Systemic lupus erythematosus (SLE) is often considered the prototype systemic autoimmune disease, as virtually all components of the immune system contribute to the characteristic autoimmunity and tissue pathology. The utility of lupus research extends beyond defining lupus-specific mechanisms, as the disease can serve as a model system for consideration of immune system responses to microbial infection and control of hematologic malignancies. Especially in recent years, as new concepts have evolved to explain mechanisms that link the nucleic acid targets of lupus auto-antibodies to immune system activation and inflammation, the intellectual rewards of research on this most complex medical syndrome have grown. Yet this is a disease with high impact on patients, particularly women in the reproductive years. The satisfaction derived from new understanding of disease mechanisms will only be fully realized when those insights are translated into new therapies. Despite some frustrations in efforts to develop new lupus drugs, clinical care of lupus patients continues to improve, and the scope of clinical research in search of new lupus therapies has significantly expanded to include both traditional and new biologic agents.
The etiopathogenesis of lupus comprises genetic contributions, environmental triggers, and stochastic events, as demonstrated in murine models in the late 1980s [1
]. These factors play out at the level of the immune system, with multiple genetic hits and an undefined complement of exogenous or endogenous triggers required for initiation of autoimmunity. When the genetic load is sufficient, immune triggers are available and chance favors effective immune system activation, the disease process can move forward [2
] (Figure ). A concept that has been developed in recent years considers the kinetics of the disease, with lupus autoantibodies present in serum of lupus patients up to 5 years prior to the development of clinical manifestations of disease [3
]. It is notable that autoimmunity, when considered in a population of lupus patients, develops in a stereotypical manner, with anti-Ro and anti-La antibodies, common to several systemic autoimmune diseases, developing early in the pre-clinical stage of disease, while anti-Sm and anti-RNP antibodies, those that are more specific for SLE, developing very close to the time that disease becomes clinically apparent.
Figure 1 Stages of lupus pathogenesis. Genetic factors and environmental triggers, whether exogenous or endogenous, along with stochastic events, act on the immune system to initiate autoimmunity. Autoantibodies and their antigens, cytokines and chemokines amplify (more ...)
It is now recognized that autoantibodies and their associated nucleic acids can play an amplifying role in immune system activation, most likely through stimulation of innate immune pathways. Insights into the genetic variations that are associated with lupus, along with this new awareness of how autoimmunity, immune dysfunction, and tissue damage develop over time, are providing a more complete picture of disease risk, the steps in pathogenesis, and most significantly, new therapeutic targets.