Developments in the clinical understanding of lupus

Abstract

Advances in genetics and new understanding of the molecular pathways that mediate innate and adaptive immune system activation, along with renewed focus on the role of the complement system as a mediator of inflammation, have stimulated elaboration of a scheme that might explain key mechanisms in the pathogenesis of systemic lupus erythematosus. Clinical observations identifying important comorbidities in patients with lupus have been a recent focus of research linking immune mechanisms with clinical manifestations of disease. While these advances have identified rational and promising targets for therapy, so far the therapeutic trials of new biologic agents have not met their potential. Nonetheless, progress in understanding the underlying immunopathogenesis of lupus and its impact on clinical disease has accelerated the pace of clinical research to improve the outcomes of patients with systemic lupus erythematosus.

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 immune system activation and generate tissue damage. Autoantibody production occurs years prior to the development of clinical signs and symptoms of systemic lupus erythematosus (SLE). Organ damage has likely occurred by the time lupus is diagnosed. Sx, symptoms; Dx, diagnosis.

Figure 2

Genetic determinants of lupus pathogenesis. Genome-wide association studies are confirming previous data identifying genetic variants that are statistically associated with systemic lupus erythematosus and are finding new lupus-associated genes. Most lupus-associated genes represent common variants, but several (C2, C4, C1q and TREX1) are characterized by rare mutations. We suggest that lupus-associated genes contribute to one or more essential mechanisms that must be implemented to generate lupus susceptibility. Some genetic variants will facilitate innate immune system activation, particularly type I IFN production; other genetic variants will result in increased availability of self-antigen; and other genetic variants will alter the threshold for activation or regulation of cells of the adaptive immune response, resulting in production of autoantibodies. Additional genetic variants might promote inflammation and damage to target organs or fail to protect those organs from proinflammatory mediators. The lupus-associated genetic variants prepare the immune system and target organs to be responsive to exogenous or endogenous triggers. Lupus-associated genes are shown in red.