ABSTRACT
Autoimmunity is an inappropriate response of the immune system against selfcomponents. Th is response can cause serious tissue and organ damage which, in many cases, has fatal consequences. A variety of mechanisms have been proposed for the induction of autoimmunity. For example, aberrant apoptosis and/or the disposal of apoptotic cells have been implicated in loss of self-tolerance and the subsequent development of both systemic and organ-specifi c autoimmunity. Human and mouse studies have identifi ed a number of molecules in apoptotic pathways which when defective become major contributing factors to the development of disease. Th e human autoimmune lymphoproliferative syndrome is due to mutations in Fas which result in the failure of Fas-mediated apoptosis. Similarly, on certain genetic backgrounds Fas-and FasL-defi cient mice show lympho-accumulation, autoimmune glomerulonephritis and vasculitis. In systemic lupus erythematosus overexpression of pro-survival signals such as BAFF and
Bcl-2 as well as defective apoptotic cell clearance have been implicated in disease pathogenesis. Dysregulated pro-and anti-apoptotic pathways may also be involved in other autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes. A signifi cant body of information from mouse mutants along with data from knockout and transgenic models has elucidated to the contribution of apoptosis to autoimmune phenomena and off ers a rich pool of candidate molecules for human disease. More importantly, modulation of apoptotic cell death and the enhancement of apoptotic cell removal appear to be an exciting prospect as novel therapies for autoimmune diseases.
