Autoimmune Lymphoproliferative Syndrome with Somatic<i>Fas</i>Mutations

Hölzelova, Eliska; Vonarbourg, Cédric; Stolzenberg, Marie-Claude; Arkwright, Peter D.; Selz, Françoise; Prieur, Anne Marie; Blanche, Stéphane; Bartůňková, Jiřina; Vilmer, E; Fischer, Alain; Deist, Françoise Le; Rieux-Laucat, Frédéric

doi:10.1056/nejmoa040036

Cited by 288 publications

(266 citation statements)

References 36 publications

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…Single-positive mononuclear cells (CD4, CD8, CD14, CD20), DNT cells, and buccal epithelial cells from one patient with a somatic mutation resulting in loss of a restriction endonuclease site (HpyCHIII) were tested for the presence or absence of the mutation observed in the DNT cell population. We confirmed that the mutation was present in less than 10% of PBMCs but not in buccal epithelial cells (data not shown), similar to the findings of Holzelova et al 10 In addition, all 12 somatic mutations resulted in known (N ϭ 4) or predicted (N ϭ 8) functional loss of normal FAS signaling ( Table 1). Ten of the mutations were predicted to lead to a premature stop codon; 4 of these have been previously observed associated with ALPS as a germline mutation and 6 were newly identified.…”

Section: Fas Mutations Are Identified In Purified Dnt Cells But Not supporting

confidence: 79%

“…We sought to confirm and extend the findings of Holzelova et al 10 by screening 31 ALPS type III and phenotype patients for somatic mutations in FAS. Both ALPS type III and ALPS phenotype patients are defined as having an unknown underlying genetic mutation, with ALPS phenotype patients lacking a demonstrable in vitro apoptosis defect affecting the FAS pathway.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Dowdell

Niemela

Price

et al. 2010

Blood

132

View full text Add to dashboard Cite

Section: Fas Mutations Are Identified In Purified Dnt Cells But Not supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Dowdell

Niemela

Price

et al. 2010

Blood

132

View full text Add to dashboard Cite

“…This mechanism may explain the clinical features seen in autoimmune lymphoproliferative syndrome (ALPS), a disease characterized by somatic mutations in the Fas/Fas-ligand pathway, leading to compensatory expansion of DN Tregs that are unable to prevent autoimmunity (Holzelova et al, 2004). In this context, ALPS provided evidence of the important role DN Tregs play in maintaining peripheral tolerance in healthy individuals.…”

Section: Discussionmentioning

confidence: 88%

Double‐negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation

McIver¹,

Serio²,

Dunbar³

et al. 2008

Br J Haematol

View full text Add to dashboard Cite

SummaryDouble-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/ Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vb) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vb family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.

show abstract

“…According to genotype, ALPS can be classified as types Ia, Ib, and II, which are due to germline mutations in CD95 (TNFRSF6), CD95 ligand (TNFSF6), and caspase 10 (CASP10), respectively (10)(11)(12)(13). Additionally, somatic mutations of CD95 in ␣␤ DNTs can also cause ALPS of type Im (mosaic) (14). All of these mutations impair extrinsic, Fas receptor-mediated apoptosis (10).…”

mentioning

confidence: 99%

NRAS mutation causes a human autoimmune lymphoproliferative syndrome

Oliveira

Bidère

Niemela

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

220

173

View full text Add to dashboard Cite

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4 ؊ , CD8 ؊ ␣␤ T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders. autoimmunity ͉ B cell lymphoma 2-interacting mediator of cell death ͉ intrinsic apoptosis ͉ lymphoma ͉ lymphoproliferation

show abstract

Autoimmune Lymphoproliferative Syndrome with SomaticFasMutations

Abstract: Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.

Cited by 288 publications

References 36 publications

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Double‐negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation

NRAS mutation causes a human autoimmune lymphoproliferative syndrome

Contact Info

Product

Resources

About