Other Nephritogenic Autoantibodies

Among the non-anti-DNA autoantibodies involved in kidney damage, those directed to a-enolase have recently been shown to be associated with nephritis. They are detectable in 27% of SLE patients (70% of them have active nephritis) (Pratesi et al., 2000), in 30% of mixed cryoglobulinemia patients with renal involvement (Sabbatini et al., 1997), in 40% of ANCA-positive vasculitis patients (Moodie et al, 1993), in 69% of patients with the primary form of the membranous nephritis, and in 58% of patients with secondary membranous nephritis (Wakui et al., 1999). Taken together, these data suggest that antibodies specific for a-enolase may play a role in nephritis.

Alpha-enolase is a ubiquitous glycolytic enzyme. Although it is expressed in virtually all tissues, the kidney and the thymus contain the highest amount of the enzyme. It is present in the cytoplasm, but in a variety of cells it is also expressed on the membrane, where it acts as a member of the plasminogen receptors family (Miles et al., 1991; Moscato et al., 2000). In normal kidney, a-enolase is highly expressed in tubuli and almost undetectable in glomeruli. In SLE and MC nephritic kidneys, the enzyme is overexpressed in tubuli and present in active inflammatory lesions. In SLE, enolase is also detectable in different sites of the glomeruli (mesangium, glomerular, and parietal epithelium, and especially in the crescents) (Migliorini et al., 2002). It is not clear how enolase expression is regulated in the kidney and how inflammatory stimuli lead to its overexpression. As a-enolase is ubiquitous, it is possible that anti-enolase antibodies form CICs, but the high amounts of enzyme in the kidney also allow in situ formation of complexes. In this regard, membrane expression of enolase is of utmost importance, because antienolase antibodies could directly cause glomerular and tubular injury by complement fixation. Autoantibodies may also interfere with enolase function as plasminogen receptor.

Plasminogen receptors are a heterogeneous group of proteins with carboxy-terminal lysines, characterized by a low affinity for plasminogen, a high density, and a ubiquitous distribution on different cell types. Plasminogen activation to plasmin takes place on fibrin surfaces or on cell membranes, where plasmin has increased fibrinolytic activity and is protected from inactivation. Fibrin deposits are abundant in nephritis and represent a marker of poor prognosis. The role of the fibrinolytic pathway in renal disorders has been analyzed in mice deficient in plasminogen, or in tissue plasminogen activator, or in urokinase-like plasminogen activator (Kitching et al., 1997). The proliferative glomerulonephritis due to in situ formation of ICs is more severe in mice deficient in fibrinolysis, as compared to wild-type mice. Thus, a downregulation of the fibrinolytic activity that impairs fibrin clearance may worsen glomerular inflammatory lesions. Recently, an anti-enolase monoclonal antibody was shown to be able to inhibit plasmin generation on the surface of cells (Lopez-Alemany et al., 2003). Moreover, anti-enolase antibodies able to inhibit plasminogen binding to a-enolase have been detected in patients with SLE or MC and active nephritis (Moscato et al., 2000). The role of autoantibodies endowed with such a property in the induction and perpetuation of renal damage remains under investigation. It could help unraveling the pathogenic mechanisms underlying tissue damage.

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