ICAM-1, but not L-selectin, significantly suppressed (∼48%) the development of skin sclerosis in TSK/+ mice. Similarly, ICAM-1 antisense oligonucleotides inhibited skin fibrosis in TSK/+ mice. Although T cell infiltration was modest into the skin of TSK/+ mice, ICAM-1 deficiency down-regulated this migration, which is consistent with the established roles of endothelial ICAM-1 in leukocyte infiltration. In addition, altered phenotype or function of skin fibroblasts was remarkable and dependent on ICAM-1 expression in TSK/+ mice. ICAM-1 expression was augmented on TSK/+ dermal fibroblasts stimulated with IL-4. Although growth or collagen synthesis of TSK/+ fibroblasts cultured with IL-4 was up-regulated, it was suppressed by the loss or blocking of ICAM-1. Collagen expression was dependent on the strain of fibroblasts, but not on the strain of cocultured T cells. Thus, our findings indicate that ICAM-1 expression contributes to the development of skin fibrosis in TSK/+ mice, especially via ICAM-1 expressed on skin fibroblasts.

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Section: S Ystemic Sclerosis (Ssc)mentioning

confidence: 99%

Intercellular Adhesion Molecule-1 Deficiency Attenuates the Development of Skin Fibrosis in Tight-Skin Mice

Matsushita

Hasegawa

Matsushita

et al. 2007

The Journal of Immunology

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“…These autoantibodies were detected with a recombinant peptide expressing the proline-rich region of fibrillin-1 (12,13). Interestingly, the tsk mouse also has been found to produce anti-fibrillin Abs as well (15). Therefore, we tested the hypothesis that affinity-purified human autoantibodies to fibrillin-1 from SSc patients might induce activation of normal human dermal fibroblasts using microarray screening of ECM gene expression profiles and quantitative RT-PCR, immunoblotting, and immunohistochemistry assays of certain ECM components known to play important roles in the profibrotic phenotype of the SSc fibroblast.…”

Section: S Cleroderma or Systemic Sclerosis (Ssc)mentioning

confidence: 99%

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Zhou

Tan

Milewicz

et al. 2005

The Journal of Immunology

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Fibroblasts from patients with systemic sclerosis (SSc) are activated producing excessive amounts of extracellular matrix (ECM) components. Recently, we identified a new SSc-specific autoantibody against portions of fibrillin-1, a major component of ECM microfibrils and regulator of TGF-β1 signaling. To examine a potential pathogenic role of anti-fibrillin-1 autoantibodies, normal human fibroblasts were treated with affinity-purified autoantibodies isolated from SSc sera and then examined for alterations in gene and protein expression levels using microarrays, quantitative RT-PCR, immunoblots, and immunofluorescence. Compared with fibroblasts cultured in normal medium or in medium containing normal human IgG, anti-fibrillin-1 autoantibody-treated normal dermal fibroblasts showed increased expression of COL and several other ECM components characteristically overexpressed in SSc fibroblasts. This was accompanied by phosphorylation and nuclear translocation of Smad3. Neutralization of TGF-β1 with anti-TGF-β1 Abs significantly diminished the activation of fibroblasts by anti-fibrillin-1 autoantibodies. These data indicate that anti-fibrillin-1 autoantibodies can induce the activation of normal dermal fibroblasts into a profibrotic phenotype resembling that of SSc by potentially causing the release of sequestered TGF-β1 from fibrillin-1-containing microfibrils in the ECM.

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“…The recombinant human Fbn-1 peptide (rFbn-1) was generated from pET-3xa E.coli expression vector kindly provided by Dr F. Ramirez (Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, NY, USA) and purified from bacterial lysates as previously described [15]. rFbn-1 is a 30 kDa fragment which contains the proline rich C region (aa 395-446) of Fbn-1 protein.…”

Section: Autoantigensmentioning

confidence: 99%