Severe Impairment of Regulatory T-Cells and Th1-Lymphocyte Polarization in Patients with Gaucher Disease

Abstract

We investigated peripheral blood T-lymphocyte subpopulations and intracellular expression of IFN-g, IL-4, IL-10, and IL-13, by whole blood flow cytometry, in 22 type I Gaucher disease (GD) patients. Results were compared with those of 19 sex-and age-matched controls. Patients with GD exhibited decreased frequencies and absolute numbers of CD3+/CD4+ helper T lymphocytes (40.8 AE 9.8% vs. 49.4 AE 5.7%, p ¼ 0.002, and 0.77 AE 0.33 vs. 1.04 AE 0.28 Â 10 9 /mL, p ¼ 0.011), as well as increased frequencies of CD3+CD8+ suppressor T lymphocytes (23.8 AE 8.0% vs. 18.4 AE 3.8%, p ¼ 0.010), resulting in a significantly decreased CD4/CD8 cell ratio (p < 0.001). Moreover, they had significantly increased percentages of IFNg-producing both CD4+ and CD8+ T cells (p ¼ 0.0003 and p ¼ 0.023, respectively), implying a TH-1 polarization pattern. Finally, patients with GD had decreased percentages and absolute numbers of CD4 +CD25 dim T lymphocytes (p ¼ 0.033 and p ¼ 0.007, respectively), of CD4+CD25 high T lymphocytes (p ¼ 0.039 and p ¼ 0.016, respectively), and of CD4+CD25 high FOXP3+ regulatory T cells (p ¼ 0.036 and p ¼ 0.019, respectively). Our results demonstrate that patients with GD have a significant numerical impairment of T-helper lymphocytes and a constitutive TH1 direction pattern of activation of both CD4+ and CD8+ cells, associated with a significant decrease of T-regs. Ineffective T-cell control may explain the chronic inflammatory reaction and the increased incidence of lymphoid malignancies, which have been repeatedly reported among patients with GD.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Patients with GD exhibit a decreased number of CD4ϩ helper lymphocytes and increased frequencies of CD8ϩ suppressor lymphocytes, resulting in a significantly decreased CD4/CD8 cell ratio. Impairment of regulatory T cells, along with increased IFN-␥-producing CD4ϩ and CD8ϩ T cells, was noted, indicating a TH-1 polarization pattern (93,161,165). These patients manifested decreased percentages and absolute numbers of CD4ϩCD25 dim , CD4ϩCD25 high , and CD4ϩCD25 high FOXP3ϩcells, respectively (93,161,165).…”

“…In adipocytes, AMP-DNM counteracted TNF-␣-induced abnormalities in GSL concentrations, reversing the abnormalities in insulin signaling transduction in vitro. In ob/ob mice, HFD mice, and ZDF rats, AMP-DNM normalized the elevated tissue of GC and GM3 levels, subsequently lowering the circulating glucose level, hence improving oral glucose tolerance and insulin sensitivity in muscle and liver (5,6,161). AMP-DNM resulted in a 70% reduction of GSLs in the liver hepatoma cell line HepG2 (20,21,165).…”

“…However, cases of type I GD coexisting with relatively low serum immunoglobulins, impaired antibody production, and recurrent bacterial infections have been described (82,83,87). All of these underscore that ineffective T cell control exposes GD patients to inflammatory reactions, poor immune responses against infectious agents, and impaired immune surveillance associated with an increased risk of neoplasm (93,95,118,122,161,165). A contrasting point of view suggests that GC accumulation may result to several evolutionary advantages (79,88,83), as secondary biochemical pathways upstream and downstream of GC that regulate phospholipid metabolism are affected in GD.…”

“…An inhibitor of GCS, an enzyme that catalyzes the conversion of Cer to GSLs, improved insulin sensitivity and T2DM (5,6,154,158,161,162). GENZ-123346 is a specific inhibitor of GCS, an enzyme that catalyzes an important step in the conversion of Cer to GSLs.…”

“…The iminosugar derivative N-(5=-adamantane-1=-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) is a smallmolecule inhibitor of GCS (5,6,161). In adipocytes, AMP-DNM counteracted TNF-␣-induced abnormalities in GSL concentrations, reversing the abnormalities in insulin signaling transduction in vitro.…”