Apoptosis

AICD; activation-induced cell death; cell death; 

The term "apoptosis" was first coined by pathologists Kerr, Wyllie and Currie in 1972.

Apoptosis (Greek from apo - away - and ptosis - fall - in the figurative sense for the falling of leaves from the trees) is a special form of cell death occurring under physiological conditions in addition to terminal differentiation (see also necroptosis). There is a selective, gentle elimination of cells with encapsulation and elimination of the nuclear substance, potential autoantigens and harmful cell contents. In contrast to necrosis (e.g. in dermatitis solaris), no inflammatory reaction develops! For normal embryonic development, for immune functions (see below Immunity, acquired) and the maintenance of tissue homeostasis, apoptosis represents a key essential biological phenomenon. Misdirected apoptosis is found in neoplasms, viral and autoimmune diseases. This also affects cutaneous T-cell lymphomas.

Apoptosis and Inflammation: Apoptosis, unlike (uncontrolled) necrosis, does not trigger an acute inflammatory response. Apoptotic cells are removed by phagocytosis by macrophages or dendritic cells. This prevents the uncontrolled release of inflammatory cell contents and consequent damage to neighboring cells (Nabhan S 2014). Phagocytes are attracted by specific chemokines ("find-me" signals) such as lysophosphatidylcholine, sphingosine-1- phosphate or low ATP and UTP concentrations. Specific surface signals, so-called "Eat-me" signals, subsequently mediate phagocytosis of apoptotic cells. This includes, for example, the exposure of the phospholipid phosphatidylserine (PS) from the cytosolic side of the cell to the cell surface (Introduction 1.5.3. Lauber K et al. 2004; Yoshida H et al. 2005; Gude DR et al. 2008).

Apoptosis and necrosis: Morphologically, necrotic and apoptotic cells can be clearly distinguished. Whereas apoptosis results in cell shrinkage and strangulation of apoptotic corpuscles with intact membranes, necrosis is not accompanied by vesicle formation, but rather severe cell swelling (oncosis) and eventually complete cell lysis (Van Cruchten S et al. 2002). Another distinguishing feature is chromatin condensation and enzymatic cleavage of DNA into fragments of defined length in apoptotic cells (Oberhammer FA et al 1994). In necrotic cells, on the other hand, the formation of DNA fragments of different lengths occurs because fragmentation here occurs at random sites (Zhang JH et al. 2000).

Apoptosis and skin diseases:

• Keratinocytes physiologically become apoptotic after 28 days of development. In addition to shedding through the stratum corneum, apoptosis of deeper keratinocytes with shedding through the dermoepidermal basement membrane may occur. Phagocytosis of "apoptotic bodies" is impeded and delayed. Proven disturbances of apoptosis, as found in chilblain lupus and systemic lupus erythematosus (mutations of the TREX1 gene), can lead to the initiation of these autoimmune diseases, which are based on a lichenoid dermatitic tissue reaction(interface dermatitis) in the skin.
• FAS-FAS ligand-initiated apoptosis of keratinocytes plays a significant role in the fixed drug response.
• Dermatoses with single cell keratinization (so-called colloid corpuscles or cytoid corpuscles, dyskeratoses):
  • Lichen ruber
  • lupus erythematosus
  • Spitz nevus
  • Bowenoid papulosis
  • M. Darier
  • Lichen striatus
  • Steroid-induced skin atrophy
  • Incontinentia pigmenti
  • lichenoid actinic keratosis
  • acrodermatitis enteropathica
  • focal acantholytic dyskeratosis
  • Fixed drug reaction.
• Developmentally, gentle elimination of UV-aged skin cells is useful for the elimination of virus-infected or UV-damaged cells by apoptosis.
• In addition to apoptosis, clustering of potentially immunogenic cellular autoantigens in apoptotic corpuscles (cytoid corpuscles) and cell membrane prominences may result from UVB, possibly as target antigens of AMA and ANA in SLE.
• UVB may confer a selection advantage to keratinocytes with inactivating point mutations at the p53 gene, as they cannot become sunburn cells (apoptosis via p53) and thus proliferate uninhibited. See also Table 3; (see further below Photocarcinogenesis).
• Resistance to apoptosis is apparently also a characteristic of cutaneous T-cell lymphomas.

The process of apoptosis can be divided into two phases: the initiation phase and the effector phase. During the initiation phase, three processes are distinguished:

• Extrinsic (Type I apoptosis)
• Intrinsic (Type II apoptosis).

Apoptosis mediated by the Apoptosis-Inducing Factor (AIF):

Extrinsic pathway (Type I apoptosis): This pathway is initiated by ligand binding to a receptor of the TNF receptor family (e.g., Fas = Apo-1 = CD95; see Tumor Necrosis Factor-α below). The best-known apoptosis effectors are the Fas ligand and its receptor, Fas. (Note: The name “Fas” has no specific meaning and is a coincidence resulting from the discovery of this protein in 1985; its significance as the apoptosis receptor protein “Apo-1” was not recognized until later).The mature Fas protein has 319 amino acids and a molecular weight of 48 kilodaltons. It is divided into three domains: an extracellular domain, a transmembrane domain, and a cytoplasmic domain.

In addition to the Fas receptor and Fas ligand, there are numerous other ligand-receptor interactions that lead to apoptosis. One example is the interaction between TNF and its receptor TNFR-1. Both the Fas ligand and TNF belong to the “TNF superfamily,” while Fas and TNFR-1 belong to the “TNF receptor superfamily.” These “death receptors” possess a “death domain” (abbreviated DD) in their cytoplasmic region. Ligands include, for example, tumor necrosis factor (TNF) and other cytokines produced, among others, by T lymphocytes. First, the TNF receptor-associated protein (TRADD) is activated. Subsequently, the “Fas-associated death domain” (FADD) binds to the DD of TRADD. FADD (see alsoFLIP) also possesses a “death effector domain” (DED), via which a protease—the so-called initiator caspase proCaspase 8 (see Caspases below)—binds to the complex. What remains are shrunken, minute fragments of the former cell. Each cell fragment is still enclosed by an intact cell membrane (the cell dies within its intact envelope). These apoptotic structures, visible in HE-stained preparations as eosinophilic cell bodies (so-called “cytoid bodies”; see below: Lichen planus), contain components of the former cell organelles. Cytoid bodies are phagocytosed by macrophages. Through these mechanisms, for example, numerous leukocytes not infected with HIV are eliminated in HIV-infected individuals. The HIV virus uses the Nef protein (a viral protein and a key molecule for HIV) to induce programmed cell death in immune cells that have not yet become diseased. The inhibitor "Fasudil" can block this mechanism.

Intrinsic pathway (Type II apoptosis or the intrinsic pathway)

Mitochondria are also capable of initiating the process of apoptosis. When mitochondria are damaged, they release the protein cytochrome C and other pro-apoptotic factors such as Smac/DIABLO, which in turn activate the caspases. This pathway can be triggered by tumor suppressors, such as p53 (see below: tumor suppressor genes), a protein that is activated by DNA damage. p53 is a potent inducer of apoptosis. As the “guardian of the genome,” it prevents cells with DNA mutations from entering the S phase of mitosis. Furthermore, a number of toxic substances, such as chemotherapeutic agents, can act directly on the mitochondria and thereby induce type II apoptosis. The most important proteins involved in the suppression of apoptosis are the “anti-apoptotic” members of the Bcl-2 family (Bcl-2 and Bcl-xL) and apoptosis-inhibiting proteins (IAPs) such as survivin.

Apoptosis in T-Lymphocytes and Cutaneous T-Cell Lymphomas

The type of apoptosis in T cells is called AICD, or “activation-induced cell death.” T cells are activated via the TCR, the T-cell receptor. Reactivation leads to the formation of reactive oxygen species (ROS) and the release of intracellular calcium. Both signals induce the formation of the CD95 ligand (CD95L), which is secreted from the cell. It can then bind to the CD95 receptor on the cell itself or on neighboring T-cells, thereby triggering apoptosis. This mechanism is important for terminating an immune response. In cutaneous T-cell lymphomas, “resistance” of the AICD plays an etiopathogenetic role.    

The course of apoptosis can be followed very well under the light microscope. First, the cell in question detaches from the tissue. As the process progresses, the cell becomes more and more eosinophilic and becomes increasingly smaller. The cell nucleus becomes smaller and denser (pycnotic). Finally, a homogeneously eosinophilic apoptosis corpuscle (cytoid corpuscle) remains. This is then broken down by macrophages. In contrast to necrosis, apoptosis does not trigger an acute inflammatory reaction.

Blockade of apoptosis induction may contribute to tumorigenesis. Down-regulation of CD95 expression or mutations in the CD95 gene have been observed in a number of malignancies, particularly malignant lymphomas. CD95-induced apoptosis is therefore thought to contribute to the elimination of lymphoma cells (evidence also for mycosis fungoides and Sezary syndrome. Here, c-FLIP (inhibitor molecule) plays a role. C-FLIP is a caspase-8/-10 homolog that also binds to FADD, but due to lack of catalytic activity prevents activation of caspases in the DISC (death-inducing complex) and thus apoptosis induction. Apoptosis resistance (AICD) results, which may play a significant role in the pathogenesis of cutaneous T-cell lymphomas.

1. Budd RC (2002) Death receptors couple to both cell proliferation and apoptosis. J Clin Invest 109: 437-441
2. Cataisson C et al (2003) Activation of Cutaneous Protein Kinase Calpha Induces Keratinocyte Apoptosis and Intraepidermal Inflammation by Independent Signaling Pathways. J Immunol 171: 2703-2713
3. Choi HJ edt al. (2006) Possible role of fas/fas-ligand-mediated apoptosis in the pathogenesis of fixed drug eruption. Br J Dermatol 154: 419-425
4. Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348: 1365-1375
5. Hildeman DA et al (2003) T cell apoptosis and reactive oxygen species. J Clin Invest 111: 575-581
6. McHugh NJ (2002) Systemic lupus erythematosus and dysregulated apoptosis-what is the evidence? Rheumatology (Oxford) 41: 242-245
7. Paus, R et al (1995) Necrobiology of the skin: Apoptosis. dermatologist 46: 285-303
8. White SR et al (2002) Corticosteroid-induced apoptosis of airway epithelium: a potential mechanism for chronic airway epithelial damage in asthma. Chest 122(6 Suppl): 278S-284S

Apoptosis induction and suppression

Comparison apoptosis and necrosis

Examples of apoptosis modulation by dermatologically applied therapy methods