Abnormal T cell signal transduction in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an acute and chronic autoimmune disease of indeterminate etiology characterized by protean clinical symptoms and signs. Although this syndrome can occur in children or the elderly (1), SLE predominantly affects women in their childbearing years. Current information suggests that a complex interaction between environmental agents and disease susceptibility genes may predispose to SLE. Although many of these genes have not yet been identified, it is currently believed that the expression of such genes may predispose to aberrant cellular and humoral immune responses. Altered immune responses to autoantigens then result in pathologic autoantibody production, formation and deposition of antigen– antibody complexes, and propagation of a chronic inflammatory process that destroys organ parenchyma and results in end-stage organ failure, such as end-stage renal disease (2). At the cellular level, T lymphocytes mediate this altered immune response in SLE. Indeed, compared with normal controls in whom a balance of T cell functions exists (Figure 1A), diverse T cell dysfunctions result in an imbalance in the functions of T cell subsets in SLE (3–5) (Table 1 and Figure 1B). A pan–T cell dysfunction appears to exist that is characterized by exaggerated CD4 and diminished CD8 T cell activities. Moreover, natural killer (NK) cell functions are also defective (6). Due to the loss of effective CD8 T and NK cell feedback on B cells (7), forbidden B cell clones produce autoantibodies directed against an array of intraand extracellular autoantigens. Inquiries into the mechanism(s) causing these T cell dysfunctions have led to the identification of several new defects of signal transduction and have begun to reveal their molecular basis. It is timely, therefore, to review our progress during the 6 years since this subject was previously reviewed (8) to assess how abnormal signaling events contribute to our understanding of T cell dysfunctions in SLE. Second, we address the impact these signaling defects are likely to have on regulation and expression of IL2, a representative T cell–specific gene. Third, we summarize new signaling abnormalities that contribute to T cell apoptosis and necrosis, impaired protein translation, and altered DNA methylation. Fourth, we highlight initial genetic approaches in SLE T cells designed to bypass and to reconstitute a signaling defect and its effect on interleukin-2 (IL-2) production. Finally, we identify likely directions of future research that are anticipated to yield new information and novel insights into T cell effector dysfunctions in SLE.