PATIENTS WITH GAUCHER DISEASE SHOW AN IMMUNE-DYSREGULATION PATTERN SECONDARY TO A DEFECT OF APOPTOSIS
Author(s): ,
Maurizio Miano
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Annalisa Madeo
Affiliations:
Rare Diseases Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Enrico Cappelli
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Francesca Fioredda
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Elena Palmisani
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Paola Terranova
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Tiziana Lanza
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Roberta Vené
Affiliations:
Molecular Oncology and Angiogenesis Unit,IRCCS AOU San Martino-IST,Genova,Italy
,
Chiara Vernarecci
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Andrea Beccaria
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Rosario Maggiore
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Daniela Guardo
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy;Haematology Clinic, Department of Internal Medicine (DiMI),University of Genova, IRCCS AOU San Martino-IST,Genova,Italy
,
Carlo Dufour
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
,
Concetta Micalizzi
Affiliations:
Haematology Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
Maja Di Rocco
Affiliations:
Rare Diseases Unit,IRCCS Istituto Giannina Gaslini,Genova,Italy
EHA Library. Miano M. Jun 15, 2019; 266731; PS1114
Dr. Maurizio Miano
Dr. Maurizio Miano
Contributions
Abstract

Abstract: PS1114

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

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.

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. 

 

 

Session topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research

Keyword(s): Apoptosis, Gaucher disease, Immune deficiency, Lymphoproliferative disorder

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