Defective FAS-Mediated Apoptosis and Immune Dysregulation in Gaucher Disease.

ABSTRACT

BACKGROUND: Gaucher disease (GD) is a rare disorder characterized by defective function of ß-glucocerebrosidase, which leads to progressive accumulation of its substrate in various organs, particularly the mononuclear phagocyte system. Hepatosplenomegaly and cytopenia represent the disease's most common features, but patients with GD also show hyperinflammation, hypergammaglobulinemia, and immune dysregulation involving B, T, and natural killer cells. As clinical phenotype can be underhand, symptoms can overlap with autoimmune lymphoproliferative syndrome (ALPS) or other ALPS-like disorders. OBJECTIVE: To evaluate the ALPS-like immunological pattern and apoptosis function in patients with GD. METHODS: We evaluated lymphocyte subsets and immunophenotypic and serological features of ALPS (double-negative T cells [DNTs], B220+DNTs, CD27+, T-reg/HLA-DR ratio, IL-10, IL-18, vitamin B12) in a population of patients with GD. Moreover, we tested FAS/TRAIL-induced apoptosis and CASP8/CASP10/PARP function in patients showing an immune-dysregulation pattern. RESULTS: A total of 41 patients (33 treated, 8 treatment-naïve) were studied. Nine (21%) and 7 (17%) of 41 patients had high DNT and B220+DNT counts, respectively. Overall, 10 of 41(24%) patients showed immunological features suggestive of ALPS that were more frequent in treatment-naïve subjects (P = .040 vs P = .031) and in those with early onset of the disease (P = .046 vs P = .011), respectively. FAS-induced apoptosis and caspase activation were further evaluated in these 10 patients and were found to be defective in 7 of them. CONCLUSIONS: We show that patients with GD may have ALPS-like features and FAS-mediated apoptosis defects that are more pronounced in treatment-naïve subjects and in patients with early onset of the disease. Therefore, diagnostic workup of patients with an ALPS-like phenotype should include screening for GD.