Scleroderma. A model for fibrosis.
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B-Lymphocytes↗
Biomedical subjects
R Fleischmajer
Publications and source records attributed to R Fleischmajer.
Collagen synthesis in generalized morphea.
Synthesis of collagen and non-collagenous proteins was measured in fibroblast cultures derived from different layers of the dermis from a patient with an early stage of localized scleroderma. Increased synthesis of collagen was found in fibroblasts grown from the subcutaneous fat of this patient, whereas cells obtained from the papillary dermis revealed normal metabolism. These data agree with the results obtained in previous experiments with cells derived from patients with progressive systemic sclerosis in primary culture, thus indicating that the two diseases have a common pathomechanism. Several subcultures of the activated fibroblast populations were also studied. Normal collagen synthesis in these cultures was observed after the fifth passage, probably indicating selection of cell populations or loss of the previous phenotype.
Adipose Tissue↗
Normolipemic subcutaneous xanthomatosis.
A patient with diabetes mellitus is described in whom an unusual xanthomatosis developed involving large areas of the subcutaneous tissue and vocal cords. Few lesions were present on the skin. Plasma lipid, lipoprotein, apolipoprotein, and cholestanol levels revealed normal patterns. Electron microscopy showed macrophages with vacuolar and crystal lipid inclusions. Results of lipid and enzyme analysis of the subcutaneous xanthoma were similar to those of xanthomas derived from a patient with diabetes mellitus and type V hyperlipidemia. The mechanism of this xanthomatosis remains unknown.
Diabetes Complications↗
Collagen fibril formation during embryogenesis.
Chicken embryo skin of different ages and adult skin were labeled with antibodies against the amino propeptide and carboxyl propeptide of type I collagen and processed for indirect immunoelectron microscopy by the ferritin technique. The results indicate that the formation of thin collagen fibrils involves polymerization of pN-collagen. Fibrils that are thicker than 35-40 nm do not appear to contain the amino propeptide. How fibrils increase in size is not clear, but growth may involve mechanisms such as lateral aggregation of subfibril structures or fusion of thin fibrils. Carboxyl propeptides were localized near or in contact with thin collagen fibrils, but they did not appear to be arranged in a periodic manner along the fibrils. In experiments using antibodies against the amino propeptides of type III collagen, fibrils 20-40 nm in diameter were also labeled in a periodic fashion. pN-Collagen chains were extracted from embryonic skin and identified by NaDodSO4/polyacrylamide gel electrophoresis and by immunoblotting. The presence of significant amounts of pN-collagen in skin from 10- and 12-day chicken embryos agreed well with the labeling of amino propeptides by immunoelectron microscopy. This study provides evidence for the role of the amino propeptide in collagen fibrillogenesis in embryonic skin.
Animals↗
Increased procollagen mRNA levels in scleroderma skin fibroblasts.
Procollagen messenger RNA activity in scleroderma and normal skin fibroblasts was measured using a cell-free translation assay. Radioactive translation products were fractionated by electrophoresis and the ratio of procollagen to total incorporation was determined from densitometric scans of gel fluorograms. In 4 scleroderma cell lines 1.78% (+/- 0.10) of incorporated [35S]-methionine was in procollagen, compared to 1.00% (+/- 0.20) in 5 normal controls. These values are consistent with previously reported increases in the rates of collagen synthesis obtained with intact cells and show that most if not all of the increase can be explained on the basis of elevated translatable procollagen messenger RNA in scleroderma fibroblasts.
Adult↗
The vascular, inflammatory, and fibrotic components in scleroderma skin.
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Autoimmune Diseases↗
Pseudoxanthoma elasticum and mitral-valve prolapse.
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Adult↗
Normolipemic tendon and tuberous xanthomas.
Tendon and skin xanthomas have been found in association with familial hypercholesterolemia, broad beta disease, beta sitosterolemia, and cerebrotendinous xanthomatosis. We are reporting a patient with tendon and tuberous xanthomas accompanied by normal plasma lipids. In addition, the plasma and xanthoma concentration of cholestanol was normal, while beta sitosterol was absent. These data rule out the disorders listed and suggest that this patient's disorder may represent a new normolipemic xanthomatosis.
Adult↗
Ultrastructural identification of extension aminopropeptides of type I and III collagens in human skin.
Human skin was labeled with purified antibodies against type II and III collagens and against their extension aminopropeptides by using the ferritin technique. Both aminopropeptides were visualized mainly along thin collagenous fibrils (diameter, 20-40 nm) and rarely in nonfibrillar regions of the skin. The labeling showed a periodicity of 60-65 nm resembling the D (67 nm) stagger of collagen molecules. Blocking of antibodies with aminopropeptides and treatment of tissues with procollagen NH2-terminal protease abolished labeling. Antibodies against type I collagen uniformly labeled approximately equal to 80% of the fibrils (diameter, 20-80 nm), while reaction with antibodies against type III collagen was restricted to thin fibrils. It is currently thought that the aminopropeptides of procollagen molecules are cleaved after they are released from the cell and before fibril formation. Our data indicate that aminopropeptides are removed at the fibrillar level and that fibril growth can be regulated by extracellular procollagen processing.
Amino Acid Sequence↗
Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture.
Primary cultures of fibroblasts obtained from the papillary, reticular and subcutaneous layer of scleroderma skin were analyzed for protein synthesis by metabolic labeling and radioimmunoassays. Several of these cultures showed a 10- to 20-fold increase in the production of total protein and collagen as well as of fibronectin and type III procollagen as compared to cells from unaffected individuals. Most of the increases were noted in the reticular and subcutaneous layers. With cells from other patients increased synthesis was found in some of the explants or for only some of the products. The heterogeneity observed here could represent heterogeneity in the disease, in the cells studied or in the state of the disease at the time the cells were obtained.
Adult↗
Capillary alterations in scleroderma.
Electron microscopy of capillaries was performed in scleroderma skin. The main alterations were (1) gaps, vacuolization and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum (RER) accompanied by perivascular fibrosis. Perivascular cellular infiltrates and endothelial cell damage appear to precede the stage of fibrosis.
Adult↗
Immunoelectron microscopy of type III collagen in normal and scleroderma skin.
Normal and scleroderma skin was studied by indirect immuno-electron microscopy with specific antibodies against Type III collagen. Fine collagen fibrils, 200-400 A in diameter were labeled with antitype III collagen antibodies. These antibodies attached to the collagen fibril forming rings with a 650 A periodicity. Fibrils with more than 600 A in diameter were only labeled with antitype I collagen antibodies. Type III collagen was found around small blood vessels, adipocytes and smooth muscle cells, thus, corresponding to the distribution of reticulin.
Antibodies↗
Immunofluorescence analysis of collagen, fibronectin, and basement membrane protein in scleroderma skin.
Scleroderma skin and the subcutaneous tissue was studied by indirect immunofluorescence with specific antibodies against interstitial collagens and procollagens, against fibronectin and against the basement membrane proteins Type IV collagen and laminin. Staining for Type I procollagen and fibronectin was distinctly increased in the lower dermis and subcutaneous tissue. When compared with normal skin the data suggests that fibrosis may start around capillaries and in close proximity to adipose cells. Additional changes in the distribution to Type IV collagen and laminin were found in some patients and probably reflect the alterations in small blood vessels.
Adult↗
Collagen in the cellular and fibrotic stages of scleroderma.
The collagen in localized and systemic scleroderma skin was studied by light microscopy with silver impregnation (50 patients), electron microscopy (14 patients), and immunofluorescence microscopy using specific antibodies against Type I and Type III collagens (12 patients). In the cellular stage, the dermis and adipose tissue revealed perivascular or diffuse cellular infiltrates (mostly lymphocytes, plasma cells, and macrophages), accompanied by deposition of Type III collagen. The lower dermis also showed an increase in Type III collagen. In the fibrotic stage, the papillary layer showed a reduction and/or clumping of Type III collagen as compared to normal skin. The lower dermis and the adipose tissue revealed compact collagen consisting exclusively of Type I collagen or a mixture of Type I and Type III collagen. The pattern of Type III collagen distribution was similar to that of reticulin, thus suggesting that at least some reticulin fibrils may represent Type III collagen.
Adipose Tissue↗
Hypolipidemic drugs.
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Cholestyramine Resin↗
Scleroderma, eosinophilia, and diffuse fasciitis.
Skin induration without internal organ involvement, blood and tissue eosinophilla, and fascilitis are features of diffuse fascilitis. However, cellular infiltrates (lymphocytes, plasma cells, and eosinophils) may also be present in the dermis, fat, and muscle. Blood eosinophilia (mild and transient) and skin eosinophilia were observed in about 20% of patients with systemic and localized scleroderma.
Adult↗
Unilateral keratosis follicularis.
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Adolescent↗
Connective tissue synthesis by cultured scleroderma fibroblasts. II. Incorporation of 3h-glucosamine and synthesis of glycosaminoglycans.
Fibroblasts from normal and scleroderma skin, grown tissue culture, were incubated with 3H-glucosamine for 24 hours. No definite trends could be established in 3H-glucosamin incorporation or glycosaminoglycan synthesis. Over 90% of the total 3H activity as well as the glycosaminoglycans synthesized were secreted into the medium. Characterization of glycosaminoglycans showed that in both the medium and cells, hyaluronic acid ins the major glycosaminoglycan in normal and scleroderma fibroblasts. In the medium, hyaluronic acid represented 87% of the total glycosaminoglycans; it was slightly decreased in the cells. Fibroblasts were compared from the upper and lower areas of the affected dermis and an uninvolved dermal area of the same scleroderma patients.
Adult↗