Systemic lupus erythematosus: from genes to organ damage

Abstract

Systemic lupus erythematosus (SLE) is a disease characterized by inappropriate response to self-antigens. Genetic, environmental and hormonal factors are believed to contribute to the development of the disease. We think of SLE pathogenesis as occurring in three phases of variable duration. A series of regulatory failures during the ontogeny of the immune system lead to the emergence of auto-reactive clones and the production of auto-antibodies (phase I). As the immune response to self-antigens broadens, the auto-antibody repertoire is enriched (phase II) and clinical manifestations eventually ensue (phase III). The final result is tissue damage that if not treated will lead to the functional failure of such important organs as the kidney and brain.

Fig. 1

Aberrant T:B cell cooperation in SLE. SLE T cells display an aberrant phenotype upon activation. They express persistently CD154 (CD40 ligand) that provides help to B cells and do not undergo readily activation-induced cell death due to the upregulation of cyclo-oxygenase 2 and deficient production of interleukin-2. At the same time, IL-17+ T cells infiltrate tissues and contribute to local inflammation. Impaired toleragenic mechanisms lead to the escape to the periphery of auto-reactive B cells, which are prone to produce autoantibodies with help by T cells. Apoptosis of cells (such as keratinocytes after UV exposure) leads to ample auto-antigen availability that is not handled appropriately by the reticulo-endothelial system. In turn, immune complexes containing autoantigens and autoantibodies deposit in tissues causing complement-mediated injury.