Autoimmune lymphoproliferative syndrome

2006-07-01   Umberto 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

Identity

Name

Autoimmune lymphoproliferative syndrome

Inheritance

autosomal dominant or recessive

Omim

601859 , 603909 , 616100

Mesh

D056735

Orphanet

3261 Autoimmune lymphoproliferative syndrome

Umls

C1328840

Clinics

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.

Alias

TNFRSF6 Tumor necrosis factor receptor superfamily member 6, Fas, APO1, APT1, apoptosis antigen 1, CD95

Description

encoded in 9 exons spanning 25 Kb

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

Alias

TNFSF6, Tumor necrosis factor superfamily member 6, apoptosis antigen ligand 1, APT1LG1, CD95 ligand, CD95L, CD178

Description

encoded in 4 exons spanning 7.8 Kb

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.

Alias

caspase-10, MCH4, FLICE2

Description

encoded in 9 exons spanning 37 Kb

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

Alias

caspase-8, FADD-like ICE, FLICE, MACH, MCH5

Description

encoded in 10 exons spanning 54 Kb

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.

Alias

perforin, PFN1, pore forming protein, PFP, HPLH2, FLH2

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

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.

Bibliography

Pubmed IDLast YearTitleAuthors
123530352002Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.Chun HJ et al
167208362006Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.Clementi R et al
166277522006A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.Del-Rey M et al
91084071997Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation.Dianzani U et al
75401171995Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.Fisher GH et al
154593022004Autoimmune lymphoproliferative syndrome with somatic Fas mutations.Holzelova E et al
100908851999Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Jackson CE et al
75391571995Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.Rieux-Laucat F et al
104129801999Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.Wang J et al
87876721996Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.Wu J et al

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