The vascular endothelium in scleroderma.
Explore the source record for details and available documents.
Antigen-Presenting Cells↗
Biomedical subjects
M B Kahaleh
Publications and source records attributed to M B Kahaleh.
Raynaud's phenomenon and vascular disease in scleroderma.
Raynaud's phenomenon is the most common sign of vascular involvement in scleroderma. Careful clinical evaluation using a simple definition of Raynaud's phenomenon is the most reliable and reproducible method in the diagnosis. The assessment of microvascular function by laboratory methods is still not specific or sensitive enough for individual patient evaluation. The study of mechanisms involved in the pathogenesis of primary and secondary Raynaud's phenomenon offers the best window for investigation of the early pathogenetic stages in scleroderma. The structural vascular disease in scleroderma is well documented. Still, the impact of endothelial involvement on organ functions is just beginning to be identified and appreciated. Dysregulation of vascular tone control and deficiency of the vasodilatory neuropeptides in scleroderma is proposed as a mechanism in the development of Raynaud's phenomenon. Decreased fibrinolysis and enhanced platelet aggregation is documented and undoubtedly contributes to microvascular thrombosis. The nature of endothelial injury is still elusive, yet markers of endothelial activation and injury continue to be described. Therapy directed toward the vascular disease continues to focus on the alleviation of vascular spasm. Calcitonin gene-related peptide is the newest agent in our therapeutic armamentarium.
Clinical Trials as Topic↗
Mast cell changes in scleroderma. Presence of MCT cells in the skin and evidence of mast cell activation.
OBJECTIVE: To analyze the concentration and distribution of the MCT (tryptase-positive, chymase-negative) and MCTC (tryptase-positive, chymase-positive) types of mast cell in cutaneous lesions of scleroderma. METHODS: Biopsy specimens were obtained from skin lesions in 24 patients with scleroderma, and subjected to double immunohistochemical analysis using mouse monoclonal anti-tryptase and anti-chymase antibodies. RESULTS: Dermal mast cell concentrations were below the normal range in 12 of the specimens, most of which were obtained between 1 and 4 years after disease onset. All other specimens contained normal concentrations of mast cells. MCT cells were present in 12 specimens and comprised between 8% and 100% of the total mast cells. Extracellular tissue deposits of tryptase-positive and/or chymase-positive granular material were observed in 8 specimens, suggesting possible mast cell degranulation. CONCLUSION: These findings are in contrast to those in normal skin, where MCTC cells are essentially the only type of mast cell present in the dermis. The results suggest that mast cells are involved in the pathogenesis of cutaneous lesions in scleroderma.
Adult↗
Enhanced expression of high-affinity interleukin-2 receptors in scleroderma: possible role for IL-6.
Scleroderma (systemic sclerosis) is characterized by tissue fibrosis, a distinctive vascular and microvascular disorder, and a perivascular mononuclear cell infiltration of involved organs. The pathogenesis of scleroderma is not known; however, there is evidence for a cell-mediated immune mechanism in the disease. Enhanced IL-2 production has been documented both in vivo and in vitro. In this study, the effect of IL-2 on lymphocyte proliferation in vitro was examined. An enhanced proliferative response to IL-2 was seen in scleroderma lymphocytes over that in matched control lymphocytes. Since high-affinity IL-2 receptors (HIL-2-R) mediate the growth-promoting activity of IL-2, we examined HIL-2-R expression on lymphocytes from 13 scleroderma and 11 matched control subjects by a radioiodinated IL-2 binding assay. Significantly higher numbers of HIL-2-R were noted in scleroderma cells (3054 +/- 618 in scleroderma vs 1721 +/- 181 in control cells, mean +/- SD; P less than 0.001). The addition of IL-6 to control cell cultures 24 hr prior to binding determination led to changes in IL-2 binding that were identical to scleroderma cell binding characteristics, while the addition of neutralizing IL-6 antibody to scleroderma cells led to a reduction in HIL-2-R expression. Other cytokines (IL-1, IL-3, IL-4, IL-5, TNF, LT, IFN-gamma, and TGF-beta) had no effect on IL-2 binding, suggesting that IL-6 may mediate the enhanced expression of HIL-2-R. This conclusion was further supported by the finding that scleroderma lymphocytes released in vitro 10- to 20-fold higher concentrations of IL-6 than control cells. The data demonstrate an amplification of IL-2 binding in scleroderma and suggest IL-6 as the mediator of this phenomenon.
Humans↗
Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial.
BACKGROUND AND DESIGN: In a pilot study of extracorporeal photochemotherapy, two patients with systemic sclerosis who received this therapy experienced significant clinical improvement. These results prompted the development of a multicenter trial to examine the benefit of extracorporeal photochemotherapy in the treatment of systemic sclerosis. Seventy-nine patients with systemic sclerosis of recent onset (mean symptom duration, 1.83 years) and progressive skin involvement during the preceding 6 months entered a randomized, parallel-group, single-blinded clinical trial comparing extracorporeal photochemotherapy treatments given on 2 consecutive days monthly with treatment with D-penicillamine at a maximum dose of 750 mg/d. Blinded clinical examiners evaluated skin severity score (thickness), percent surface area involvement, oral aperture, and hand closure. Serial skin biopsies and pulmonary function studies were also performed. RESULTS: Following 6 months of treatment, significant improvement in skin severity score occurred in 21 (68%) of 31 patients receiving photochemotherapy and in eight (32%) of 25 receiving D-penicillamine treatment, while significant worsening occurred in three (10%) of 31 receiving photochemotherapy and in eight (32%) of 25 receiving penicillamine treatment, thus indicating a significantly higher response rate for individuals who received photochemotherapy (P = .02). At both the 6- and 10-month evaluation points, the mean skin severity score, mean percent skin involvement, and mean oral aperture measurements were significantly improved from baseline among those who received photochemotherapy. Mean right and left hand closure measurements had also improved significantly by 10 months of therapy. By comparison, among the patients treated with D-penicillamine, none of the parameters of cutaneous disease had improved significantly after 6 months of therapy, although for those individuals in whom treatment was continued, the mean skin severity score and mean percent skin involvement had improved by 10 months. Skin biopsy studies revealed a correlation between clinical improvement and decreased thickness of the dermal layer. Adverse effects of extracorporeal photochemotherapy were minimal and did not require discontinuation of treatment in any of the patients receiving this therapy; six patients permanently discontinued the use of D-penicillamine treatment due to adverse effects. CONCLUSIONS: For patients with systemic sclerosis of recent onset, extracorporeal photochemotherapy is a well-tolerated treatment that may partially reverse the process that results in cutaneous sclerosis.
Adult↗
Endothelin, an endothelial-dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action.
The vascular endothelium is an important functional unit in the regulation of the vascular and perivascular environment. Various chemical and physical stimuli mediate an endothelial-dependent vasoconstriction through the release of endothelial soluble factors, such as the recently recognized endothelium-derived vasoconstrictor peptide called endothelin. The presence of circulating endothelin and the effect of cold exposure on plasma endothelin levels were investigated in patients with scleroderma and in healthy control subjects. Radioimmunoassay demonstrated a mean +/- SD plasma level of 10.7 +/- 7.3 pg/ml in the patients (n = 19) and 3.7 +/- 2 in the control subjects (n = 16) (P less than 0.005). These levels were also assessed in 5 control subjects and 5 scleroderma patients before and after 30 minutes of total body cooling (to 15 degrees C). The endothelin level did not change significantly in either group; however, 2 scleroderma patients showed a significant increase after cooling. The effects of endothelin on fibroblast proliferation and collagen synthesis were evaluated in order to assess the impact of released endothelin on the interstitium. A significant mitogenic effect and a collagen synthesis-enhancing effect, which were dose-dependent, were seen. The strong, characteristically prolonged, vasoconstrictor activity coupled with the profibrotic effect demonstrated here make it likely that disturbances in the control of endothelin production can contribute to the pathogenesis of scleroderma.
Cold Temperature↗
Soluble immunologic products in scleroderma sera.
To investigate the role of immune mechanisms in scleroderma (systemic sclerosis, SSc), we measured the levels of selected cytokines and soluble immune markers in patient sera. Forty-two patients and 14 matched healthy controls are the subject of this report. In the SSc group, tumor necrosis factor (TNF) was found in 8/42 (29 +/- 539 pg/ml, mean level +/- SD) and lymphotoxin in 36/42 (1:409-1:200, serum dilution). Interleukin beta (IL-1 beta) was observed in 23/42 (44 +/- 29, U/ml). IL-2 was identified in 36/42 patients with a mean level of 286 +/- 406 U/ml, soluble interleukin-2 receptor in 42/42 (1055 +/- 393, U/ml), soluble CD4 antigen in 27/42 (1:10-1:320, serum dilution), and CD8 in 42/42 (470 +/- 134, U/ml). TNF, lymphotoxin, IL-1 beta, Il-2, and CD4 were not detected in the control group. IL-2 receptor levels in control subjects were 520 +/- 171 U/ml, significantly lower than those of scleroderma (P less than 0.001), and CD8 levels (582 +/- 140) were significantly higher than in scleroderma (P less than 0.05). The data suggest an ongoing activation of immune cells, particularly the CD4+ subset in SSc and indicate a potential role for the released mediator TNF, IL-1 beta, and lymphotoxin in the disease process.
Adult↗
Vascular disease in scleroderma. Endothelial T lymphocyte-fibroblast interactions.
The accumulated body of evidence suggests a role for a cell-mediated immune mechanism in the pathogenesis of scleroderma vascular disease. The most likely target for immune injury is either the endothelial cell itself or components of its basal lamina, which include type IV collagen and laminin. Whatever the specific target, the net effect is persistently altered endothelial cell dysfunction. However, the molecular basis for the development of endothelial cell injury is not known. Direct investigations of perivascular infiltrating cells have not been possible yet; published studies have focused on the in vitro effects of peripheral blood mononuclear cells and selected cytokines on endothelial cell behavior and function. Understanding the multiple cellular effects of various cytokines on endothelial cells may further the knowledge of the vascular disease. Systematic study of interactions between endothelial cells and cells of the immune system may provide the molecular basis for vascular injury and open yet unidentified avenues for therapy. Furthermore, monitoring parameters of endothelial cell injury may help to define the disease in an earlier and more meaningful fashion. Circulating levels of EC products such as von Willebrand factor, plasminogen activator, and prostacyclin/thromboxane metabolites may permit a precise definition of disease activity and assist the clinician in monitoring responses to therapy.
Cytotoxicity, Immunologic↗
Interleukin-2 in scleroderma: correlation of serum level with extent of skin involvement and disease duration.
STUDY OBJECTIVE: To assess whether interleukin-2 has a role in the pathogenesis of scleroderma. DESIGN: Observe serum effect on the in-vitro growth of an interleukin-2-dependent cytotoxic T-cell line and determine serum level by an enzyme-linked immunosorbent assay. SETTING: Outpatient rheumatology clinic of a university medical center. PATIENTS: Sera were collected from 47 patients with scleroderma, 20 patients with rheumatoid arthritis, and 14 matched control subjects. MEASUREMENTS AND MAIN RESULTS: A significant mitogenic effect was observed in sera from patients with scleroderma of recent onset; a lower proliferative response was seen in rheumatoid sera. Matched control sera had no mitogenic activity. Sera from patients with scleroderma of recent onset supported the in-vitro growth of an interleukin-2-dependent cytotoxic T-cell line. Matched control sera had no similar mitogenic activity. Interleukin-2 was found in sera from 41 of 47 patients with scleroderma (204 +/- 356 U/mL, mean +/- SD), in 9 of 20 patients with rheumatoid arthritis (2.04 +/- 5.16), and in none of 14 matched control subjects. There was a positive correlation between serum level and the skin progression index (skin score/disease duration). CONCLUSIONS: The presence of interleukin-2 in scleroderma sera strongly supports a role for T-cell activation in scleroderma. The association between serum levels and disease progression indicates that this T-cell process may participate in the progression of the disease.
Adult↗
A strategy for determining the pathogenesis of systemic sclerosis. Is transforming growth factor beta the answer?
Explore the source record for details and available documents.
Humans↗
Transitions in generalized scleroderma.
Explore the source record for details and available documents.
Female↗
Effect of lymphotoxin and tumor necrosis factor on endothelial and connective tissue cell growth and function.
In an approach to understand the immune basis of human vascular and fibrotic disorders, the effects of recombinant human tumor necrosis factor alpha (rTNF) and lymphotoxin (rLT) on the in vitro growth and function of vascular and connective tissue cells were studied. Both rTNF and rLT stimulated fibroblast growth and protein, fibronectin, and collagen synthesis in dose-dependent fashion. In contrast, endothelial cell (EC) growth was inhibited by both cytokines; true EC cytotoxicity was seen at high concentrations (greater than or equal to 500 mu/ml). Addition of recombinant interferon-gamma markedly enhanced EC cytotoxicity while the growth factor beta-transforming growth factor reversed EC growth inhibition. Both rTNF and rLT stimulated factor VIII-Ag synthesis by EC. These contrasting effects of rTNF and rLT on fibroblast and endothelial cell growth and function in vitro are intriguing because they are the same contrasting effects observed in vivo in connective tissue and vascular disorders, raising the possibility of a role for these cytokines in these disorders. Study of the in vitro and in vivo mechanisms of these diverse effects may contribute to the understanding of certain human disorders characterized by endothelial injury and fibroblast activation leading to fibrosis.
Animals↗
Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis.
Several human diseases are characterized by vascular pathology, fibroblast activation, and excessive fibrosis (e.g., scleroderma, chronic graft versus host disease, pulmonary fibrosis). An intense inflammatory exudate of mononuclear cells which are derived from the peripheral blood precedes the vascular and fibrotic changes. We examined, in vitro, the effects of human peripheral blood mononuclear cell culture supernatants (PBM-SN) on the growth and survival of human endothelial cells (EC) and of human dermal fibroblasts (FB). The same PBM-SN consistently induced inhibition of EC and stimulation of FB proliferation. PBM-SN derived from 42 patients with scleroderma induced 32 +/- 5% (mean +/- SE) more inhibition of EC and 42 +/- 18% more stimulation of FB compared with PBM-SN derived from 30 healthy subjects. Depletion of phagocytic cells or adherent cells from PBM resulted in SN with no demonstrable activity on either EC or FB. Partial purification of PBM-SN on ion exchange and gel filtration chromatography revealed the presence of two fractions that stimulated and one fraction that inhibited FB proliferation, and two fractions that inhibited and one that stimulated EC proliferation. These data suggest that monocytes are capable of releasing mediators that stimulate or suppress EC or FB. However, when activated by surface adherence, resulting SN inhibit EC and stimulate FB proliferation. Serum is required for the expression of FB proliferation.
Cell Adhesion↗
Effect of scleroderma serum on human fibroblast collagen production: possible selection through proliferation.
The effects on cell proliferation and on collagen and protein synthesis of prolonged exposure of control and scleroderma skin fibroblasts to control and scleroderma serum were studied. The previously described mitogenic effect originally noted at 3 days was observed to a lesser degree at 21 days, at which time a doubling of protein synthesis and a 3-fold increase in collagen synthesis were noted. Since earlier studies of shorter exposure times did not show effects on protein or collagen synthesis, the prolonged exposure of heterogeneous mass cultures of dermal fibroblasts to the mitogenic effects of scleroderma serum may result in the emergence of high collagen producing cells.
Cell Count↗
Enhanced platelet adhesion to collagen in scleroderma. Effect of scleroderma plasma and scleroderma platelets.
The effect of plasma on platelet adhesion to collagen coated microtiter wells was investigated in 22 patients with scleroderma and 26 control subjects. In the control subjects, platelet adhesion was 38 +/- 13% (mean +/- SD) of adhesion with buffer alone; in scleroderma patients adhesion was 64 +/- 20% (p less than 0.001). No correlation was seen between the effect of plasma on platelet adhesion to collagen and the plasma levels of either FVIII/von Willebrand factor antigen or fibronectin in either scleroderma or control subjects. Furthermore, scleroderma platelets demonstrated enhanced adhesion compared to control platelets when tested in the presence of either control or scleroderma plasma.
Blood Vessels↗
A fibroblast mitogen present in scleroderma but not control sera: inhibition by proteinase inhibitors.
Fibroblast mitogenic activity (MA) has been identified in scleroderma (SD) sera. Control and scleroderma skin fibroblasts in early passage were observed for replication (cell counts) after 72 h of serum exposure. SD sera at 15% concentration induced a significant increase in control fibroblast numbers when compared with control sera; this effect was not seen with SD cells while at higher serum concentrations (30%); SD cells were slightly responsive to the MA. MA was completely abrogated by the proteinase inhibitors STI and TLCK which did not affect mitogens in healthy sera. Circulating mitogenic proteinases selective for fibroblasts could play a role in the fibrosis of SD by modulating fibroblast replication.
Animals↗
Acute rheumatic fever after thyroid abscess in an adult.
Explore the source record for details and available documents.
Abscess↗
Endothelial injury in scleroderma. A protease mechanism.
The mechanism of action of the previously reported serum ECA in patients with scleroderma has been studied. Gel filtration (Sephadex G-200) followed by ion exchange chromatography (DEAE-Sephadex A-50, Tris buffer, pH 8, 1.5M NaCl) yielded a 13-fold enriched fraction. ECA biological activity was abolished by preincubating the active fraction with several protease inhibitors (STI, aprotinin, TLCK, and PMSF); exposure of target cells to protease inhibitors did not inhibit ECA. ECA-rich fractions have esterolytic activity (3H-TAME), which was irreversibly inhibited by TLCK and PMSF in a time-, temperature-, concentration-, and pH-dependent fashion. In separate studies, functional protease inhibitor activity in scleroderma sera was determined by the capacity of serum to inhibit BAPNA hydrolysis by trypsin (TIC). TIC was 1.32 +/- 0.15 (milligrams of trypsin inhibited by 1 ml of serum +/- S.D.) in 20 control sera, and 0.54 +/- 0.18 (p less than 0.001) in 38 scleroderma sera. A positive correlation was found between TIC and percent inhibition of endothelial cell 3HTdR uptake induced by the same serum (r = 0.94, p less than 0.001). These studies suggest that ECA is mediated in vitro via a protease mechanism associated with a functional deficiency of protease inhibitors in scleroderma sera.
Cells, Cultured↗