Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma)

Abstract

Objective. Perivascular infiltrates in skin, subcutaneous tissue, and internal organs are a characteristic feature of early systemic sclerosis (SSc). We studied the first step of migration of peripheral blood mononuclear cells (PBMC) through the vessel wall to the extravascular space, i.e., adhesion of PBMC to endothelial cells (EC), in patients with various forms of SSc (limited scleroderma, diffuse scleroderma, and the transitional form).Methods. Radioisotope-labeled patient PBMC were coincubated with umbilical cord EC in vitro, and the percentage adhesion was measured.Results. Adhesion of PBMC to EC was markedly decreased, while adhesion of isolated active rosetteforming cells (ARFC) was significantly increased, in SSc patients compared with healthy controls. Decreased adhesion of PBMC to EC was found to correlate with a diminished percentage of ARFC in the peripheral blood. Preincubation of PBMC from healthy donors with interleukin-2 (IL-2) enhanced their adhesion to EC, while preincubation of PBMC from SSc patients with this cytokine resulted in a decrease in adhesion in 10 of 14 individuals. IL-1, interferon-y, and transforming growth factor p had no significant effect on adhesion of of PBMC to EC among the SSc subgroups were not significant . Conclusion.Our findings suggest that in SSc, activation of subpopulations of PBMC leads to their enhanced adhesion to vascular endothelium in vivo and to migration of these cells to the extravascular space, resulting in the elimination from the peripheral blood of those PBMC with high ability to adhere to EC.

IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines.

“…In vitro studies have found that PBMCs from SSc patients adhere abnormally to endothelial cells with an overall reduction in binding but with enhanced binding of a subfraction of activated cells; this is consistent with the concept that lymphocyte traffic across endothelium is chronically upregulated in SSc lesions and leads to a depletion of circulating responsive cells (22). There is now considerable recent evidence for enhanced expression of adhesion molecules on endothelium in SSc patients, both within lesions and at clinically uninvolved sites (23)(24)(25)(26), together with increased circulating levels of soluble forms of adhesion molecules and other markers of endothelial activation or damage, including vWF, endothelin-1, and thrombomodulin (27)(28)(29)(30)(31)(32)(33).…”

Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion

“…Previous studies have shown that SSc peripheral blood mononuclear cells and SSc dermal fibroblasts are hyperadhesive 19. Here we found that JAM-A is overexpressed on SSc dermal fibroblasts and mediates the adhesion of myeloid U937 cells to both SSc dermal fibroblasts and proximal and distal SSc skin.…”

Differential expression of junctional adhesion molecules in different stages of systemic sclerosis

“…JAM‐A and JAM‐C may therefore contribute to the proadhesive phenotype of dermal ECs, inflammatory/immune cells, and fibroblasts and participate in the complex intercellular cross‐talk among these different cell types in early‐stage SSc. Indeed, previous studies have shown that SSc ECs, peripheral blood mononuclear cells, and activated fibroblasts are hyperadhesive (8–13, 37, 38). The increased expression of JAMs on blood vascular ECs from patients with early‐stage SSc may mediate the influx of inflammatory/immune cells into the dermis, where they may stimulate fibroblasts by both direct contact and the release of profibrotic mediators (1, 8).…”