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Abnormalities in the secretion of regulating enzymes may play a role in the build-up of connective tissue fiber in patients with scleroderma (SSc). In this disease, white blood cells infiltrate the tissue and contribute to an inflammatory reaction that stimulates connective tissue formation. A family of enzymes produced in fibroblasts, connective tissue-forming cells, moderates this reaction. Skin biopsies were taken from seven patients with SSc, analyzed for these enzymes, and compared with samples from seven healthy individuals. Slides were made, stained, and examined under the microscope and cells were cultured and analyzed. One of the enzymes was expressed at much lower levels than found in normal tissue. This enzyme cleaves the protein that forms the fibrous matrix in which fibroblasts are embedded. This enzyme may also play a role in moderating the cellular adhesion of white blood cells to fibroblasts.

Scleroderma, or systemic sclerosis (SSc), is a disease of connective tissue (skin, bone, cartilage, etc.) which affects multiple body systems. It features an increased deposition of collagen, the major structural protein in connective and other tissues, and this causes formation of fibrous lesions. The process by which SSc arises is still unclear, but inflammation, damage to blood vessels, activation of fibroblasts (cells that give rise to connective tissue), autoimmune mechanisms (involving inappropriate formation of antibodies against the body's own molecules), and interactions between cells and connective tissue components are involved. One known problem is that fibroblasts that are adjacent to blood vessels supplying skin in affected skin areas produce abnormally high levels of collagen. These fibroblasts are often associated with immune cells that contribute to inflammation. To better understand this feature, the reactions between normal or SSc fibroblasts with T cells (T lymphocytes, immune cells important for fighting infection) were studied. About twice as many T cells attached to SSc fibroblasts as to normal fibroblasts. Much of the extra binding was associated with two surface proteins, ICAM-1 (intercellular adhesion molecule type 1) and LFA-1 (lymphocyte function-associated antigen type 1). ICAM-1-mediated adhesion between T cells and normal or SSc fibroblasts was affected similarly by addition of several cytokines, hormone-like proteins that affect functions of lymphocytes and other cells. SSc fibroblasts tended to have higher levels of ICAM-1. The study indicates that in SSc, increased binding of T cells is related to the presence of fibroblasts with higher levels of ICAM-1. (Consumer Summary produced by Reliance Medical Information, Inc.)

In this study we have examined the mechanism underlying the contact-mediated transfer of a lysosomal enzyme from lymphocytes to fibroblasts in culture. We found that although antibody against the mannose 6-phosphate lysosomal targetting receptor (MPR) completely inhibited fibroblast uptake of the lysosomal enzyme β-glucuronidase (Gus) from the culture medium, it had no effect on the transfer of the enzyme from normal lymphocytes. In contrast, the presence of antibody that prevented the adhesion of the lymphocytes to the fibroblasts inhibited Gus acquisition but had no effect on endocytosis. Immunogold electron microscopy of the contact site between the two types of cell showed that the transfer of Gus involved uncoated vesicles localized near the cell surface of the fibroblast at sites of contact with the lymphocytes. The acquired lymphocyte enzyme was shown to be transported to the fibroblast lysosomes.