Maurizio Miano, Italy
IRCCS Istituto Giannina Gaslini Haematology UnitPresenter of 1 Presentation
IMMUNE-DYSREGULATION AND APOPTOSIS DEFECT IN PATIENTS WITH GAUCHER DISEASE
Abstract
Background and Aims
Gaucher Disease(GD) is a congenital disorder secondary to GBA1-gene mutations causing the impairment of the β-glucocerebrosidase(GBA) enzyme with progressive accumulation of its substrate(glucocerebroside, GC) in monocyte/macrophage system and various organs. Bone infiltration, hepatosplenomegaly and cytopenia represent the most common clinical features which might overlap with Autoimmune Lymphoproliferative Sindrome(ALPS) ones.GD patients also show hyperinflammatory features -secondary to machrophages activation- and an aspecific impaiment involving B,T,and NK-cells. The aim of this study is to evaluate ALPS-like immunological and serological pattern in a cohort patients with GD and to test apoptosis function in those showing ALPS-like features.
Methods
Lymphocytes subsets and ALPS-related serum biomarkers (Double-Negative T-cells,B220+DNTs,CD27+,T-regs/HLA-DR ratio,IL-10,IL-18,VitB12) were analyzed in GD patients followed-up at Istituto Gaslini. Furthermore, in those patients showing an ALPS-like phenotype, apoptosis function was analyzed after FAS–induced stimulation of EBV-immortalized B-cells and Western-blot analysis of CASP10,CASP8, and PARP proteins.
Results
41 patients(8 naive,33 treated)were studied. 10/41(24%) patients showed an ALPS-like immunological pattern which was more frequent in naïve patients(p=0.003) and in patients with an earlier onset of the diesease(p=0.010). EBV-immortalized B-cells of 7/10 patients were further studied and all of them showed a defective apoptosis and caspases activation(Fig1).
Conclusions
This study shows for the first time that untreated subjects with early-onset GD present an immune-dysregulation pattern secondary to an apoptosis defect as seen in ALPS patients. These results suggest that diagnostic work-up of both diseases must consider this clinical/biochemical overlap. Further studies are needed to evaluate the potential role of cell-membrane lipids impairment on FAS receptor structure as a cause of such defect.