Gaucher Disease

Gaucher disease (GD) is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to sphingolipid accumulation in cells of the mononuclear-macrophage lineage known as Gaucher cells. Gaucher cells infiltrate several organs (spleen, liver, bone marrow) and are considered as the main culprit of GD pathophysiology. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease.

A growing number of studies performed in our lab indicate that the pathophysiology of GD may involve mature red blood cells (RBCs) and erythroid progenitors. Indeed, some symptoms of the disease as anemia, splenomegaly and vaso-occlusive events suggest that the erythroid lineage could be involved in the disease (7).

We have previously demonstrated that the erythrocytes from patients exhibit abnormal properties including increased sphingolipids levels (1, 4, 5), altered deformability and adhesion properties (4, 8) that may trigger ischemic events in GD. Furthermore, we have highlighted a correlation between the sphingolipid overload in RBCs and their altered properties (1).

Using erythroid progenitors-cultures derived from peripheral CD34⁺ cells, we also demonstrated that GD patients exhibit ineffective erythropoiesis with increased plasma levels of erythropoietin (EPO) and GDF15 factor, an ineffective erythropoiesis marker (6). This unsuspected dyserythropoïesis was independent of the macrophages and could participate to the basis of anemia in GD.

The identification of molecules that are deregulated in GD RBCs represents an important issue and could represent pertinent markers of the disease. We found a decreased expression of the GPI-anchored cell surface protein semaphorin 7A (Sema7A) in mature erythrocytes from untreated GD patients, in parallel to increased levels of the soluble form in the plasma of these patients (2). Because Sema7A is known to regulate the activity of immune cells, the increased level of soluble Sema7A in GD patients could contribute to inflammation in several tissues. Sema7A could also represent a simple and pertinent marker of inflammation in GD.

Perspectives:

Future studies are needed to clarify the biological role of Sema7A in GD including inflammation.

RBCs and their interactions with macrophages may be crucial in the pathogenesis of GD. Beyond ischemic events, abnormal GD RBC properties may be responsible for their enhanced splenic destruction. The abnormal erythrocytes from GD patients could be more phagocytosed by macrophages. Moreover, this increased erythrophagocytosis could contribute to phenotypic changes in macrophages leading to the formation of Gaucher cells.

Thus, RBCs could be the primary dysfunctional cells, leading to formation of Gaucher cells in the spleen as potentially in the bone marrow where erythrophagocytosis is frequently reported.

Bibliography :

1. Dupuis, L., et al. Effects of sphingolipids overload on red blood cell properties in Gaucher disease. J Cell Mol Med, 2020. 24(17): p. 9726-9736.

2. Franco, M., et al. Semaphorin 7A: A novel marker of disease activity in Gaucher disease. Am J Hematol, 2020. 95(5): p. 483-491.

3. Lefebvre, T., et al. Involvement of hepcidin in iron metabolism dysregulation in Gaucher disease. Haematologica, 2018.

4. Franco, M., et al. Effect of velaglucerase alfa enzyme replacement therapy on red blood cell properties in Gaucher disease. Am J Hematol, 2017. 92(9): p. E561-E563.

5. Chipeaux, C., et al. Optimization of ultra-high pressure liquid chromatography - tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher's disease. J Chromatogr A, 2017. 1525: p. 116-125.

6. Reihani, N., et al. Unexpected macrophage-independent dyserythropoiesis in Gaucher disease. Haematologica, 2016.

7. Franco, M. and C. Le Van Kim, [Red blood cell, a new player in the pathophysiology of Gaucher disease]. Med Sci (Paris), 2013. 29(12): p. 1086-8.

8. Franco, M., et al. Abnormal properties of red blood cells suggest a role in the pathophysiology of Gaucher disease. Blood, 2013. 121(3): p. 546-55.