Enzyme replacement therapy reverses B lymphocyte and dendritic cell dysregulations in patients with Gaucher Disease

Gaucher disease (GD) is caused by mutations in the GBA gene encoding lysosomal enzyme, β-glucocerebrosidase (GCase). GCase deficiency results in accumulation of its substrates in cells of macrophage lineage, affecting multiple organ systems. Enzyme replacement therapy (ERT) with recombinant human GCase is the standard of care to treat GD. In GD, it is well established that there are immune alterations, clinically presenting as lymphadenopathy, gammopathies, and predisposition to hematological cancers. We examined the effect of ERT on immune dysregulations in treatment-naïve GD patients longitudinally after the initiation of ERT. Immunophenotyping was performed in peripheral blood samples obtained before and after ERT. T and B lymphocyte subsets, NK, NKT and dendritic cells were evaluated. In all treatment naïve patients at baseline, transitional B cells, characterized by CD21^low expression were markedly elevated. After establishment of stable-dose therapy, CD21^low cells were significantly reduced and subsequent increase in CD21^Hi B lymphocytes indicated improved B cell maturation. Class-switching and memory B cell defects which were noted prior to treatment were found to be normalized. An increase in dendritic cells also resulted after the treatment. Our data shows that GD affects across various immune cell types and ERT or its effects directly improve affected immunological parameters.