Systemic Sclerosis Anti-Endothelial Cell Antibodies in

Systemic sclerosis (SSc), or scleroderma, is characterized byearly vascular endothelial cell (EC) damage, followed by cuta-neous and visceral fibrosis. There is substantial interest in therole of anti-EC antibodies (AECA) in SSc as recent findingshave brought new insights into the understanding of thepathogenicity of such autoantibodies.A number of methods have been used to detect AECA in-cluding indirect immunofluorescence (IIF), cell enzyme-linkedimmunosorbent assay (ELISA), radioimmunoassay, and West-ern blotting (WB). The cell substrates used include EC derivedfrom different origins, viz arteries and human umbilical veinsand microvessels, as well as endothelial lineage cells (the prev-alence of AECA detected in SSc varies from 28 to 85% of thesamples tested). Given the differences in the tests and cellorigins, the results vary from one study to another. Theseautoantibodies are not specific for SSc. Yet, assuming that SScaffects mainly microvessels, one may predict that microvascularECs reflect the in vivo situation more reliably than other cellsubstrates.Some AECA-containing sera from patients with SSc gener-ate complement-mediated or antibody-dependent cellularcytotoxicity (ADCC). Incubation of EC with AECA also makessome changes in the functions of the cells. These include in-creased production of cytokines, such as interleukin-1 (IL-1)and IL-6; enhanced expression of adhesion molecules, andinduction of a procoagulant stage. Furthermore, EC-reactiveantibodies sustain leukocyte adherence to ECs, and an anti-body subset may be capable of initiating apoptosis of ECs.In addition, apoptosis of ECs is an early finding in animalmodels of spontaneous disease. As demonstrated with humans(but not with mice), this apoptosis may be initiated by AECA.Clearly, the detection of AECA deserves much attention in thediagnosis and treatment of SSc. Identification of the epitopestargeted by these antibodies is currently in progress. Suchstudies would probably be helpful for monitoring patients withSSc.SSc occurs as a continuum from benignprimary Raynaud’sphenomenon through severe diffuse disease. The disease isthus multifactorial in nature, and indeed the pathophysiologyof such a nonorgan-specific autoimmune condition, referred toas “the mosaic of autommunity” (51), involves genetic, envi-ronmental, hormonal, and immunologic features (8). However,the precise mechanism of the initial microvascular injury re-mains largely unknown. Unequivocally, the earliest changesconsist of EC damage. Then, intimal proliferation and vascularwall thickening occur to different organs, along with mast cellinfiltration and cutaneous as well as visceral fibrosis (44).Over the recent years, several investigators have claimedthat the production of AECA is relatively common in patientswith SSc, although the evidence has long been lacking that suchautoantibodies are pathogenic (36). Patients with SSc have alsobeen found to produce antibodies that react with two specificcellular components: the kinetochore, targeted by anticentro-mere antibodies in a number of patients with limited SSc, in-cluding the CREST syndrome (calcinosis, Raynaud’s phenome-non, esophagal dysmotility, sclerodactyly, and telangiectasias),and the topoisomerase I recognized by anti-Scl70 antibodiesin certain patients with diffuse SSc (8). It is noteworthy thatAECA are significantly associated with antiphospholipid (PL)antibodies (aPL) in a number of connective tissue diseases.This review summarizes the current knowledge on the asso-ciation of AECA with SSc and analyzes the potential role ofthese antibodies in the development of the disease amonga subgroup of patients. The vascular endothelium (whichpresents as a continuous monolayer) is in close contact withflowing blood components and is endowed with numerousfunctions, such as inflammation, thrombosis-hemostasis, lym-phocyte migration, and wound healing (29). In this respect, sev-eral effects of AECA are now being unraveled with the benefitof very recent data.