|Inheritance||autosomal dominant or recessive|
|Phenotype and clinics|| Paediatric onset with : |
1) autoimmunity, that is predominantly haematological, but any other autoimmunity can be displayed.
2) enlargement of the spleen and/or lymph nodes due to accumulation of polyclonal lymphocytes.
3) peripheral blood expansion of T cells expressing the TCRalpha/beta but not CD4 and CD8 (double-negative T cells).
4) decreased function of the Fas death receptor.
|Neoplastic risk||increased risk of lymphomas|
|Treatment||vigorous immune suppression|
|Evolution||autoimmunity may remit in adulthood but lymphoproliferation generally persists. Increased risk of lymphomas in adulthood.|
|Prognosis||good on survival, but autoimmune haemolytic anaemia may be occasionally lethal.|
|Genes involved and Proteins|
|Note|| The disease is due to inherited defects decreasing function of the Fas (CD95) death receptor, involved in switching off the immune response by triggering apoptosis of activated lymphocytes. |
The mutation mostly hits the Fas gene ( type-Ia), but rare mutations of the Fas ligand gene ( type-Ib) or the caspase-10 gene (ALPS-type-IIa) gene have also been described. Two siblings carrying a homozygous mutation of the caspase-8 gene displayed ALPS plus hypogammaglobulinemia and increased susceptibility to infections; this disease has been named caspase-8 deficiency, but some authors included it in ALPS as ALPS type-IIb.
Caspase-8 and caspase-10 are involved in Fas signalling.
Some authors used the term type-III to name the disease caused by unknown mutations hitting the Fas signalling pathway, others used it to name displayed by patients with normal Fas function.
Rieux-Laucat described a subgroup of patients carrying somatic mutations of the Fas gene in a subset of peripheral lymphocytes (mosaic type-Ia or type-Iam).
Since most patients with -Ia are heterozygous, the term type-0 has been used to name the rare and aggressive disease caused by homozygous mutations of the Fas gene.
The genetic background may influence the disease onset. Variants of the gene of perforin can act as predisposition factors.
|Description||encoded in 9 exons spanning 25 Kb|
|Description||protein of 320 aa. Several isoforms originating from alternative splicing have been described. It contains three Cysteine-rich Domains and one Death Domain.|
|Expression||expressed by activated lymphocytes, but also in multiple tissues and cell types.|
|Localisation||type-1 transmembrane protein|
|Function||death receptor. It triggers apoptosis upon ligation by its ligand (Fas ligand, FasL). It is involved in switching off the immune response and cell-mediated cytotoxicity.|
|Homology||Belongs to the tumor necrosis factor receptor family, subgroup pf death receptor|
|Germinal||multiple loss-of-function mutations have been reported in . They may decrease Fas expression or cause expression of receptors with dominant negative activity on Fas function. Mutations in the death domain have the highest penetrance.|
|Somatic||somatic mutations of the Fas gene have been reported in type-Iam|
|Description||encoded in 4 exons spanning 7.8 Kb|
|Description||protein of 281 aa|
|Expression||activated cytotoxic cells (CTL and NK) and TH1 cells, but also expressed in other tissues|
|Localisation||type II transmembrane protein|
|Function||triggers apoptosis of Fas-expressing cells|
|Germinal||two patients with type-Ib have been described to date. One carried a 84-bp deletion in exon 4 causing a 28-aa in-frame deletion. The other carried a A247E substitution in exon 4. Both mutations decreased FasL function.|
|Description||encoded in 9 exons spanning 37 Kb|
|Description||protein of 479 amino acids|
|Function||cystein-aspartate protease (caspase) triggering apoptosis. It is involved in the extrinsic pathway of apoptosis.|
|Germinal||heterozygous L285F and I406L substitutions have been detected in 2 patients with type-IIa|
|Description||encoded in 10 exons spanning 54 Kb|
|Description||protein of 496 amino acids. Several isoforms deriving from alternative splicing have been described.|
|Function||cystein-aspartate protease (caspase) triggering apoptosis. It binds to the adapter molecule FADD that associates with the intracytoplasmic tail of death receptors such as Fas and triggers the extrinsic pathway of apoptosis.|
|Germinal||homozygous R248W substitutions has been described in two siblings with plus immunodeficiency. The mutated protein lost the enzyme activity.|
|Note||biallelic mutations of PRF1 cause the familial hemophagocytic lymphohistiocytosis (HLH), an immune deficiency ascribed to decreased capacity of cytotoxic lymphocytes (CD8+ T cells and NK cells) to kill virus-infected cells.|
|Description||encoded in 3 exons spanning 5.4 Kb|
|Description||protein of 436 aa|
|Expression||expressed by cytotoxic effector lymphocytes (activated cytototoxic T cells and NK cells)|
|Localisation||it is stored in the lytic granules and secreted against the target cell|
|Function||it polymerizes on the membrane of target cells and forms pores|
|Homology||high sequenze homology to the C9 complement component|
|Germinal|| several PRF1 mutations have been associated with HLH and lymphomas. These mutations can inhibit either expression or function of perforin. |
A heterozygous N252S amino acid substitution has been described in one patient with type-Ia (i.e. carrying also a heterozygous mutation of the Fas gene) and one patient with type-III (i.e. with defective Fas function caused by an unknown gene alteration). It has been suggested that the PRF1 mutation may cooperate with the mutation hitting the Fas system in inducing ALPS development.
|Orphanet||Autoimmune lymphoproliferative syndrome|
|Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.|
|Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM|
|Cell. 1995 ; 81 (6) : 935-946.|
|Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.|
|Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP|
|Science (New York, N.Y.). 1995 ; 268 (5215) : 1347-1349.|
|Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.|
|Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD|
|The Journal of clinical investigation. 1996 ; 98 (5) : 1107-1113.|
|Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation.|
|Dianzani U, Bragardo M, DiFranco D, Alliaudi C, Scagni P, Buonfiglio D, Redoglia V, Bonissoni S, Correra A, Dianzani I, Ramenghi U|
|Blood. 1997 ; 89 (8) : 2871-2879.|
|Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.|
|Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ|
|Cell. 1999 ; 98 (1) : 47-58.|
|Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.|
|Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM|
|American journal of human genetics. 1999 ; 64 (4) : 1002-1014.|
|Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.|
|Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ|
|Nature. 2002 ; 419 (6905) : 395-399.|
|A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.|
|Del-Rey M, Ruiz-Contreras J, Bosque A, Calleja S, Gomez-Rial J, Roldan E, Morales P, Serrano A, Anel A, Paz-Artal E, Allende LM|
|Blood. 2006 ; 108 (4) : 1306-1312.|
|Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.|
|Clementi R, Chiocchetti A, Cappellano G, Cerutti E, Ferretti M, Orilieri E, Dianzani I, Ferrarini M, Bregni M, Danesino C, Bozzi V, Putti MC, Cerutti F, Cometa A, Locatelli F, Maccario R, Ramenghi U, Dianzani U|
|Blood. 2006 ; 108 (9) : 3079-3084.|
|Autoimmune lymphoproliferative syndrome with somatic Fas mutations.|
|Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM, Blanche S, Bartunkova J, Vilmer E, Fischer A, Le Deist F, Rieux-Laucat F|
|The New England journal of medicine. 2004 ; 351 (14) : 1409-1418.|
|REVIEW articles||automatic search in PubMed|
|Last year publications||automatic search in PubMed|
|Written||07-2006||Umberto Dianzani, Ugo Ramenghi|
|Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Sciences, łA. Avogadro˛ University of Eastern Piedmont, via Solaroli 17, I-28100 Novara, Italy|
|This paper should be referenced as such :|
|Dianzani U, Ramenghi U . Autoimmune lymphoproliferative syndrome. Atlas Genet Cytogenet Oncol Haematol. July 2006 .|
|URL : http://AtlasGeneticsOncology.org/Kprones/AutoimmLymphoID10116.html|
The various updated versions of this paper are referenced and archived by INIST as such :
|http://documents.irevues.inist.fr/bitstream/2042/38370/1/07-2006-AutoimmLymphoID10116.pdf [ Bibliographic record ]|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Mon Dec 2 17:59:45 CET 2013|
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