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Autoantibodies against PDGF Receptor in Scleroderma by Filemon K. Tan

Posted Sep 11 2009 4:57pm

The existence of autoantibodies in scleroderma was described more than 40 years ago. Indeed, such autoantibodies, some highly disease-specific, are present in virtually all patients with scleroderma. Although the important autoantibodies are directed against nuclear components, it is clear that most patients with scleroderma also have antibodies against extracellular-matrix and cell-surface proteins, proteases, fibroblasts, and endothelial cells.

What would be needed to demonstrate that autoantibodies in scleroderma are pathogenic, not just epiphenomena resulting from a loss of tolerance? The presence of an autoantibody long before the onset of clinical disease would constitute circumstantial evidence of the causation of disease. This finding has been well documented in systemic lupus erythematosus and rheumatoid arthritis but has yet to be reported in scleroderma.

If the autoantibody is central to disease development, it must be present in most, if not all, patients with scleroderma and must be disease-specific. The various scleroderma antinuclear antibodies correlate with certain disease features, but the individual subtypes are mutually exclusive, with each present only in a minority of patients with scleroderma.

Koch's third postulate would require that the autoantibody in question cause disease when introduced into a healthy animal, although the demonstration that the autoantibody affects key cellular processes that are important in disease pathogenesis in model systems is often used as a surrogate. Svegliati Baroni et al. describe a stimulatory autoantibody against platelet-derived growth factor receptor (PDGFR) that seems to fulfill some of these characteristics.

Yamakage et al. initially noted the selective up-regulation of PDGFR in scleroderma fibroblasts, probably resulting from defects in the signaling of transforming growth factor (TGF-) that render the fibroblasts more sensitive to platelet-derived growth factor (PDGF). Later, Sambo et al. observed that fibroblasts constitutively produce a large amount of reactive oxygen species (ROS) through the NADPH oxidase (NOX1).

ROS can mediate apoptosis and activate nuclear factor-B, which, in turn, activates the expression of inflammatory genes, including adhesion molecules and cytokines. The same group later reported the discovery of a signaling loop in normal fibroblasts in which PDGF triggered increased production of ROS by the activation of NOX1. ROS, in turn, activate the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway, which induces the viral Harvey rat sarcoma (H-ras) gene.

This gene can also further activate ERK1/2 through the v-raf-1 murine leukemia viral oncogene homologue 1 (Raf1) cascade. Activation of H-ras sets into motion a diverse set of intracellular pathways, including the anticancer target protein kinase B and nuclear factor-B, which influences apoptosis, inflammation, and collagen synthesis.





Selective Up-Regulation of PDGFR by Fibroblasts in Scleroderma.
Unlike normal fibroblasts, fibroblasts in scleroderma increase the expression of PDGFR in response to transforming growth factor (TGF-), rendering the cells more sensitive to platelet-derived growth factor (PDGF). The Ras–ERK1/2–ROS signaling pathway is triggered by PDGF or anti-PDGFR, which then activates NADPH oxidase (NOX1) to produce reactive oxygen species (ROS). These, in turn, activate extracellular signal-regulated kinases 1 and 2 (ERK1/2), which induce the Harvey rat sarcoma (H-ras) gene. This signaling loop is present in normal fibroblasts but is relatively amplified in fibroblasts in patients with scleroderma.

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