Apoptosis: Inherited Disorders


Apoptosis is a mechanism of programmed cell death used in organ remodelling during development and for eliminating unnecessary or dangerous cells. In the immune system, apoptosis maintains homeostasis by limiting lymphocyte responses. Genetic defects in apoptosis leads to disturbed lymphocyte homeostasis and, potentially, autoimmunity or neoplasia. An important apoptosis disorder in humans involves the death receptor Fas. However, recently, disorders in the apoptosis pathways triggered by trophic factor withdrawal or deoxyribonucleic acid (DNA) damage have also been described. Dual roles of certain molecules for both apoptotic and normal nonapoptotic lymphocyte function can account for combined apoptosis and immunodeficiency disorders.

Key concepts

  • Lymphocytes undergo propriocidal regulation, in which the cells that are actively proliferating are most susceptible to programmed cell death. This form of negative regulation limits the maximal intensity of immune responses and establishes the basal state of homeostasis after an immune response.

  • Apoptosis occurs when T lymphocytes become activated to express death receptors, undergo repeated antigenic stimulation through the T‐cell receptor, or cease to produce growth factors such as IL‐2. Apoptotic pathways stimulated by death receptors, and those stimulated by intracellular derangements, are both utilized.

  • Mice and humans who have defective apoptosis display progressive accumulation of lymphocytes, systemic autoimmunity and a predisposition to lymphoid malignancy.

  • Most genetic lesions responsible for the prototypical disease in humans, autoimmune lymphoproliferative syndrome (ALPS), involve the Fas death receptor that mediates extrinsic apoptosis. ALPS can also result from a mutation in NRAS that impairs Bim‐mediated apoptosis during cytokine deprivation.

  • Humans with caspase‐8 or SH2D1A (SAP) deficiencies have lymphoproliferative disease and immunodeficiency, illustrating the dual roles of these molecules for lymphocyte apoptosis and nonapoptotic lymphocyte function.

  • p53 mutations responsible for cancer susceptibility in the Li–Fraumeni syndrome impair genotoxic stress‐induced apoptosis, through effects on Puma and other Bcl‐2 family members.

Keywords: apoptosis; autoimmune lymphoproliferative syndrome/ALPS; caspase‐8 deficiency state/CEDS; X‐linked lymphoproliferative syndrome/XLP; Li–Fraumeni syndrome

Figure 1.

The Fas‐mediated apoptosis pathway. Apoptosis is initiated by trimerized Fas ligand (FasL) binding to its extracellular docking site on trimerized Fas. Fas–FasL interaction initiates intracellular recruitment of FADD (Fas‐associated protein with death domain) to the trimerized cytoplasmic death domains of Fas, which together with caspase‐8 and ‐10 molecules form a death‐inducing signalling complex. Activation of the initiator caspase‐8 and ‐10 leads to a lethal proteolytic cascade, involving other effector caspases and ultimately causing mitochondrial damage, membrane changes, proteolysis, nuclear condensation and chromosomal degradation. Intracellular changes sensed by Bcl‐2 family members can also lead to mitochondrial disturbances that activate caspases.

Figure 2.

Girl with autoimmune lymphoproliferative syndrome (ALPS), showing massive cervical adenopathy.

Figure 3.

Schematic representation of Fas mutations found in ALPS patients. Most mutations are found in exon 9, within the intracellular death domain of Fas. This causes a dominant interfering effect in which most Fas receptors, which are composed of trimers, have at least one mutant chain. The defective complex is thus unable to recruit the other signalling components necessary for propagating signals for programmed cell death.



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Further Reading

Kroemer G, Gulluzzi L, Vandenabeele P et al. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation 16: 3–11.

National Institute of Allergy and Infectious Diseases (2008) Autoimmune Lymphoproliferative Syndrome http://www3.niaid.nih.gov/topics/ALPS/.

OMIM Ataxia telangiectasia Mutated (Includes Complementation Groups A, C and D) (ATM); MIM number: 208900. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=208900.

OMIM Caspase 8 (CASP8); MIM number 601763. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763.

OMIM Caspase 10 (CASP10); MIM number 601762. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601762.

OMIM Tumor Necrosis Factor Ligand Superfamily, Member 6 (TNFSF6); MIM number 134638. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134638.

OMIM Tumor Necrosis Factor Receptor Superfamily, Member 6 (TNFRSF6); MIM number: 134637. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134637.

OMIM Tumor protein p53 (Li‐Fraumeni syndrome) (TP53); MIM number: 191170. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170.

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How to Cite close
Su, Helen C, and Lenardo, Michael J(Sep 2009) Apoptosis: Inherited Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005529.pub3]