PS1114 PATIENTS WITH GAUCHER DISEASE SHOW AN IMMUNE‐DYSREGULATION PATTERN SECONDARY TO A DEFECT OF APOPTOSIS

Abstract

Background:Gaucher Disease (GD) is a congenital disorder secondary to GBA1 gene mutations that cause a defective function of the catabolic enzyme β‐glucocerebrosidase (GBA) and a progressive accumulation of its substrate‐ glucocerebroside (GC) in various organs, in particular in mononuclear phagocite system. Bone infiltration, hepatosplenomegaly and cytopenia represent the most common features of the disease. Since clinical manifestation can be subdolous, in some cases, phenotype can overlap with Autoimmune Lymphoproliferative Sindrome (ALPS). Nonetheless, GD patients were also shown to have hyperinflammatory features‐ secondary to machrophages engorgement and actviation‐ and an aspecific impaiment involving B, T and NK cells. In addition, some patients also showed more specific ALPS‐like immune‐dyregulation features suggesting an underlying apoptosis defect.Aims:To evaluate specific ALPS‐like immunological and serological pattern (Double Negative T‐cells, TCR alfa/beta B220, B‐memory cells, T‐regs/HLA‐DR ratio, IL‐10, IL‐18,) in a cohort patients with GD and to test apoptosis pathway function in those showing ALPS‐like features.Methods:All patients were diagnosed with GD by enzyme assay on lymphocytes culture or fibroblasts and by characterization of pathogenetic variants of GBA1. Lymphocytes subsets and ALPS‐related serum biomarkers (IL‐10, IL‐18, sFAS, Vit.B12) were analyzed in 41 GD patients followed‐up at Istituto Giannina Gaslini. Furthermore, in those patients who showed 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: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 out of these 10 patients were further studied and all of them showed a defective FAS‐induced apoptosis and caspases activation. Fig 1 shows apoptosis evalutation of the selected population.Summary/Conclusion:To the best of our knowledge, this study shows for the first time that untreated subjects with early‐onset GD present an immune‐dysregulation pattern secondary to a defect of apoptosis as seen in ALPS patients. These results suggest that diagnostic work‐up of both diseases must take into consideration their clinical and 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.image