Autoimmunity versus tolerance: can dying cells tip the balance?

Apoptosis is a physiological process of self-destruction for cells that are damaged or programmed to die. Apoptosis occurs through a series of regulated events that allow cellular debris to be contained and efficiently phagocytosed without initiating a proinflammatory immune response. Recent data have linked physiological apoptosis and the uptake of apoptotic cells by macrophages and some subsets of dendritic cells to the maintenance of peripheral immune tolerance. However, when cells die through necrosis, spilling their intracellular contents, or are infected with various pathogens, activation of antigen-presenting cells and induction of an immune response can occur. Receptors for extrinsic pathogen-associated structures, such as membrane bound Toll-like receptors (TLRs) or intracellular Nod-like receptors (NLRs) can also respond to cross-reactive host molecules from dying cells and may focus autoimmune responses onto these antigens. Several autoimmune disorders have been linked to defects in the apoptotic process. Defective apoptosis of immune cells leads to autoimmunity, as in autoimmune lymphoproliferative syndrome (ALPS) associated with mutations in the death receptor Fas. Defective clearance of apoptotic cell debris can also lead to autoantibody production. We will discuss how cell death and apoptotic cell clearance may affect the finely tuned balance between peripheral immune tolerance and autoimmunity.