Directing Autoimmunity to Nucleoprotein Particles

Over half a million people in the United States have sys-temic lupus. Most are women in their childbearing years. They usually have arthritis and scarring rashes, and about half have kidney involvement that may progress to renal failure. With time, there is an increasing likelihood that the brain will be involved, often resulting in loss of cognitive ability, seizures, and psychosis. Although the clinical features are highly variable, the patients are unified by the constant presence of autoimmunity to nucleoproteins, particularly to chromatin and small nuclear RNA-protein particles such as the U series of snRNPs that mediate pre-messenger RNA processing, and the Ro antigen (1). The resulting autoantibodies account for much of the tissue injury. For example, anti-DNA antibodies are harmful because they form immune complexes with extra cellular DNA and trigger an Arthus type of tissue injury, and sometimes they cross-react with cell surface proteins to exert a direct cytotoxic effect (2). Because of their central role in pathogenesis as well as their diagnostic usefulness, much effort has focused on understanding the mechanisms that account for these autoantibodies (3). Among many early clues, it was noted that IFN might have pathogenic importance in lupus. For example IFN levels are typically elevated in patients with lupus, and IFN accelerates disease in NZB/W lupus mice (4, 5). Subsequently, it became apparent that IFN treatment of patients with neo-plastic and viral diseases regularly induces fever, lethargy, and arthralgias much like the symptoms found among patients with active lupus. Occasionally, these patients develop anti-nuclear antibodies and a small number go on to express overt lupus (6–8). Finally, it was reported that IFN-␣ in sera from patients with lupus causes monocytes to differentiate into effective antigen presenting cells that are hypothesized to enhance formation of autoreactive T cells (9). This line of inquiry is extended now in two reports in this issue. The paper by Santiago-Raber et al. demonstrates that type I IFNs are essential for most of the autoimmune phenotype in NZB lupus mice (10). The paper by Bennett et al. shows that peripheral blood mononuclear cells from pediat-ric patients with lupus regularly have alterations in gene transcription that are attributable to changes induced by IFN-␣ and the effects of accelerated granulopoiesis (11). Here, I will suggest that the emerging insights concerning IFN-␣ , den-dritic cell (DC) biology, and apoptosis provide a rationale for autoimmunity in humans with lupus that is focused on …