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Autoimmune lymphoproliferative syndrome (ALPS)


Synonym: Canale-Smith syndrome

Primary disorder of immune regulation due to a genetic defect in any of the following genes:

1. TNFRSF6 (tumor necrosis factor receptor superfamily 6, CD95, Fas), ALPS type IA

2. TNFSF6 (tumor necrosis factor superfamily 6, Fas ligand, FasL, CD95L), ALPS type IB

3. CASP10 (Caspase-10), ALPS type IIA

4. CASP8 (Caspase-8), ALPS type IIB

5. NRAS (neuroblastoma RAS viral oncogene homolog), ALPS type IV


Note that clinical ALPS due to unknown gene defect is referred to as type III. Also note that clinically similar disease has been associated with somatic mutations of TNFRSF6 (Fas) [1].

Clinical background

The main clinical feature considered required for a diagnosis of ALPS is chronic non-malignant lymphadenopathy and/or splenomegaly [2, 3]. Supporting clinical features include: autoimmune disease (predominantly cytopenias, other disorders may be seen), positive family history of ALPS, characteristic lymph node or splenic histology (retention of lymph node architectural features with marked paracortical T zone expansion), and mutation in one of the above genes.

Immunologic background

A defining immunologic characteristic is an elevated number of circulating double negative T cells (DNT, CD3+TCRαβ+CD4CD8 [2, 3]. The number should be at least >1% of all lymphocytes [2, 3], or >2.6% of T lymphocytes [4]. However, this level of expansion may not be present in all cases. Another important feature is defective antigen induced apoptosis in cultured activated lymphocytes in vitro [2, 3]. The common functional pathway linking the diverse genetic defects in this disorder to a single clinical phenotype is impairment of programmed cell death (apoptosis) [3]. Fas and Fas ligand are cell membrane molecules whose interaction initiates apoptotic cell death in the Fas-expressing cell. Via several intermediates, caspases 8 and 10 are activated and lead to further downstream signalling events resulting in apoptotic cell death. Activating NRAS mutation (one patient described) does not interfere with Fas/FasL signalling [5]. Instead, activation of N-Ras blocks intrinsic non-receptor mediated mitochondrial apoptosis. Although the mechanism is not clearly defined, it is presumed that autoreactive T cell clones that would normally be destined for apoptotic death are permitted to expand and cause disease through the failure of the apoptotic mechanism.

Animal models

The phenotypes of the naturally occurring mouse mutants lpr (lymphoproliferation) and gld (generalized lymphoproliferative disease) led to the initial descriptions of human Fas and Fas ligand, respectively, and their associations with ALPS [6]. The phenotypes of these mouse mutants are analagous to the corresponding human disorders. Homozygous caspase-8-deficient mice die during embryonic development [7]. Deletion of N-Ras in mice is not associated with an overt immunologic phenotype [8]. Deletion of caspase-10 has not been described.


1. Holzelova, E., et al., Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med, 2004. 351(14): p. 1409-18.

2. Oliveira, J.B. and S. Gupta, Disorders of apoptosis: mechanisms for autoimmunity in primary immunodeficiency diseases. J Clin Immunol, 2008. 28 Suppl 1: p. S20-8.

3. Worth, A., A.J. Thrasher, and H.B. Gaspar, Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol, 2006. 133(2): p. 124-40.

4. Teachey, D.T., et al., Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood, 2005. 105(6): p. 2443-8.

5. Oliveira, J.B., et al., NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A, 2007. 104(21): p. 8953-8.

6. Krammer, P.H., CD95's deadly mission in the immune system. Nature, 2000. 407(6805): p. 789-95.

7. Varfolomeev, E.E., et al., Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity, 1998. 9(2): p. 267-76.

8. Umanoff, H., et al., The murine N-ras gene is not essential for growth and development. Proc Natl Acad Sci U S A, 1995. 92(5): p. 1709-13.

9. Bleesing, J.J., et al., Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood, 2001. 98(8): p. 2466-73.


Responsible person

Francisco A. Bonilla, M.D., Ph.D.; Petar Zarev, M.D., Ph.D.


Last update: 2009-07-15 11:42:41
Immunologic phenotypes (Autoimmune lymphoproliferative syndrome (ALPS))

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