The role of apoptosis in systemic lupus erythematosus.

Abstract

When it was described by Kerr et al. [1], the phenomApoptosis can be induced actively, through ligation of specific receptors such as Fas or TNFR, or passively, enon of apoptosis, or programmed cell death, was greeted with a resounding lack of interest. The importhrough lack of essential survival signals [8]. All cells in the body require continuous positive signals to stay alive tance of this phenomenon is such that it is now very difficult to pick up any journal in a biomedical field [15]. In the case of T lymphocytes, for example, these signals include interleukin (IL)-2 and interferon beta without finding at least one paper on the subject. It has become apparent that the process is ubiquitous, repres(IFN-b), which act by upregulating expression of antiapoptotic molecules such as Bcl-2 and L [16, 17]. enting a vital part of growth and differentiation in all tissues. The fundamental mechanisms of apoptosis and These molecules, in turn, suppress the release of cytochrome c from mitochondria [18, 19]. In the absence the genes that control it are highly conserved between species as diverse as worms and humans [2, 3]. of a positive signal for survival, cytochrome c forms a complex with APAF-1 and caspase 9, to form a caspase 3 Immunological research in apoptosis has focused on three areas in particular: (1) the selection of new activating unit [20]. Caspase 3 is the fulcrum between regulation of apoptosis and execution of the cell. When lymphocytes, both B and T cells, before antigen challenge [4–6 ]; (2) the regulation of clonal expansion and the activation of caspase 3 reaches a threshold level, its autocatalytic activity sets off a catastrophic chain reacresolution, including the elimination of apoptotic cells [7–10]; (3) the selection of memory cells [7–9, 11–14]. tion that leads to the activation of all the caspase 3 in the cell [21]. This is the point of irrevocable commitment About 10 million new lymphocytes are produced in the bone marrow each day [11] and during a viral infection to apoptosis. The active caspase 3 subsequently activates a range of downstream mediators that co-ordinate the the total number of lymphocytes may easily double, mostly with a vast number of activated cytotoxic T cells ordered destruction of the cell [22]. Active induction of apoptosis may either facilitate the release of cytochrome [11]. These cells must be eliminated at the end of the response, to avoid an exponential increase in the size c, or directly activate caspase 3 by a different route. In each case, caspase 3 activation defines the point of of the immune system [7]. However, this homeostatic balance must be achieved within a framework that commitment and the convergence point for all apoptosis induction pathways. accommodates the generation and persistence of memory cells, to permit a more potent response on In vitro, the terminal phase of apoptosis is ‘blebbing’. Minute balloon-like membrane extrusions bud off from subsequent re-challenge. Rescue from apoptosis is the crucial selection event in immunological memory for the surface of the cell, incorporating nuclear and cytoplasmic material. In vivo, this rarely happens, because both B and T lymphocytes. apoptotic cells are very effectively removed by phagocytes, which use a range of recognition systems to Apoptosis identify them [10, 23]. Apoptosis is an active process that leads to the ordered destruction of cells, avoiding the release of intracellular A question of tolerance contents into the extracellular microenvironment, where they have a powerful inflammatory effect. Apoptotic Immunological tolerance is a compromise that works cells undergo a series of distinct physical changes, includfor most people most of the time. Tolerance to self ing alteration of the surface lipid membrane, cytoskeletal operates through a number of mechanisms, but is prindisruption, cell shrinkage and a characteristic pattern of cipally the domain of T lymphocytes. T cells are selected DNA fragmentation. in the thymus from a population of immature thymocytes expressing randomly generated antigen receptors. Unlike B cells, which use surface-expressed antibody Submitted 1 June 1999; revised version accepted 17 June 1999. as a receptor and consequently can recognize native Correspondence to: M. Salmon, Division of Immunity and antigens, T cells only recognize short peptide antigens Infection, Rheumatology Research Group, The Medical School, The University of Birmingham, Birmingham B15 2TT, UK. presented in the groove of class I (CD8 cells) or class II