Immunological Characterization of (Tight Skin/NZB)F1 Hybrid Mice with Connective Tissue and Autoimmune Features Resembling Human Systemic Sclerosis

Bocchieri, Maureen H.; Christner, Paul J.; Henriksen, Paul D.; Jimenez, Sergio A.

doi:10.1006/jaut.1993.1029

Cited by 13 publications

(12 citation statements)

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“…Crosses placing the Tsk mutation on a CD4-deficient background revealed that skin fibrosis, but not lung fibrosis, was decreased; in contrast, a CD8-deficient background had no detectable effect on Tsk skin and lung fibrosis (Wallace et al 1994). Crosses making the Tsk mutation congenic on NZB, a strain prone to autoimmune disorders, exacerbates the fibrosis and autoimmune response (Bocchieri et al 1993). Adoptive transfer experiments with bone marrow and spleen cells from Tsk/+ mice showed that skin fibrosis could be partially replicated in the recipient animals, but the histopathology of lung disease could not (Walker et al 1989;Phelps et al 1993).…”

mentioning

confidence: 93%

The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

et al. 1998

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mentioning

confidence: 93%

The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

et al. 1998

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“…SSc skin fibroblasts have been demonstrated to produce higher amounts of collagen when compared with skin fibroblasts from healthy donors [12,13]. Similarly, increased collagen expression was found in an animal model of SSc [14]. …”

Section: Introductionmentioning

confidence: 99%

Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis

et al. 2014

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IntroductionVasculopathy, inflammatory fibrosis and functional autoantibodies (Abs) are major manifestations of systemic sclerosis (SSc). Abs directed against the angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) are associated with characteristic disease features including vascular, inflammatory, and fibrotic complications indicating their role in SSc pathogenesis. Therefore, the impact of anti-AT1R and anti-ETAR Abs on initiation of inflammation and fibrosis was analyzed.MethodsAnti-AT1R and anti-ETAR Ab-positive immunoglobulin G (IgG) from SSc patients (SSc-IgG) was used for experiments. Healthy donor IgG served as a normal control, and AT1R and ETAR activation was inhibited by antagonists. Protein expression was measured with ELISA, mRNA expression with real time-PCR, endothelial repair with a scratch assay, and collagen expression with immunocytochemistry. Transendothelial neutrophil migration was measured with a culture insert system, and neutrophil ROS activation with immunofluorescence. Neutrophils in bronchoalveolar lavage fluids (BALFs) were analyzed microscopically after passive transfer of SSc-IgG or NC-IgG into naïve C57BL/6J mice. KC plasma levels were quantified by a suspension array system. Histologic analyses were performed by using light microscopy.ResultsAnti-AT1R and anti-ETAR Ab-positive SSc-IgG induced activation of human microvascular endothelial cells (HMEC-1). Elevated protein and mRNA levels of the proinflammatory chemokine interleukin-8 (IL-8, CXCL8) and elevated mRNA levels of the vascular cell adhesion molecule-1 (VCAM-1) were induced in HMEC-1. Furthermore, activation of HMEC-1 with SSc-IgG increased neutrophil migration through an endothelial cell layer and activation of reactive oxygen species (ROS). SSc-IgG decreased HMEC-1 wound repair and induced type I collagen production in healthy donor skin fibroblasts. Effects of migration, wound repair, and collagen expression were dependent on the Ab-levels. Passive transfer of anti-AT1R and anti-ETAR Ab-positive SSc-IgG into naïve C57BL/6J mice increased neutrophil BALF counts. In parallel, increased levels of the murine functional IL-8 homologue, chemokine KC, were found in the plasma of SSc-IgG-treated mice as well as structural alterations of the lungs.ConclusionsWe conclude that angiotensin and endothelin-receptor activation via anti-AT1R and anti-ETAR Abs mediate pathogenic effects, indicating their contribution to pathogenesis of SSc. Therefore, anti-AT1R and anti-ETAR Abs could provide novel targets for therapeutic intervention in the treatment of SSc.

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“…However, immune dysregulation appears to occur subsequent to the development of tissue fibrosis in Tsk/+ mice. Crosses placing the Tsk mutation on a CD4 -/-background (as opposed to a CD8 -/-background) reveal that skin fibrosis, but not lung fibrosis, is lessened (Wallace et al 1994), whereas making the Tsk mutation congenic on NZB, a strain prone to autoimmune disorders, exacerbates the fibrosis and autoimmune response (Bocchieri et al 1993). Adoptive transfer experiments involving bone marrow and spleen cells have shown that skin fibrosis can be replicated in part, but the histopathology of lung disease cannot (Walker et al 1989;Phelps et al 1993).…”

Section: Tandem Duplication Of Fbn! Gene In Tsk Micementioning

confidence: 99%

A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.

Siracusa¹,

McGrath²,

Ma³

et al. 1996

Genome Res.

277

204

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Mice carrying the Tight skin (Tsk) mutation have thickened skin and visceral fibrosis resulting from an accumulation of extracellular matrix molecules. These and other connective tissue abnormalities have made Tskl + mice models for scleroderma, hereditary emphysema, and myocardial hypertrophy. Previously we localized Tsk to mouse chromosome 2 in a region syntenic with human chromosome 15. The microfibrillar glycoprotein gene, fibrillin 1 (FBN1), on human chromosome 15q, provided a candidate for the Tsk mutation. We now demonstrate that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. These findings provide hypotheses to explain some of the phenotypic characteristics of Tskl + mice and the lethality of Tsk/Tsk embryos.

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Immunological Characterization of (Tight Skin/NZB)F1 Hybrid Mice with Connective Tissue and Autoimmune Features Resembling Human Systemic Sclerosis

Cited by 13 publications

References 0 publications

The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis

A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.

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