Paul Anderson, MD, PhD
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.1 is current through December 2006; this topic was last changed on April*18,*2006. The next version of UpToDate (15.2) will be released in June 2007.
INTRODUCTION — Apoptosis, or physiologic cell death, differs substantially from necrosis, or pathologic cell death. Unlike necrosis, apoptosis is essential for the following processes [1-3]: Morphogenesis during embryonic development Normal cell renewal Elimination of immune effector cells that proliferate in response to microbial infection.
The morphological features of apoptosis have been appreciated for decades: cytoplasmic and nuclear condensation, fragmentation of nuclei into membrane enclosed "apoptotic bodies," and surface expression of opsonic receptors that allow neighboring parenchymal cells to rapidly phagocytose and digest the corpse [4-6]. A key feature of this physiologic death process is the preservation of plasma membrane integrity. Rapid digestion of the contained apoptotic corpse avoids the recruitment of inflammatory cells which typically cause significant "collateral damage" to surrounding normal tissues.
A review of the relationship between apoptosis and autoimmune disease is presented here. Before discussing this interaction, it is helpful to briefly review the biology underlying apoptosis.
MOLECULAR MECHANISMS OF APOPTOSIS — The biochemical pathways responsible for apoptotic cell death have been elucidated in some detail. A genetic framework for the core death program has been provided by studies of a simple multicellular eukaryote, Caenorhabditis elegans [7].
Caenorhabditis elegans — Microscopic observations of C. elegans, a translucent nematode, have identified a subset of cells destined to die by apoptosis. Chemical mutagenesis has allowed the identification of genes that regulate this process.
In the scheme presented in Figure 1, ced-3 is a downstream effector of the apoptotic program (show figure 1). It is activated by ced-4, which is inhibited by ced-9. In turn, ced-9 is inhibited by egl-1. It follows from this scheme that the expression or activation of egl-1 results in apoptotic cell death.
Higher eukaryotes — Although the genetic blueprint utilized by C. elegans is followed in higher eukaryotes, the situation is complicated by the expression of multiple genes that correspond to each step delineated in the nematode: Just as ced-3 is a downstream effector of apoptosis in C. elegans, ced-3 orthologs comprise a family of proteases in higher eukaryotes that digest structural and enzymatic constituents of the cell to bring about apoptotic death [8]. The ced-4 orthologs (APAFs, for apoptosis activating factors) bind to the caspases and facilitate their conversion from inactive zymogens to active proteases [9]. The ced-9 and egl-1 orthologs comprise a large family of proteins related to bcl-2 [10], an oncogene that is transcriptionally activated by the t(14;18) chromosome translocation found in B-cell follicular lymphomas [11,12]. (See "Clinical and pathologic features of follicular lymphoma"). Overexpression of bcl-2 inhibits apoptosis in these cells, an essential component of lymphomatous growth. Just as ced-9 prevents cell death and egl-1 promotes cell death (by preventing the function of ced-9), individual members of the bcl-2 family can interact with one another to either promote or inhibit apoptosis [13].
**Triggering apoptosis — In higher eukaryotes, the core death program can be triggered from without (external or extrinsic) or from within (internal or intrinsic) the cell: External triggering involves the ligation of dedicated death receptors by soluble or cell-associated ligands [14]. Internal triggering occurs when cells respond to environmental stress (eg, heat, x-rays, ultraviolet irradiation) by altering the function of mitochondria, an organelle that is essential not only for cell survival, but also for regulating entry into cell death.
These extrinsic and intrinsic entryways into the death program are depicted schematically in Figure 2 (show figure 2). In this example, ligation of the dedicated death receptors CD95 (Fas) or TNF-RI, results in the recruitment of adaptor molecules (eg, FADD and TRADD) [9,15-17].
**Proteolytic cascade — The adaptor molecules subsequently bind to both the cytoplasmic domain of the dedicated death receptor and to the inactive form of caspase-8, an "upstream" caspase that initiates a proteolytic cascade leading to cell death. Because the zymogenic form of caspase-8 possesses low levels of protease activity, its aggregation allows one molecule to proteolytically activate an adjacent molecule, thereby initiating the proteolytic cascade. This culminates in the activation of effector caspases (eg, caspase-3) which directly cleave structural proteins (eg, nuclear lamins and cytoskeletal gelsolins [18]) and enzymes (eg, DNA-associated protein kinase, poly(ADP)ribose polymerase, etc.) to bring about apoptotic cell death.
In response to environmental stress, changes in the permeability of the outer mitochondrial membrane results in the release of cytochrome C and other effector proteins. Cytochrome C is a cofactor that allows APAF-1 to promote the activation of caspase-9, an "upstream" caspase that is essential for initiation of the intrinsic death program; the subsequent activation of effector proteases, including caspase-3, results in apoptotic cell death [19].
These basic pathways that lead to apoptosis are regulated by several proteins that bind to death receptors, adaptors, or caspases to modulate their function [20,21]. Examples include bcl-2 family members binding to APAFs, and inhibitors of apoptosis (IAPs) binding to caspases [22]. Not surprisingly, entry into apoptosis is a highly regulated process.
Noninflammatory phagocytosis — One of the hallmarks of apoptosis is that cells undergoing programmed death are normally phagocytosed by macrophages without activating an inflammatory or immune response. The mechanism for the efficient removal of apoptotic cells is not fully elucidated. The efficiency of the phagocytic process depends upon the presence of some normal components of plasma including complement components C1q, C3, C4, and members of the pentraxin family including pentraxin-3 (PTX3) C-reactive protein, and serum amyloid P component [23]. Binding of protein S, an antithrombotic plasma protein, to phosphatidylserine on the surface of apoptotic cells also promotes their phagocytosis [24].
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