Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways.
Human and mouse natural mutants presenting with lymphoproliferative syndrome and autoimmunity (ALPS) have enlightened the role of the Fas and FasL in lymphocyte cell death and peripheral tolerance. Further study of the genetic basis of the human pathology led to the identification of apoptosis signaling defect, and pointed out to the crucial role of caspase-10 in the process of apoptosis induction. In contrast, the absence of lymproliferation in engineered mutants of 'death pathways' suggests that additional events are necessary to recapitulate the overt phenotype of ALPS patients or MRL/lpr mice. Moreover, these models highlight the roles of Fas and associated molecules, such as FADD and caspase-8, in lymphocyte development or activation. This review will discuss the main findings provided by the study of mouse models and human conditions.
Rieux-Laucat
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F
Hôpital Necker-INSERM U429, Paris, France. rieux@necker.fr
Le Deist
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F
Fischer
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A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D051379:Mice; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D020169:Caspases