The iNKT Cell-Macrophage Axis in Homeostasis and Disease.

Invariant natural killer T (iNKT) cells are CD1d-restricted, lipid-reactive T cells that exhibit preponderant immunomodulatory properties. The ultimate protective or deleterious functions displayed by iNKT cells in tissues are known to be partially shaped by the interactions they establish with other immune cells. In particular, the iNKT cell-macrophage crosstalk has gained growing interest over the past two decades. Accumulating evidence has highlighted that this immune axis plays central roles not only in maintaining homeostasis but also during the development of several pathologies. Hence, this review summarizes the reported features of the iNKT cell-macrophage axis in health and disease. We discuss the pathophysiological significance of this interplay and provide an overview of how both cells communicate with each other to regulate disease onset and progression in the context of infection, obesity, sterile inflammation, cancer and autoimmunity.

Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.

Globotriaosylceramide inhibits iNKT-cell activation in a CD1d-dependent manner.

Globotriaosylceramide (Gb3) is a glycosphingolipid present in cellular membranes that progressively accumulates in Fabry disease. Invariant Natural Killer T (iNKT) cells are a population of lipid-specific T cells that are phenotypically and functionally altered in Fabry disease. The mechanisms responsible for the iNKT-cell alterations in Fabry disease are not well understood. Here, we analyzed the effect of Gb3 on CD1d-mediated iNKT-cell activation in vitro using human cells and in vivo in the mouse model. We found that Gb3 competes with endogenous and exogenous antigens for CD1d binding, thereby reducing the activation of iNKT cells. This effect was exerted by a reduction in the amount of stimulatory CD1d:α-GalCer complexes in the presence of Gb3 as demonstrated by using an mAb specific for the complex. We also found that administration of Gb3 delivered to the same APC as α-GalCer, induces reduced iNKT-cell activation in vivo. This work highlights the complexity of iNKT-cell activation and the importance of nonantigenic glycosphingolipids in the modulation of this process.

Reduced glucosylceramide in the mouse model of Fabry disease: correction by successful enzyme replacement therapy.

Fabry disease is an X-linked lysosomal storage disease (LSD) caused by deficient activity of α-Galactosidase A (α-Gal A). As a result, glycosphingolipids, mainly globotriaosylceramide (Gb3), progressively accumulate in body fluids and tissues. Studies aiming at the identification of secondary lipid alterations in Fabry disease may be potentially useful for the monitorization of the response to enzyme replacement therapy (ERT) and development of future therapies. The focus of this study was to evaluate if α-Gal A deficiency has an effect on two key groups of molecules of sphingolipids metabolism: glucosylceramides (GlucCers) and ceramides (Cers). Studies performed in a mouse model of Fabry disease showed reduced level of GlucCer and normal level of Cer in plasma, liver, spleen, kidney and heart. Moreover, analysis of GlucCer isoforms in Fabry knockout mice showed that GlucCer isoforms are unequally reduced in different tissues of these animals. ERT had a specific effect on the liver's GlucCer levels of Fabry knockout mice, increasing hepatic GlucCer to the levels observed in wild type mice. In contrast to Fabry knockout mice, plasma of Fabry patients had normal GlucCer and Cer but an increased GlucCer/Cer ratio. This alteration showed a positive correlation with plasma globotriaosylsphingosine (lyso-Gb3) concentration. In conclusion, this work reveals novel secondary lipid imbalances caused by α-Gal A deficiency.

Enzyme replacement therapy partially prevents invariant Natural Killer T cell deficiency in the Fabry disease mouse model.

Fabry disease is a lysosomal storage disease caused by deficient activity of the α-Galactosidase A (α-Gal A) enzyme, which leads to abnormal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in the lysosome. Glycosphingolipids are known to be invariant Natural Killer T (iNKT) cell antigens. Several animal models of lysosomal storage diseases, including Fabry disease, present a defect in iNKT cell selection by the thymus. We have studied the effect of age and the impact of enzyme replacement therapy on Gb3 accumulation and iNKT cells of Fabry knockout mice. At 4 weeks of age, Fabry knockout mice already showed Gb3 accumulation and a reduction in the percentage of iNKT cells. In older mice (12-week old), we observed an accentuated peripheral iNKT deficiency. 12-week old animals also showed a reduced splenic CD4+/CD4- iNKT cell ratio due to greater loss in the iNKT CD4+ subset. Treatment of Fabry knockout mice with α-Gal A replacement therapy efficiently reduced Gb3 deposition in the liver and spleen. Moreover, enzyme replacement therapy had a positive effect on the number of iNKT cells in an organ-dependent fashion. Indeed, treatment of Fabry knockout mice with α-Gal A did not alter iNKT cell percentage in the thymus and liver but increased splenic iNKT cell percentage when compared to untreated mice. Study of animals prior to treatment indicates that enzyme replacement therapy stabilized iNKT cell percentage in the spleen. This stabilization is due to a specific effect on the iNKT CD4+ subset, preventing the decrease on the number of these cells that occurs with age in Fabry knockout mice. This study reveals that enzyme replacement therapy has a positive organ and subset-dependent effect in iNKT cells of Fabry knockout mice.