Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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apoptosis; Programmed cell death

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Kerr, 1972

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

General information
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Apoptosis and skin diseases:

  • Keratinocytes physiologically become apoptotic after 28 days of development. In addition to outflow through the horny layer, apoptosis of deeper keratinocytes can also occur with outflow through the dermo-epidermal basement membrane. The phagocytosis of "apoptotic bodies" is complicated and delayed. Proven disturbances of apoptosis, as they occur in chilblain lupus and systemic lupus erythematosus (mutations of the TREX1 gene), can lead to the triggering of these autoimmune diseases.
  • FAS-FAS ligand initiated apoptosis of keratinocytes plays an important role in the fixed drug response.
  • Dermatoses with single cell keratinization (so-called colloid corpuscles or cytoid corpuscles, dyskeratoses):
  • In terms of developmental history, the gentle elimination of UV-aged skin cells is useful to expel virus-infected or UV-damaged cells by apoptosis.
  • In addition to apoptosis, UVB can also lead to clustering of potentially immunogenic cellular autoantigens in the apoptosis corpuscles (cytoid corpuscles) and cell membrane prominences, possibly as target antigens of AMA and ANA in SLE.
  • UVB can result in a selection advantage for keratinocytes with inactivating point mutations at the p53 gene, since they do not become sunburn cells (apoptosis by p53) and can therefore proliferate uninhibited. See Table 3; (see also below photocarcinogenesis).
  • Apoptosis resistance is apparently also a characteristic feature of cutaneous T-cell lymphomas.

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The process of apoptosis can be divided into two phases: initiation and effector phase. There are three different processes of initiation:

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

Apoptosis by the apoptosis inducing factor (AIF):

Extrinsic pathway (apoptosis type I): This pathway is initiated by ligand binding to a receptor of the TNF receptor family (e.g. Fas = Apo-1 = CD95 see below tumor necrosis factor-α). The best known apoptosis effectors are the Fas ligand and its receptor Fas. (Note: The name "Fas" has no further meaning and is a coincidence in the discovery of this protein in 1985; its meaning as apoptosis receptor protein "Apo-1" was recognized only later) The mature Fas protein has 319 amino acids and a molecular weight of 48 kiloDaltons. It is divided into 3 domains: an extracellular domain, a transmembrane domain and a cytoplasmic domain. Besides Fas and Fas ligand, there are numerous other ligand-receptor interactions that lead to apoptosis. Both Fas ligand and TNF belong to the "TNF superfamily", Fas and TNFR-1 to the "TNF receptor superfamily". These "death receptors" have a "death domain", abbreviated DD) in their cytoplasmic part. Ligands are e.g. tumour necrosis factor (TNF) and other cytokines, which are produced by T-lymphocytes, among others. First, the TNF-receptor associated protein (TRADD) is activated. Then the "Fas associated protein" with the death domain (FADD) binds to the DD of the TRADD. FADD (see FLIP) also has a death effector domain - DED, through which a protease, the so-called initiator caspase proCaspase 8 (see caspases below) binds to the complex. What remains are shrunken, smallest components of the former cell. Each cell residue is still enclosed by an intact cell membrane (the cell dies in the intact envelope). These apoptotic, in the HE preparation perceived as eosinophilic cell corpuscles (so-called "cytoid bodies" or cytoid corpuscles, see Lichen planus below), contain components of the former cell organs. Cytoid bodies are phagocytized by macrophages. Through these mechanisms, numerous leukocytes not infected with the HIV virus are eliminated, e.g. in HIV-infected persons. The HI virus stimulates the immune cells that are not yet infected with the protein Nef (viral protein, a key molecule for HIV) to programmed cell death. The inhibitor "Fasudil" can stop this mechanism.

Intrinsic pathway (apoptosis type II or the pathway from within)

Mitochondria are also able to initiate the process of apoptosis. If 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 tumour suppressors such as p53 (see tumour suppressor genes below), a protein that is activated by damage to DNA. p-53 is a potent apoptosis inducer. As "guardian of the genome" it prevents DNA-mutated cells from entering the S-phase of mitosis. Furthermore, a number of toxic substances such as chemotherapeutic drugs can act directly on the mitochondria and thus 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 inhibitory proteins (IAPs) such as survivin.

Apoptosis in T lymphocytes and cutaneous T cell lymphomas

The type of apotosis T cells is called AICD = "activation-induced cell death". T cells are activated via the TZR, T cell receptor. A renewed activation leads to the formation of reactive oxygen species (ROS) and the release of intracellular calcium. Both signals induce the biolysis of the CD95 ligand (CD95L) which is released from the cell. It can dock to the CD95 receptor of its own cell or to nearby T cells to initiate apoptosis. This mechanism is important for the termination of an immune response. In cutaneous T-cell lymphomas, "resistance" of AICD plays an etiopathogenetic role.

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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.

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Blocking the induction of apoptosis can contribute to the development of tumours. In a number of malignant diseases, especially malignant lymphomas, a downregulation of CD95 expression or mutations in the CD95 gene have been observed. It is therefore assumed that CD95-induced apoptosis contributes to the elimination of lymphoma cells (evidence also for mycosis fungoides and the Sezary Syndrome. Here c-FLIP (inhibitor molecule) plays a role. C-FLIP is a caspase-8/-10 homologue, which also binds to FADD, but due to a lack of catalytic activity prevents the activation of caspases in the DISC (death inducing complex) and thus apoptosis induction. This leads to apoptosis resistance (AICD), which could play an important role in the pathogenesis of cutaneous T-cell lymphomas.

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  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

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Apoptosis induction and suppression

Apoptosis inhibitors

  • Erythropoietin

  • Androgens, estrogens

  • viral genes (e.g. EBV)

  • ACTH

  • NGF (nerve growth factor)

  • "Colony-stimulating factors"

  • SCF

  • IL-1, IL-6

  • EGF

  • Prolactin

  • CD40 Ligand, zinc

Apoptosis inducers

Withdrawal of apoptosis suppression in cells dependent on stimulation with these ligands

"death factors" in appropriately sensitive cells, usually depending on the cell cycle and degree of differentiation of the target cell as well as other cofactors and apoptosis "checkpoints":

  • TNF-α, Fas ligand

  • TGF-β1

  • Ceramides, prostaglandin

  • T-cell receptor stimulation through autoregulation

  • Endogenous retinoids

  • calcium influx, loss of adhesion, free oxygen radicals

Comparison apoptosis and necrosis





Loss of contact, nuclear condensation of single cells, cell and nuclear fragmentation, cytoskeleton remodelling, conversion into "apoptotic bodies", removal by phagocytes

Destruction of entire cell assemblies, nuclear swelling, nucleosinophilia, cell rupture with release of organelles and lysosomal enzymes


No, no scar

Yes, with scarred healing


Nucleus-controlled, influenced by the environment, passage of several checkpoints until the final "off", at the end the DNA is broken down into pieces by calcium-dependent endonucleases

Pathological influences such as hypoxia, ischemia etc. and resulting irreparable cell wall changes


minutes to hours

minutes to hours

Examples of apoptosis modulation by dermatologically applied therapy methods



  • UVB irradiation

  • Ciclosporin A

  • Radio (γ-Radiation) a

  • Zinc

  • Hyperthermia a

  • Cryotherapy a

  • PUVA

  • Dithranol

  • Glucocorticoids

  • Retinoids

  • Cytostatic drugs (e.g. cyclophosphamide, doxorubicin, 5-FU, vincristine, cisplatin, methotrexate) a


Last updated on: 29.10.2020