Systemic lupus erythematosus (SLE) is an idiopathic autoimmune syndrome characterized by protean clinical symptoms and signs, and disordered cellular and humoral immune responses leading to autoantibody production. Since the initial identification of the LE cell (1) and the first demonstration of autoantibodies directed against nuclear antigens (2), an intensive search to understand the pathogenesis of SLE has been ongoing. This led first to the discovery of autoantibodies directed against discrete nuclear antigens (3, 4), and to the gradually evolving concept that such antigens may behave as autoantigens under conditions of defective tolerance to induce generation of autoantibodies (5, 6). Later, a cellular immune dysfunction was identified (7), and this, too, has been the subject of extensive analyses both in murine models of SLE and in human lupus (for review, see refs. 8-11). What we have learned is that the cellular immune disorder of SLE is a complex, multicellular dysfunction of all mononuclear leukocytes, including monocytes/macrophages, natural killer cells, B lymphocytes, and T lymphocytes (12). However, two perplexing issues have become apparent from this collective work. First, no unifying hypothesis of the cellular immune dysfunction that provides a direction for future investigations has yet emerged. Although several theories that have provided a fundamental structure to conceptualize autoimmunity have been advanced over the years (13-15), to date no definitive mechanism leading to autoimmunity in SLE has been discovered. A second issue is the nagging concern that any aberrant cellular immune effector dysfunctions