A unifying hypothesis for scleroderma: identifying a target cell for scleroderma.

We propose that a recent change in the conception of the role of type 1 interferon and the identification of adventitial stem cells suggests a unifying hypothesis for scleroderma. This hypothesis begins with vasospasm. Vasospasm is fully reversible unless, as proposed here, the resulting ischemia leads to apoptosis and activation of type 1 interferon. The interferon, we propose, initiates immune amplification, including characteristic scleroderma-specific antibodies. We propose that the interferon also acts on adventitial stem cells, producing myofibroblasts, rarefaction, and intimal hyperplasia--three morphologic changes that characterize this disease. Regulator of G-protein signaling 5 (RGS5), a regulator of vasoactive G-protein-coupled receptors, is a cell type-specific marker of pericytes and scleroderma myofibroblasts. RGS5 may provide a key link between initial hyperplasia and fibrosis in this disease.

Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis.

BACKGROUND: The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD) resembles the appearance of fibrosis in scleroderma (SSc). Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed skin biopsies of normal controls (n = 24), patients with SSc (n = 30) and c-GVHD with dermal fibrosis (n = 133)). Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001) average vessels in SSc biopsies (9.8) when compared with c-GVHD (16.5). Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05), respectively). In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies. CONCLUSIONS/SIGNIFICANCE: The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.

Is scleroderma a vasculopathy?

Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic noninflammatory macrovascular and microvascular changes with dramatic and possibly occlusive formation of a thickened neointima. Scleroderma vessels also have an unusual endothelial phenotype, with loss of normal markers including vascular endothelial (VE)-cadherin. These endothelial cells express type 1 interferon and regulator of G protein signaling 5 (RGS5), two molecules associated with vascular rarefaction. These genes may be important because tissue is hypoxic with high levels of vascular endothelial growth factor (VEGF), especially early in the disease. The combination of VEGF and rarefaction is not necessarily paradoxical. VEGF-mediated angiogenesis creates labile vessels that may not survive unless the vessel acquires a smooth muscle coat. The combination of interferon and RGS5 is consistent with an antiangiogenic phenotype. We offer a hypothesis that places vascular injury at the center of this disease and also suggest possible clinical approaches for arresting and/or reversing the disease.

Plasmacytoid dendritic cells and interferon levels are increased in lymphatic malformations.

OBJECTIVE: Describe the presence of plasmacytoid dendritic cells and type 1 interferon and the activation of interferon signaling pathway in lymphatic malformations. DESIGN: Retrospective case series. MATERIALS: Nineteen lymphatic malformations with matching clinical data were compared to control tissue (normal skin and lymph node). METHODS: Paraffin-embedded tissue was evaluated for plasmacytoid dendritic cells, type 1 interferon, and type 1 interferon signaling with immunohistochemistry and RNA in situ hybridization. Staining results were compared with controls and correlated with clinical data with descriptive statistics and Mann-Whitney tests. RESULTS: Lymphatic malformations had increased staining for plasmacytoid dendritic cells, interferons alpha and beta, and phosphorylated signal transducer and activator of transcription 1 compared with controls (P < 0.05). Significantly increased interferon beta staining was present in recurrent lymphatic malformation tissue compared with nonrecurrent lymphatic malformations. CONCLUSION: Lymphatic malformations have unusual ongoing local immune activation, possibly affecting recurrence.

The pathology of scleroderma vascular disease.

Systemic sclerosis is characterized by three distinct pathologic processes: fibrosis, cellular/humoral autoimmunity, and specific vascular changes. Although a mild vasculitis may sometimes be present, the vascular pathology of scleroderma is not necessarily inflammatory and is best characterized as a vasculopathy. In this article, the authors propose that SSc vasculopathy is the result of an early event involving vascular injury that eventuates in a vicious cycle mediated in part by the immune process. The subsequent vascular malformation and rarefaction may be a function of systemic angiogenic dysregulation, with over expression of vascular endothelial growth factor but a lack of proper interactions with smooth muscle cells needed to stabilize and organize blood vessels.