Apoptosis: Inherited Disorders

Helen C Su, National Institutes of Health, Bethesda, Maryland, USA
Michael J Lenardo, National Institutes of Health, Bethesda, Maryland, USA

Published online: September 2009

DOI: 10.1002/9780470015902.a0005529.pub3

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.
close
 References
    Bi LL, Pan G, Atkinson TP et al. (2007) Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) type 1b. BMC Medical Genetics 8: 41–55.
    Bidere N, Su HC and Lenardo MJ (2006) Genetic disorders of programmed cell death in the immune system. Annual Review of Immunology 24: 321–352.
    Bouillet P, Metcalf D, Huang DC et al. (1999) Proapoptotic Bcl-2 relative Bim required for certain responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735–1738.
    Chen M, Wang Y, Wang Y et al. (2006) Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311: 1160–1164.
    Chipuk JE, Bouchier-Hayes L, Kuwana T et al. (2005) PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309: 1732–1735.
    Chun HJ, Zheng L, Ahmad M et al. (2002) Pleiotropic lymphocyte activation defects due to caspase-8 mutation cause human immunodeficiency. Nature 419: 395–399.
    Cohen PL and Eisenberg RA (1991) Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annual Review of Immunology 9: 243–269.
    Del-Rey M, Ruiz-Contreras J, Bosque A et al. (2006) A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood 108: 1306–1312.
    Drappa J, Vaishnaw AK, Sullivan KE, Chu J-L and Elkon KB (1996) Fas gene mutations in the Canale–Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. New England Journal of Medicine 335: 1643–1649.
    Fischer SF, Bouillet P, O'Donnell K et al. (2007) Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells. Blood 110: 3978–3984.
    Fisher GH, Rosenberg FJ, Straus SE et al. (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81: 935–946.
    Hao Z, Duncan GS, Seagal J et al. (2008) Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity 29: 615–627.
    Holzelova E, Vonarbourg C, Stolzenberg MC et al. (2004) Autoimmune lymphoproliferative syndrome with somatic Fas mutation. New England Journal of Medicine 351: 1409–1418.
    Hughes PD, Betz GT, Fortner KA et al. (2008) Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 28: 197–205.
    Hutcheson J, Scatizzi JC, Siddiqui AM et al. (2008) Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 28: 206–217.
    Jackson CE, Fischer RE, Hsu AP et al. (1999) Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. American Journal of Human Genetics 64: 1002–1014.
    Legembre P, Barnhart BC, Zheng L et al. (2004) Induction of apoptosis and activation of NF-kappaB by CD95 require different signalling thresholds. EMBO Reports 5: 1084–1089.
    Mabrouk I, Buart S, Hasmin M et al. (2008) Prevention of autoimmunity and control of recall response to exogenous antigen by Fas death receptor ligand expression on T cells. Immunity 29: 1–12.
    Oliveira JB, Bidere N, Niemela JE et al. (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proceedings of the National Academy of Sciences of the USA 194: 8953–8958.
    Raval A, Tanner SM, Byrd JC et al. (2007) Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129: 879–890.
    Rieux-Laucat F, Le Deist F, Hivbroz C et al. (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268: 1347–1349.
    Siegel RM, Frederiksen JK, Zacharias DA et al. (2000) Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288: 2354–2357.
    Sneller MC, Straus SE, Jaffe ES et al. (1992) A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. Journal of Clinical Investigation 90: 334–341.
    Snow AL, Oliveira JB, Zheng L et al. (2008) Critical role for Bim in T cell receptor restimulation-induced death. Biology Direct 3: 34–51.
    Stranges PB, Watson J, Cooper CJ et al. (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26: 629–641.
    Straus SE, Jaffe ES, Puck JM et al. (2001) The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germ line Fas mutations and defective lymphocyte apoptosis. Blood 98: 194–200.
    Su HC, Bidere N, Zheng L et al. (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307: 1465–1468.
    Takahashi T, Tanaka M, Brannan CI et al. (1994) Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76: 969–976.
    Vaishnaw AK, Orlinick JR, Chu J-L et al. (1999) The molecular basis for apoptotic defects in patients with CD95 (Fas/APO-1) mutations. Journal of Clinical Investigation 103: 355–363.
    Wang J, Zheng L, Lobito A et al. (1999) Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98: 47–58.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG et al. (1992) Lymphoproliferative disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314–317.
    Weant A, Michalek RD, Khan IU et al. (2008) Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 28: 218–230.
    Zhu S, Hsu AP, Vacek MM et al. (2006) Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Human Genetics 119: 284–294.
 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.
    ePath National Institute of Allergy and Infectious Diseases (2008) Autoimmune Lymphoproliferative Syndrome http://www3.niaid.nih.gov/topics/ALPS/.
    ePath OMIM Ataxia telangiectasia Mutated (Includes Complementation Groups A, C and D) (ATM); MIM number: . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=208900.
    ePath OMIM Caspase 8 (CASP8); MIM number . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763.
    ePath OMIM Caspase 10 (CASP10); MIM number . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601762.
    ePath OMIM Tumor Necrosis Factor Ligand Superfamily, Member 6 (TNFSF6); MIM number . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134638.
    ePath OMIM Tumor Necrosis Factor Receptor Superfamily, Member 6 (TNFRSF6); MIM number: . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134637.
    ePath OMIM Tumor protein p53 (Li-Fraumeni syndrome) (TP53); MIM number: . http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170.

Related Sub-Topics:

Immunodeficiency | Autoimmunity | Cells of the Immune System | Intracellular and Extracellular Signalling | Cell Death and Cellular Senescence | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Apoptosis: Inherited Disorders
 
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]