Nucleolin as the earliest target molecule of autoantibodies produced in MRL/lpr lupus-prone mice

To elucidate the autoantigen against which autoantibodies are produced in t he earliest phase of the disease:process of systemic lupus erythematosus (S LE), serum samples were collected individually and serially from 10 NZB/NZW F1 and 10 MRL/lpr mice. Using immunoblots with mouse thymoma cell (EL-4) l ysates as substrates, all mice were found to generate autoantibody against an either 150-kDa, 110-kDa, 75-kDa, or 55 kDa molecule in as early as 4 wee ks. Anti-DNA antibodies occurred almost at the same time or after those aga inst these four molecules. The number of antigens reactive with autoantibod ies in immunoblots increased gradually with age. Antibodies against histone molecules were produced after 8 weeks of age. Among the four antigens, the 110-kDa molecule was identified as nucleolin, which is an abundant nucleol ar phosphoprotein. Nucleolin binds DNA, RNA, and nucleic acid-binding prote ins such as histone H1. Nucleolin is a target of granzyme A of cytotoxic T cells, and autoantibodies against it are found in sera from patients with S LE as well as from those with various viral infections. These results indic ate that nucleolin is one of the immunodominant molecules that break down s elf-tolerance and initiate autoantibody-spreading in a mouse model of SLE. (C) 2000 Academic Press.