Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent.
ABSTRACT Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with low-dose ERT and re-evaluating the use of ERT in asymptomatic patients.
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ABSTRACT: This review attempts to illuminate the glycolipid antigen presentation properties of CD1d, how CD1d controls the function of natural T (iNKT) cells and how CD1d and iNKT cells interact to jump-start the immune system. It is postulated that the CD1d-iNKT cell system functions as a sensor, sensing alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of a neo-self glycolipid, presumably by infectious assault of antigen-presenting cells, activates iNKT cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jump-start the immune system.Immunology 07/2003; 109(2):171-84. · 3.71 Impact Factor
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ABSTRACT: While CD8 lymphocytes possess pro-fibrogenic properties and NK (non-T) cells are anti-fibrogenic, the role of NKT lymphocytes in liver fibrosis is still unclear. Beta-glucosylceramide (GC), a naturally occurring glycolipid, exerts modulatory effects on these cells. To explore the role of NKT cells in hepatic fibrosis via GC. Hepatic fibrosis was induced by biweekly intra-peritoneal (IP) carbon tetrachloride (CCl(4)) administrations for 7 weeks in 5 groups (A-E) of male C57Bl/6 mice. Mice were treated with daily IP GC injections in groups A and C, or daily oral doses in groups B and D. GC was administered either for the duration of the study period (in groups A and B), or for the last 3 weeks of CCl(4) induction (groups C and D). GC-treated mice were compared with non-treated fibrotic controls (group E) and naive rodents (group F). Liver fibrosis, injury parameters and FACS analysis of lymphocytes were assessed. Marked amelioration (P < 0.0001) of hepatic fibrosis observed in all GC-treated mice without altering reactive oxygen species production. As determined by Sirius red-stained liver tissue sections and measured by Bioquant morphometry; all CCl(4)-administered groups significantly (P < 0.0001) increased the relative fibrosis area compared with naive animals. The increases were 14.4 +/- 1.03-fold in group A, 7.9 +/- 0.37-fold in group B, 5.2 +/- 0.2-fold in group C, 10.3 +/- 0.4-fold in group D and 23.8 +/- 1.9-fold in group E. Western blot analysis for alpha smooth muscle actin from liver extracts followed a similar pattern, increasing in groups A-E. A significant decrease in liver damage was observed in all GC-treated groups, as noted by a decrease in transaminase serum levels (P < 0.005). The beneficial effect of GC was associated with a significant decrease in the intra-hepatic NKT and CD8 lymphocytes as well as their attenuation of both T(h)1 and T(h)2 cytokines. Administration of GC had a significant anti-fibrotic effect following CCl(4) administration. This effect was associated with an altered NKT and CD8 lymphocyte distribution and a cytokine shift. Immune modulation using GC may have a role in the treatment of fibrosis and other immune-mediated disorders.International Immunology 08/2007; 19(8):1021-9. · 3.14 Impact Factor
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ABSTRACT: Malignant neoplastic disorders are more common in patients with Gaucher disease (GD) than in the general population. Very few cases of primary malignant bone tumors in association with GD have been reported to date. Thus, the recommendations for an adequate therapy are often based on limited professional experience. To their knowledge, the authors report the first case of a leiomyosarcoma of the bone in a patient with GD and report another patient with GD and an anaplastic large cell non-Hodgkin lymphoma with localized osseous manifestation. A review of the literature is included. The clinical, radiologic, and histologic data of the authors' two patients who had GD and primary malignant bone tumor are presented. Epidemiologic data, clinical data, and treatment results from published reports of 18 patients who had GD and various malignancies and the authors' 2 patients were compared and evaluated. Radiographic examination showed a destructive osteolytic lesion in a case of a leiomyosarcoma of the bone and in a case of anaplastic, large-cell, non-Hodgkin lymphoma. In both cases, the bone marrow architecture was partially effaced by sheets of large histiocytic cells with striated or fibrillary cytoplasm. In both patients, chemotherapy was performed. Whereas the patient who had the leiomyosarcoma showed poor recovery of the bone marrow that necessitated withdrawal of aggressive chemotherapy, the patient who had non-Hodgkin lymphoma and enzyme therapy tolerated the chemotherapy well. In spite of local control after preoperative radiotherapy and hemipelvectomy, the first patient developed lung metastases and finally died. The second patient was continuously free of disease at a follow-up examination 32 months after chemotherapy and radiotherapy. In a total of 20 patients who had malignant disorders and GD, the numbers of males and females were equivalent, and the mean age was 55 years. Approximately 33% presented with a cancer originating in the bone. In 16 patients, follow-up data were available. Of these, after a mean follow-up of 36 months (range, few days-108 mos), only 2 patients were continuously free of disease, and one patient was alive with disease. The other patients had died of disease or hemorrhagic complications of GD. Because there is a relatively high incidence of malignant disorders of the bone, the study suggested that malignant disorders have to be included in the differential diagnosis of painful lytic lesions in patients who have GD. Evaluation of the expense and value of enzyme therapy to patients who have GD should be undertaken with regard to the incidence of malignant disorders and patient survival.Cancer 03/2001; 91(3):457-62. · 5.20 Impact Factor