New target antigens for antiendothelial cell antibodies

Abstract

Numerous connective tissue diseases, such as systemic lupus erythematosus (SLE), and infectious states, such as leprosy, are characterized by early vascular endothelial cell (EC) damage. There is substantial interest in the role of anti-EC antibodies (AECA) in such an injury. Due to the diversity of AECA-associated conditions, these autoantibodies are likely to be heterogeneous, and, therefore, identification of their antigens (Ag) to be difficult. They may be classified into three groups: membrane components, ligand–receptor complexes and Ag derived from the blood and attached to the cell surface. New technologies have been developed to sort it out, such as expression libraries and two-dimensional electrophoresis. A handful of Ag have hitherto been recognized viz. heat-shock protein 60 in SLE and leprosy, or plasminogen activator inhibitor-1 in SLE and Wegener granulomatosis. In reality, most of the target Ag for AECA remain to be identified.

Introduction

Endothelial cells (EC) lining the vasculature contribute to the development of inflammatory responses. Because they have long proved to be a target for immune-mediated assault (Youinou, 1995; Meroni et al., 1996; Meroni and Youinou, 1996), it could have been predicted that damage of these vessels occurs through antibodies (Ab) to EC antiendothelial cell Ab (AECA). Such autoreactivity was originally described by indirect immunofluorescence analysis, with tissue sections as the substrate in sera from patients with systemic lupus erythematosus (SLE). The reliability of this staining was then settled (Cines et al., 1984), using F(ab’)₂ fragments. The impetus was thus provided for a host of studies to assess AECA in a number of settings delineated only by widespread vascular lesions. These include autoimmune conditions, such as SLE, rheumatoid arthritis (RA), systemic sclerosis (SSc), Wegener granulomatosis (WG), as well as infectious states, such as Kawasaki syndrome (KS), Behçet disease (BD), leprosy and cytomegalovirus (CMV) infection.

One may infer from the impressive diversity of conditions involved (Table 1) that AECA represent a mixed family of autoAb. Moreover, it may be stated that natural AECA exist, on the basis that they are produced by coculture of Epstein-Barr virus-infected B cells with EC. Furthermore, endothelium varies in phenotype (Fukuda et al., 1986), biology (Maruyama, 1998) and pathophysiologic implications (Belmont et al., 1996). This view is further supported by the finding that sera apparently negative on a given EC type become positive if appropriate substrate cells are used (Renaudineau et al., 2004).

The corollary of such a diversity is that the target antigens (Ag) differ from one group of AECA to another (Youinou et al., 1995; Praprotnick et al., 2001; Meroni et al., 2001; Castillo et al., 2001). Still, we are unable to identify most of them, and, even worse, the Ag status of endothelium from different sites is far from being completed. It has even been established that cytokines render EC immunogenic, whilst similar resting cells are not. Some AECA damage EC from capillaries and other bind to macrovascular EC. Not only would their in-depth analysis bring about new insights into the understanding of their pathogenesis, but their availability might provide a new asset for the clinician in the optimal management of inflammatory autoimmune conditions.