Immunological cells and functions in Gaucher disease

Abstract

The macrophage (MΦ) has been the focus of causality, research, and therapy of Gaucher disease, but recent evidence casts doubt its solitary role in the disease pathogenesis. The excess of glucosylceramide (GC) in such cells accounts for some of the disease manifestations. Evidence of increased expression of C-C and C-X-C chemokines (i.e., CCL2,CXCL1, CXCL8) in Gaucher disease could be critical for monocyte transformation to inflammatory subsets of macrophages and dendritic cells (DC) as well as neutrophil (PMNs) recruitment to visceral organs. These immune responses could be essential for activation of T- and B-cell subsets, and the induction of numerous cytokines and chemokines that participate in the initiation and propagation of the molecular pathogenesis of Gaucher disease. The association of Gaucher disease with a variety of cellular and humoral immune responses is reviewed here to provide a potential foundation for expanding the complex pathophysiology of Gaucher disease.

FIGURE 1. A schematic for a model of inflammatory propagation of Gaucher

MΦ activation due to excess of glucosylceramide (GC) could trigger the release of C-C chemokines, e.g., monocyte chemoat-tractant protein-1(MCP1) or CC chemokine ligand-2 (CCL2),which cause the recruitment of blood MOs into the different visceral organs. These cells then mature into MΦs and DCs subsets. Because of the GCase defects in these cells, excess of GC accumulates and in turn activates the release of interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-6, and transforming growth factor-β (TGF-β). The cytokines IFN-γ and Il-4 cause the development of T helper-1 (Th1) and Th2 cell-mediated responses, whereas IL-6 facilitates the development of follicular T cells (Tfh). These responses lead to the formation and activation of the germinal center that triggers B-cell differentiation and immunoglobulin (IgG, IgA, and IgM) production, and hypergammaglobulinemia. IL-6 together with TGF-β impact Th17 cell development, which induces the production of IL-17 and subsequently the production of CXCL8/IL8 to recruit blood PMNs into Gaucher disease visceral organs. In addition to CXCL8/IL8, GC-engorged MΦs also secrete KC/CXCL1, IL-1β, IFN-γ, and TNF-α, which are critical for the recruitment of PMNs and release of their activation products (e.g., TNF-α, IL-6, IL-1α, IL-1β, and IL-1Ra) into the visceral organs. Also, TNF-α together with IFN-γ and IL-1β induce iNOS followed by the production of NO to trigger immunological inflammation in Gaucher disease.