Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome

Abstract

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and expansion of TCRαβ+ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing ALPS type Ia (ALPS-Ia). However, other mutations, namely of the FasL gene (ALPS-Ib) and the caspase-10 gene (ALPS-II) are occasionally detected, whereas some patients do not present any known mutations (ALPS-III). Recently, mutations of the NRAS gene have been suggested to cause ALPS-IV.

CD3+CD4−CD8− (double negative) T cells: Saviours or villains of the immune response?

“…In a study conducted on patients suffering from ALPS [45] (also known as Canale-Smith syndrome) the authors demonstrated that the percentage of DN T cells increased from 1% (observed in physiological conditions) to 40% [46]. These results together with other evidence [26][27][28][29] suggest that the increased number of DN T cells may represent a sensitive test or biomarker to screen patients who should undergo testing for ALPS. In this regard it is interesting to mention that the analysis of DN T cell levels has been used to distinguish ALPS from other autoimmune disease such as Evans syndrome [27] or sarcoidosis [47].…”

“…Interestingly, these patients share similar clinical features with lpr and gld mice and a selective accumulation of DN T cells in peripheral blood [25][26][27][28][29].…”

Acute myeloid leukemia developing in patients with autoimmune diseases

“…147 Fas, a death receptor belonging to the tumor necrosis factor receptor superfamily, is defective in ADs and is also linked to cancer susceptibility. 144,148,149 The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B,PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway, known to be altered in leukemia, 150,151 is also involved in the pathogenesis of some ADs. [152][153][154][155][156] The mitogen-activated protein kinases (MAPKs) pathway mediates signal transduction in response to various stimuli, including stress and inflammation.…”

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

“…7 Caspase-8 and -9 activity was assessed in cell lysates on the basis of fluorometric assays. 8,9 Transfection of HeLa and 293T cells was accomplished via Lipofectamine (Life Technologies, Grand Island, NY), whereas transfection of HMC-1 cells by electroporation (Amaxa Cell Line Nucleofactor; Lonza Group Ltd, Basel, Switzerland). 10 NK activity was assessed by using a 51 Cr release assay, and Fas-induced cell death was evaluated as previously described.…”