Autoimmune lymphoproliferative syndrome with somatic Fas mutations

Charles University in Prague, Praha, Praha, Czech Republic
New England Journal of Medicine (Impact Factor: 54.42). 10/2004; 351(14):1409-18. DOI: 10.1056/NEJMoa040036
Source: PubMed

ABSTRACT Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro.
Susceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III.
Heterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells.
Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.

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    • "Ce syndrome est lié à des mutations du gène FOX P3 qui code pour l'ADNbinding protein scurfin nécessaire à l'activité des lymphocytes T régulateurs CD4+, CD25+ [19] [20] ; ● le syndrome ALPS (autoimmune lymphoproliferative syndrome ) se caractérise par des mutations du système FAS/ FAS Ligand régulant l'apoptose lymphocytaire. Ce syndrome , dont il existe plusieurs formes, se caractérise globalement par des manifestations auto-immunes cliniques et biologiques (cytopénies) et l'apparition d'une lymphoprolifération CD4–/CD8– [21] ; ● le syndrome APECED (autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy syndrome) appelé aussi APS-1 (autoimmune polyendocrine syndrome-1) est caractérisé par les mutations du gène AIRE (auto-immune regulator proteine) qui intervient dans l'éducation thymique des lymphocytes T régulateurs. Ce syndrome se caractérise par des manifestations auto-immunes essentiellement endocriniennes parfois associées à une candidose chronique [22]. "
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    • ") TCR ab + double-negative T cells (DNT) in the peripheral blood and lymphoid tissues, defective lymphocyte apoptosis in vitro, fairly characteristic histopathology and a significantly elevated lifetime risk for lymphoma (Straus et al, 2001). Inherited or somatic heterozygous mutations in the tumour necrosis factor receptor superfamily member 6 (TNFRSF6) gene encoding Fas account for 75% of all cases of ALPS, being classified as Type Ia (Holzelova et al, 2004; Puck & Straus, 2004). Mutations in Fas ligand (FasL), caspase 10 or 8 underlie cases classified as types Ib, IIa or IIb respectively. "
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    ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.
    British Journal of Haematology 06/2005; 129(4):534-8. DOI:10.1111/j.1365-2141.2005.05496.x · 4.96 Impact Factor
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