INTRODUCTION — Apoptosis refers to cell death that occurs in a programmed manner, is characterized by cellular condensation (figure 1), and is noninflammatory or even antiinflammatory through the induction of certain cytokines and generation of T regulatory cells. By these criteria, it differs from necrosis, which is often referred to as "accidental" or pathologic death and which is accompanied by cell swelling (figure 1) and inflammation. These processes and their relationship to autoimmunity have been the subject of detailed investigation .
Apoptosis plays a pivotal role in the following processes [2,3]:
●Morphogenesis and tissue remodeling during embryonic development
●Cell death associated with homeostatic control of cell numbers (eg, immune system, lungs, skin, gastrointestinal tract)
●Elimination of immune effector cells that proliferate in response to activation (eg, by microbial infection)
The morphological features of apoptosis have been appreciated for decades: cytoplasmic and nuclear condensation, incorporation of intracellular constituents into membrane-enclosed "apoptotic bodies" that may bud from the surface, and surface expression of opsonic receptors that allow cells to rapidly phagocytose and to digest the corpse . A key feature of this physiologic death process is the preservation of plasma membrane integrity. Rapid ingestion of the apoptotic corpse by phagocytes with continued digestion of the cellular constituents prevents the cell from undergoing post-apoptotic necrosis associated with rupture of the membrane and extrusion of the cell contents .
In addition, it has been determined that cells may also die by specialized forms of necrosis that are also programmed. Examples include NETosis, a term for neutrophil extracellular trap (NET)-mediated cell death, as well as necroptosis and pyroptosis. The last two forms of cell death are associated with release of inflammatory cytokines such as interleukin (IL) 6 (necroptosis) or IL-1beta (pyroptosis) and could therefore be crucially involved in autoinflammatory and autoimmune diseases (see 'Clinical correlations' below). An outline of the biochemical pathways for each of these proinflammatory forms of cell death has been described .
Autophagy is a catabolic process by which cellular components are consumed and recycled and is not per se a mechanism of cell death. Autophagy has, however, been observed to accompany cell death induced by nutrient starvation. It has a characteristic morphology associated with the formation of autophagosomes , and it will not be considered further here.
The relationship between apoptosis, as well as other forms of cell death, and autoimmune disease, is discussed in this topic review.
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 the roundworm, Caenorhabditis elegans [7,8].
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.
Ced-3 is a downstream effector of the apoptotic program (figure 2). 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. A number of different ced genes also encode proteins responsible for phagocytosis of apoptotic cells (figure 3).
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 (figure 3):
●Just as ced-3 is a downstream effector of apoptosis in C. elegans, ced-3 orthologs comprise a family of proteases called caspases in higher eukaryotes. Caspases digest structural and enzymatic constituents of the cell to bring about apoptotic death . Not all caspases are involved in the execution of apoptosis. Human caspases 1, 4, 5, and possibly 12 and mouse caspases 1, 4, 11, and 12 are involved in promoting inflammation.
●The ced-4 orthologs (apoptosis activating factors [APAFs]) bind to the caspases and facilitate their conversion from inactive zymogens to active proteases.
●The ced-9 and egl-1 orthologs comprise a large family of proteins related to B-cell leukemia/lymphoma 2 (Bcl-2) , an oncogene that is transcriptionally activated by the t(14;18) chromosome translocation found in B-cell follicular lymphomas (see "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma"). Overexpression of Bcl-2 inhibits apoptosis in these cells, an essential component of lymphomatous growth. Individual members of the Bcl-2 family can interact with one another either to promote or to inhibit apoptosis, just as ced-9 prevents cell death and as egl-1 promotes cell death (by preventing the function of ced-9) .
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 .
●Internal triggering occurs when cells respond to environmental stress (eg, heat, x-rays, ultraviolet irradiation), to deoxyribonucleic acid (DNA) damage (genotoxic injury), or to misfolded proteins (endoplasmic stress). These events alter the function of mitochondria, an organelle that is essential not only for cell survival through the generation of adenosine triphosphate (ATP) but also for the regulation of entry into cell death .
Examples of extrinsic and intrinsic triggers of apoptosis are depicted schematically in the figure (figure 4). In this example, ligation of the dedicated death receptors CD95 (Fas) or tumor necrosis factor-receptor type I (TNF-RI) results in the recruitment of adaptor molecules (eg, Fas-associated protein with death domain [FADD] and tumor necrosis factor receptor type I-associated death domain protein [TRADD]) [14,15].
Proteolytic cascade — The adaptor molecules subsequently bind both to 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 induces conformational changes that allow proteolytic cleavage of 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) and enzymes, such as the inhibitor of caspase-activated DNase (ICAD). Cleavage of ICAD leads to the release of active CAD, which enters the nucleus and cleaves nucleosomes at the linker region, yielding the characteristic "DNA ladder." The end result is apoptotic death of the cell.
In response to environmental stress or cell damage (figure 5), the BH3 members of the Bcl-2 family such as Bak and Bax alter the permeability of the outer mitochondrial membrane, resulting 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 .
These basic pathways that lead to apoptosis are regulated by several proteins that bind to death receptors, adaptors, or caspases to modulate their function. Examples include Bcl-2 family members that titrate each other [17,18] and may bind to APAFs; inhibitors of apoptosis (IAPs), some of which attenuate caspase activity ; as well as the PI-3 Akt pathway that activates NFk-B and also blocks death effectors . 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 phagocytosed by macrophages and dendritic cells and promote an antiinflammatory immune response through induction of the cytokines, transforming growth factor (TGF)-beta or interleukin (IL) 10 . Phagocytosis is, in part, triggered by the expression of phosphatidylserine on the dying cell surface which, in turn, is recognized directly either by cell surface receptors or by opsonins (bridging molecules), which link the apoptotic cells with phagocytes . The efficiency of the phagocytic process depends upon the presence of the opsonins that include normal serum components such as the complement proteins C1q, C3, C4, and members of the pentraxin family, including pentraxin-3 (PTX3) and C-reactive protein (CRP) [21,22]. Binding of protein S, an antithrombotic plasma protein, to phosphatidylserine on the surface of apoptotic cells also promotes their phagocytosis .
CLINICAL CORRELATIONS — A number of observations indicate that dysregulated apoptosis or defective clearance of apoptotic cells may contribute to the onset or perpetuation of autoimmune disease, most likely because cells lose membrane integrity and leak their contents (post-apoptotic necrosis) [1,24-26]. There are also other mechanisms by which stimulation of the immune system by necrotic cells induce inflammation and may provoke autoimmunity . These include NETosis (neutrophil extracellular trap [NET]-mediated cell death), a process by which neutrophils stimulated by certain bacteria, cytokines, or immune complexes may die; necroptosis, a form of regulated necrosis that is dependent upon receptor-interacting protein kinase 3 (RIPK3) and occurs when caspases like caspase-8 are defective; and pyroptosis, a necrotic form of macrophage death associated with the release of interleukin (IL) 1-beta [1,26-30].
Autoimmune lymphoproliferative syndrome — The most striking example of abnormal apoptosis leading to disease is a rare autosomal dominant condition known as autoimmune lymphoproliferative syndrome (ALPS). Its onset in early childhood is heralded by lymphadenopathy, hepatosplenomegaly, and autoimmune phenomena including hemolytic anemia, thrombocytopenia, and autoimmune neutropenia, often in combination (ie, Evans syndrome). (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
Mutations in Fas or the Fas ligand (FasL) found in these patients interfere with the elimination of activated lymphocytes following exposure to self or foreign antigens. The persistence of these cells results in expanded populations of lymphocytes and predisposes to autoimmune phenomena and to the development of lymphomas. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)
Some patients require medical intervention for autoimmune manifestations, particularly clinically significant cytopenias, and usually respond to brief courses of glucocorticoids or other immunosuppressive drugs. (See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)
Systemic lupus erythematosus — Although mutant mice bearing inactivating mutations in Fas or FasL develop a clinical syndrome that resembles systemic lupus erythematosus (SLE), mutations in this death receptor pathway are only very rarely described in human SLE. Nevertheless, defective apoptosis may be involved in the activation of the immune system and production of autoantibodies reactive with self proteins, a common abnormality in those with SLE. (See "Epidemiology and pathogenesis of systemic lupus erythematosus".)
A large number of spontaneous or engineered mutations in mice reveal that defective uptake of apoptotic cells predisposes to lupus-like diseases. Examples include mice deficient in opsonins such as C1q and MFG-E8, as well as mutations of receptors responsible for ingestion of apoptotic cells [24,31]. There is evidence that this process may be perturbed in some patients with SLE. Impaired phagocytosis of apoptotic cells by macrophages in the germinal centers of lymph nodes of patients has been noted .
Dendritic cells, which are antigen-presenting cells that migrate in search of antigen, also efficiently recognize and phagocytose apoptotic cells [32,33]. Via a poorly understood mechanism, this process allows the dendritic cells to transfer peptides derived from the digested corpse to major histocompatibility complex (MHC) molecules expressed on its cell surface. The ability of the dendritic cell to present peptides derived from other cells is known as "cross priming." By this process, antigens expressed by poorly immunogenic cells, such as tumor cells, can be presented to the immune system by a highly efficient, professional antigen-presenting cell. (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)
A possible adverse consequence of the ability of dendritic cells to present antigens from apoptotic cells is that self antigens may provoke an immune response (figure 6). The immune system employs elaborate mechanisms of central and peripheral tolerance to prevent this possibility, processes that may be dysfunctional in SLE. This is supported by the observation that proteins modified by cleavage (by caspases or granzymes) or by posttranslational changes (eg, stress kinase phosphorylation, crosslinking by transglutaminase, ubiquitination and deimination of arginine residues) during cell death may be targeted by SLE autoantibodies, suggesting that dead or dying cells might serve as a reservoir of autoantigens in these patients [34,35]. Stimulation of the immune system by cells that die through necrosis, NETosis (neutrophils stimulated by certain bacteria, cytokines, or immune complexes die by this process), or necroptosis (this occurs when caspases like caspase 8 are defective and receptor interacting protein kinase 3 is activated) also cause inflammation and may provoke autoimmunity [30,36]. A common pathway for stimulation of the innate immune system is release of nucleic acids from late apoptotic cells or from necrotic cells. These nucleic acids are sensed as viruses by specialized receptors such as toll-like receptors (TLR) within phagocytic cells resulting the release of type 1 interferon and other inflammatory cytokines .
Abnormalities in biochemical pathways of apoptosis or in clearance of apoptotic cells in patients with SLE could be caused by genetic or environmental factors. Mutations in the genes encoding C1q and C-reactive protein (CRP), which facilitate the clearance of apoptotic cells, have been described [38,39], and genetic variations in ITGAM/CR3, which promotes the clearance of apoptotic cells , have been implicated in genome-wide association studies (GWAS) of SLE . Because viruses typically encode antiapoptotic proteins, viral infection could delay the apoptotic program, resulting in post-apoptotic necrosis and also the accumulation of modified self peptides . An example may be the viral FADD-like IL-1-beta-converting enzyme (FLICE)-inhibitory protein (FLIP), which serves as a substrate for caspase-8, thereby diverting the protease cascade and prolonging cell survival.
Rheumatoid arthritis — Autoantibodies likely contribute to the pathophysiology of rheumatoid arthritis (RA). The presence of antibodies reactive with self immunoglobulin (ie, rheumatoid factor) and with citrullinated proteins, such as vimentin, collagen, and enolase, are sensitive markers of this disease. Citrulline results from an oxidative post-translational modification of arginine produced by peptidyl arginine deiminase (PAD), an enzyme that can be activated during apoptosis  but is more commonly activated by the form of programmed necrosis called NETosis . Other targets of anti-citrullinated peptide antibodies (ACPA) have also been identified, and the role of these antibodies in RA is a matter of significant interest [27,29]. (See "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Autoantibodies' and "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies' and "Pathogenesis of rheumatoid arthritis".)
Abnormal (reduced) apoptosis in synoviocytes or macrophages has also been proposed to contribute to the synovial proliferation that is characteristic of this disease [43,44].
Systemic sclerosis — Endothelial cell apoptosis, mediated by antiendothelial cell antibodies and lymphocytes, has been suggested as a pathogenic mechanism in scleroderma. Examples include increased apoptosis in a chicken model of disease and the ability of sera from patients with scleroderma (plus activated lymphocytes) to induce programmed cell death in cultured human dermal endothelial cells [45,46]. Whether expression of type 1 interferon in this disease [47,48] plays a role remains to be determined. (See "Pathogenesis of systemic sclerosis (scleroderma)".)
●Apoptosis refers to cell death that occurs in a programmed manner, is characterized by cellular condensation, and is noninflammatory or antiinflammatory. Apoptosis plays a pivotal role in morphogenesis and tissue remodeling during embryonic development, in cell death associated with homeostasis (the billions of cells that die each day in the immune system, lungs, skin, and gastrointestinal tract), and in elimination of immune effector cells that proliferate in response to activation (eg, by microbial infection). (See 'Introduction' above.)
●Necrotic forms of cell death may be programmed or non-programmed. Classic necrosis is not programmed; it is referred to as "accidental" or pathologic cell death and is accompanied by loss of cell membrane integrity, cell swelling, and inflammation. Programmed necrosis can result from neutrophil NETosis, a term for neutrophil extracellular trap (NET)-mediated cell death (see 'Introduction' above); from necroptosis; and from pyroptosis. Immune activation is a consequence of direct release of inflammatory cytokines from necrotic cells as well as release of nucleic acids that indirectly stimulate cytokines from phagocytes.
●In higher eukaryotes, the genetic blueprint for the core death program is complicated by the expression of multiple genes that correspond to each step regulated by just a few genes as delineated in the nematode Caenorhabditis elegans (figure 3). In higher eukaryotes, the core death program can be triggered from without (external or extrinsic) by the ligation of dedicated death receptors by soluble or cell-associated ligands or from within (internal or intrinsic) the cell, when cells respond to environmental stress (eg, heat, x-rays, ultraviolet irradiation), to damage to DNA (genotoxic injury) or to misfolded proteins (figure 4). In some cases, ligation of the dedicated death receptors (eg, CD95 [Fas]), results in the recruitment of adaptor molecules. (See 'Molecular mechanisms of apoptosis' above and 'Caenorhabditis elegans' above and 'Higher eukaryotes' above.)
●Adaptor molecules involved in externally triggered apoptosis subsequently bind both to 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 through a proteolytic cascade. In response to environmental stress or cell damage (figure 5), members of the Bcl-2 family alter the permeability of the outer mitochondrial membrane, resulting in the release of cytochrome C and other effector proteins through several steps in the activation of caspase-9, an "upstream" caspase that is essential for initiation of the intrinsic death program with the subsequent activation of effector proteases, including caspase-3. The basic pathways that lead to apoptosis are regulated by several proteins that bind to death receptors, adaptors, or caspases to modulate their function. (See 'Proteolytic cascade' above.)
●One of the hallmarks of apoptosis is that cells undergoing apoptosis are normally phagocytosed by macrophages and dendritic cells without activating an inflammatory response. The efficiency of the phagocytic process depends upon the presence of the opsonins that include normal serum components, such as the complement proteins C1q, C3, and C4, and members of the pentraxin family, including pentraxin-3 (PTX3) and C-reactive protein (CRP). (See 'Noninflammatory phagocytosis' above.)
●A number of observations indicate that abnormal cell death may contribute to the onset or perpetuation of autoimmune disease, including autoimmune lymphoproliferative syndrome, a rare genetic condition in which mutations in Fas or Fas ligand (FasL) interfere with the elimination of activated lymphocytes following exposure to self or foreign antigens and systemic lupus erythematosus (SLE), in which defective clearance of apoptotic cells or an abnormal response to cell debris may be involved in the production of type I interferon as well as autoantibodies reactive with self proteins. Abnormal cell death or responses to cell debris may possibly also contribute to the pathogenesis of rheumatoid arthritis (RA) and systemic sclerosis. (See 'Clinical correlations' above.)
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