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Autoimmune lymphoproliferative syndrome

Written2006-07Umberto Dianzani, Ugo Ramenghi
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Medical Sciences, _A. Avogadro_ University of Eastern Piedmont, via Solaroli 17, I-28100 Novara, Italy

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Atlas_Id 10116
Genes implicated inCASP8   CASP10   CTLA4   FAS   FASLG   PRF1  
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.
Gene NameFAS (Fas cell surface death receptor)
Alias TNFRSF6 Tumor necrosis factor receptor superfamily member 6, Fas, APO1, APT1, apoptosis antigen 1, CD95
Location 10q23.31
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

Gene NameFASLG (Fas ligand)
Alias TNFSF6, Tumor necrosis factor superfamily member 6, apoptosis antigen ligand 1, APT1LG1, CD95 ligand, CD95L, CD178
Location 1q24.3
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.

Gene NameCASP10 (caspase 10)
Alias caspase-10, MCH4, FLICE2
Location 2q33.1
Description encoded in 9 exons spanning 37 Kb
Description protein of 479 amino acids
Expression ubiquitous
Localisation cytosolic
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

Gene NameCASP8 (Caspase 8, Apoptosis-Related Cysteine Peptidase)
Alias caspase-8, FADD-like ICE, FLICE, MACH, MCH5
Location 2q33.1
Description encoded in 10 exons spanning 54 Kb
Description protein of 496 amino acids. Several isoforms deriving from alternative splicing have been described.
Expression ubiquitous
Localisation cytosolic
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.

Gene NamePRF1 (perforin 1)
Alias perforin, PFN1, pore forming protein, PFP, HPLH2, FLH2
Location 10q22.1
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.


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.
PMID 12353035
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.
PMID 16720836
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.
PMID 16627752
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.
PMID 9108407
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.
PMID 7540117
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.
PMID 15459302
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.
PMID 10090885
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.
PMID 7539157
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.
PMID 10412980
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.
PMID 8787672


This paper should be referenced as such :
Dianzani, U ; Ramenghi, U
Autoimmune lymphoproliferative syndrome
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):302-304.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes FAS

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