The roles of Transforming growth Factor Type ?3(TGF-?3) and mast cells in the pathogenesis of scleroderma

Abstract

Scleroderma is a connective tissue disorder characterised by excessive accumulation of collagen in the skin and internal organs. The most likely explanation for this process is local activation of collagen synthesis from fibroblasts. Our intention was to elucidate whether TGF-beta3 and mast cells play a pathogenic role in abnormal connective tissue formation in scleroderma. In this study, skin biopsies from 20 patients with scleroderma and five from healthy individuals were studied by an indirect immunoperoxidase technique to determine the immunoreactivity of TGF-beta3 in the dermis. In addition, skin samples were stained with toluidine blue to count the number of mast cells in scleroderma, and tissues were examined under the electron microscope to evaluate the ultrastructural changes. Increased TGF-beta3 immunoreactivities were detected in the dermis in the patient's skin, suggesting the presence of a subpopulation responsible for the increased collagen production. Mast cell counts in the skin of patients with scleroderma were significantly greater (19.2 +/- 4.1/unit) than those of normal controls (4.4 +/- 1.2/unit). Ultrastructural observations indicated that there is a close relationship between the mast cells and fibroblasts. These results suggest that fibrosis in scleroderma could evolve through the activation of fibroblasts and the regulatory mechanisms that appear to modulate the behavior of these cells with respect to collagen production.

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

“…Increased numbers of dermal mast cells are seen in systemic fibrosis and other fibrotic disorders such as chronic graft vs. host disease and lung fibrosis [10][11][12]. Due to the presence and increased serum IgE associated with keloids, keloid formation may likely be associated with mast cell hypersensitivity.…”

“…5 c-f). Associations of mast cells with fibroblasts have previously been identified as an important feature of fibrotic conditions such as systemic sclerosis, chronic graft vs. host disease and lung fibrosis characterised by an overproduction of collagen by fibroblasts [12,41,42]. In pulmonary fibrosis mast cells were observed in partial degranulation and in close proximity to lung fibroblasts [43,44].…”

Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis

“…Mast cell-derived molecules can both modify the production and destruction of extracellular matrix as well as promote migration and proliferation of fibroblasts in vitro [2-4]. Despite that mast cells have been shown to promote fibrosis in several organs [5,6], their relationship to fibrotic lesions and inflammatory foci in the lung has remained poorly studied.…”

Homeostatic Role of Transforming Growth Factor-β in the Oral Cavity and Esophagus of Mice and Its Expression by Mast Cells in These Tissues

“…47 IL-10 production by mast cells was found to be a critical factor for limiting contact hypersensitivity inflammatory responses, 44 but to our knowledge TGF-␤ production by mast cells has not yet been demonstrated to participate in these immunosuppressive activities. Although TGF-␤ can be produced by mast cells, this has been suggested to be detrimental in disease conditions such as scleroderma 48 or porphyria cutanea tarda. 49 We are also unaware of mast cell-deficient mice on strain backgrounds that show significant pathology in the tongue or esophagus after anti-TGF-␤ treatment making it difficult to formally test the role of mast cells in the pathology we observe.…”