Macrophage colony stimulating factor (MCSF) influences proliferation and survival of mononuclear phagocytes through the CSF-1 receptor. The DAP12 adaptor protein, which transduces signals emanating from various myeloid receptors, is critical for mononuclear phagocyte function. DAP12-mutant mice and humans show defects in osteoclasts and microglia and exhibit brain and bone abnormalities. Here, we demonstrated that DAP12 deficiency impairs MCSF-induced macrophage proliferation and survival in vitro. In addition, DAP12-deficient mice show fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerate myeloid cells inefficiently following BM transplantation. MCSF-CSF1-R signaling induced stabilization and nuclear translocation of β-catenin, which activates cell cycle genes. DAP12 was essential for phosphorylation and nuclear accumulation of β-catenin. These results outline a mechanistic explanation for the multiple defects in DAP12-deficient mononuclear phagocytes.

Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/ lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR ‫؍‬ 62.7 (P ‫؍‬ .0016) for ALPS and A91V conferred an OR ‫؍‬ 3 (P ‫؍‬ .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR ‫؍‬ 17 (P ‫؍‬ .0007) for DALD.In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression. IntroductionFas is a death receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily and induces cell death upon triggering by FasL. [1][2][3] In the immune response, it is highly expressed by activated effector lymphocytes and is involved in switching off the immune response, limiting clonal expansion of lymphocytes, and favoring peripheral tolerance. Moreover, FasL is expressed by cytotoxic T cells and NK cells and is involved in killing of target cells expressing Fas. Fas induces cell apoptosis by triggering a cascade of caspases through 2 partly interconnected pathways: the extrinsic pathway involves caspase-8-mediated direct activation of the cascade, whereas the intrinsic pathway proceeds through mitochondrial release of cytochrome c and activation of caspase-9. Both pathways converge in the activation of effector caspases, such as caspase-3, -6, and -7. [1][2][3] Defective Fas function leads to the unwanted accumulation of lymphocytes and favors autoimmunity possibly by impairing the switching off of autoreactive lymphocytes. This has been shown in the autoimmune lymphoproliferative syndrome (ALPS), an inherited disease characterized by (1) defective function of Fas, (2) autoimmune manifestations that predominantly involve blood cells, (3) polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and (4) expansion of TCR␣␤ ϩ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Moreover, ALPS patients are predisposed to develop lymphomas in adulthood. 3-11 ALPS is generally due to deleterious mutations of the Fas gene (TNFRSF6) and is classified as ALPS type-Ia, but rare mutations of other ge...

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.

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