The link between Complement System and Anemia in Gaucher disease

Abstract

Abstract Gaucher disease (GD) is the classical example of lysosomal storage disease, which happens due to mutations in GBA1 as well as the resultant deficiency of glucocerebrosidase (GCase) and the excess tissue accumulation of glucosylceramide (GC). GD patients have shown high risk for developing anemia, which is characterized by Red blood cells (RBCs) and the hemoglobin (Hb) abnormalities. The exact mechanism by which such blood aberrations progress in GD is not clear. We have described immune complexes of GC-specific IgG autoantibodies in GD, which induced massive complement activation and the resulting complement 5a (C5a) and its cognate receptor 1 (C5aR1)-mediated immune inflammation and tissue disruption in GD. Complement activation had been linked to RBCs and/or Hb abnormalities in several diseases, (e.g., atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, malaria, and β-thalassemia). Hence, we hypothesized that the C5a-C5aR1 activation is critical for anemia development in GD. To indorse this theory, blood from C5aR1 deficient (C5aR1−/−) and sufficient (C5aR1+/+) experimental mouse model of GD as well as the background matched control WT and C5aR1−/− mice were measured for RBCs and Hb with uses of automated system and the FACS staining methods. Our data illustrate that C5aR1+/+ mouse model of GD causes increased shortage of RBCs and Hb when compared to control WT or C5aR1−/− strains. Strikingly, C5aR1−/− mouse model of GD were protected from the loss of RBCs and Hb. These findings suggest that C5a-C5aR1 axis is a critical driver of disease processing of anemia in GD. Targeting C5a-C5aR1 axis may stop or slow down anemia development in GD.