Increased Incidence of Autoimmune and Lymphoproliferative Disorders in Gaucher Patients Accompanied with Significantly Impaired Dendritic Cell Function,
Authors: Rosenbaum Hanna , Bettman Noam , Katz Tamar , Avivi Irit 
Published: October 2019

Abstract
Abstract 3211
Background: Type I Gaucher disease (GD) is characterized by hepatosplenomegaly, pancytopenia and skeletal complications. Recent studies report an increased incidence of autoimmune complications and lymphoproliferative malignancies in patients with Gaucher disease (GD), suggesting the existence of an impaired immune function. The current study has investigated whether the inherent accumulation of glucocerebrosidase in monocytes and macrophages results in abnormal function of monocyte-derived dendritic cells (DCs). According to our hypothesis, this could lead to abnormal T cell polarization (regulatory versus effector cells) and function, partly explaining the markedly increased incidence of both autoimmune and hematological malignancies observed in this patient population.

Patients and Method:
Thirty three GD patients, followed at the Gaucher clinic of the Rambam Health Care Campus (Haifa, Israel), were enrolled. The study was approved by the local IRB. Monocyte-derived DCs were assessed to determine their functional properties.CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of untreated GD patients and healthy volunteers, using immunomagnetic bead separation (Miltenyi Biotec). Monocytes were developed into immature DCs (iDCs) with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 4 to 6 days. The iDC ability to process antigens was evaluated by an antigen uptake assay using 1mg/ml FITC-dextran. Mannose receptor-mediated endocytosis was measured by determining the cellular uptake of FITC-dextran, using FACS. iDCs were maturated with tumor necrosis factor α (TNF-α) for 48 hours. Stimulatory capacity of mature DCs (mDCs) was estimated by measuring the allogeneic T cell response, induced by stimulation with mDCs. T cell response was examined using proliferation and INF-g expression assays. Clinical data focusing on autoimmune phenomena and coexistence of hematological malignancies, mainly lymphoproliferative disorders (lymphoma, multiple myeloma and monoclonal gammopathy), were retrospectively collected from patient charts.

Results:
Thirty three type I GD patients, 19 males and 14 female, with a median age at analysis of 50.5 years (range 20–74), were included in the analysis. Eight (24%) patients presented with clonal lymphoproliferative disorders, including malignant lymphoma (2), multiple myeloma (3) and monoclonal gammopathies (3). In 15/33 (45%) patients, autoimmune phenomena were revealed. In 12/15 thrombocytopenic GD patients, platelet antibodies were detected, suggesting immune etiology of their thrombocytopenia. Antiphospholipid and antiDNA antibodies were found in 3 other patients with no clinical evidence for autoimmune complications. All these complications appeared prior to the administration of enzyme replacement therapy (ERT). Immunological assessment, performed in 10 untreated patients from this cohort and compared with 10 healthy volunteers, revealed a decrease in the patient DC uptake capacity compared to that observed in DCs obtained from healthy subjects (Table 1). Additionally, GD-derived DCs exhibited impaired maturation, reflected by their limited ability to induce T cell activation, as demonstrated by decreased INF-γ secretion levels and proliferation capacity (Table 1).

Conclusions:
Forty five percent of the evaluated type I Gaucher patients exhibited autoimmune phenomena. Additionally, 24% presented with lymphoproliferative disorders. DC function analysis showed a significant impairment of both iDCs and mDCs, reflected by their decreased uptake and antigen presenting capacities. These abnormalities may adversely affect T cell polarization and functional abilities, resulting in autoimmune complications as well as hematological clonal disorders. Further studies, exploring the precise association between the existence of autoimmune/lymphoproliferative disorders, and the observed in vitro immunological impairment are required.

Disclosures:
No relevant conflicts of interest to declare.