Objective. To determine whether interleukin-la (IL-la), IL-lfl, IL-2, IL-4, interferon-y (IFNy), IL-6, and tumor necrosis factor a (TNFa) are detected more frequently in sera from scleroderma patients than in sera from controls.Methods. Serum concentrations of these cytokines were measured in 78 scleroderma patients and 73 controls, using enzyme-linked immunosorbent assay, radioimmunoassay, and bioassay techniques.Results. IL-2, IL-4, and IL-6 were each detected more frequently in sera from scleroderma patients than in sera from controls. TNFa and IL-la were found with equal frequency in patient and control sera. IL-lP and IFNy were not detected in any sera.Conclusion. IL-2, IL-4, and IL-6 may be among the cytokines that contribute to the disease process in

Objective. To determine the clinical and serologic risk factors for digital ischemic events in patients with systemic sclerosis (SSc).Methods. Systemic sclerosis (SSc; scleroderma) is a heterogenous disorder with a variable course and out-

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The production and binding of transforming growth factor P (TGFP) were compared in dermal fibroblast tines derived from scleroderma patients and normal control donors. The mean 2 SEM 24-hour level of secretion of TCFP by fibroblast lines derived from the involved skin of scleroderma patients was 30.8 f 5.5 pmoles/106 cells, and it was 29.7 f 5.8 pmoles/106 cells for fibroblast lines derived from the normal skin of the healthy donors. Thus, we found that the fibroblasts themselves produced TGFP. TGFP production was equivalent in fibroblast lines derived from clinically involved and uninvolved skin of scleroderma patients. is a heterodimer that contains 1 of each of these chains (2). TGFP3 has homology with the other forms (3).TGFP is produced and secreted in latent form by a variety of cell types, including normal human placenta cells (4). peripheral blood lymphocytes (51, activated T cells (6), platelets (7.8). and embryo fibroblasts (9). Latent TGFP becomes activated by proteases or by nonenzymatic means, such as acidification, alkalinization. or exposure to denaturing agents (9.10). Once activated, TGFP is able to bind to its receptors and exert biologic effects (11). Cells exposed to activated exogenous TGFpl may increase their own production of TGFPl messenger RNA (mKNA) and protein (12,131.Specific receptors for TGFP have been identified through binding of radiolabeled TGFP (2.14, IS). These receptors have high affinity for TGFPl and varying degrees of affinity for TGFPI.2 or T G F P . Type 1 and type I1 TGFP receptor species are 65-kd and 95-kd moieties, respectively. Type 111 receptors are 250-350-kd molecules that form a 560-600-kd disulfide-linked receptor complex, which represents the major TGFP receptor species in mammalian and avian fibroblasts and epithelial cells (16). The mechanism by which TGFP activates postreceptor cellular processes remains elusive, although recent evidence suggests that a yet-undescribed protein kinase may be involved (17).TCFP appears to play a major role in wound

The surface expression of intercellular adhesion molecule 1 (ICAM-1) and class I and class I1 major histocompatibility complex molecules on cultured dermal fibroblasts from 7 scleroderma patients and 6 control donors was compared. Scleroderma fibroblast lines contained 41.0 f 3.0% (mean f SEM) cells with high levels of ICAM-1 expression (ICAM-l-high), whereas 26.9 & 1.5% of control fibroblasts were ICAM-1-high (P = 0.0003). There were no differences in the expression of class I and class 11 molecules. ICAM-1-high and ICAM-1-low fibroblasts produced equal amounts of total protein and procollagen. The increase in the number of ICAM-l-high fibroblasts in scleroderma patients may facilitate T cell activation and lymphokine production, and thus indirectly contribute to the fibrotic process.

We have constructed a model (Fig. 2) to explain the activation and regulation of autoreactive T cells by antigen. Antigen priming appears to be important for both antigen-specific and autoreactive T cells. Once activated, these T cells have the capacity to stimulate B cells to produce antibody in a very similar manner. It is possible that these two types of T cells work in concert to maintain an active immune response. Under circumstances where antigen-specific T-cell help may be limiting, autoreactive T cells may function to enhance B-cell responses. In addition, antigen appears to activate the regulatory mechanisms that are important for down-regulating the B-cell antibody response. Carrier-specific T-suppressor cells are antigen-specific in their activation but can be antigen-nonspecific in their effector function. In this way the regulatory mechanism driven by antigen can function to inactivate the antigen-specific and the autoreactive T-cell activation of B cells.

A subpopulation of scleroderma dermal fibroblasts was identified by flow cytometric analysis. Between 15% and 25% of the cells within the scleroderma fibroblast Lines had high levels of cytoplasmic granularity, as identified by side light scatter characteristics. Similar fibroblasts composed <3% of the cells within the normal fibroblast lines, although greater numbers could be induced through exposure to soluble factors derived from activated mononuclear cells. The granular subpopulation of fibroblasts produced 2-3 times as much procollagen as did the other fibroblasts. These data support the hypothesis that fibrosis in scleroderma may result in part from the activity of an inherently high procollagen-producing subset of normal fibroblasts that is expanded through exposure to immune cytokines.

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