Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease

Deegan, Patrick; Moran, Mary Teresa; McFarlane, Ian G.; Schofield, J. Paul; Boot, Rolf G.; Aerts, Johannes M. F. G.; Cox, Timothy M.

doi:10.1016/j.bcmd.2005.05.005

Cited by 112 publications

(90 citation statements)

References 36 publications

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“…Several studies also have shown a relationship between parameters of disease burden such as SSI and organ volumes and chitotriosidase levels. 32,33 Its use as a biomarker is limited by the observation that 6% of the population lacks activity and 30% carries a mutation that results in lower activities. 34 In heterozygote patients, chitotriosidase levels may be multiplied by 2 to allow adequate comparison with Gaucher patients with normal chitotriosidase genotypes.…”

Section: Discussionmentioning

confidence: 99%

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Fost

Hollak²,

Groener³

et al. 2006

Blood

132

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Dosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of US $70 000 to US $380 000 (€55 000-300 000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n ‫؍‬ 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n ‫؍‬ 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background. All follow-up parameters were matched separately at baseline, to avoid bias with respect to disease severity. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between both cohorts, whereas plasma chitotriosidase and bone marrow involvement by magnetic resonance imaging improved more quickly and was more pronounced in the higher-dosed group. Major bone complications rarely occurred in both groups.

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Section: Discussionmentioning

confidence: 99%

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Fost

Hollak²,

Groener³

et al. 2006

Blood

132

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“…It should be mentioned that the serum markers for GD (Cox 2005;Deegan et al 2005) are considered to be produced and secreted by GCs (Hollak et al 1994), with the exception of the hex B marker, which has been suggested to come from hepatocytes (Casal et al 2002) altered by GlcCerase deficiency. It is worth noting that a massive systemic inflammation syndrome was induced in adult mice carrying the GD L444P mutation, which at the same time showed only minimal storage of GlcCer.…”

Section: Glucosylceramide Transfermentioning

confidence: 99%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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SummaryGaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer‐ase) is characterized by deficient degradation of beta‐glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology—Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer‐based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non‐macrophage cells) the uncleaved GlcCer, in GlcCer‐ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long‐standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer‐ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.

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“…Laboratory findings include elevated levels of acute-phase proteins (Rogowski et al 2005) and serum immunoglobulin levels (de Fost et al 2008), frequent occurrence of monoclonal gammopathy (Arends et al 2013), detection of various autoantibodies in patients' serum (Shoenfeld et al 1995), and increased plasma levels of proinflammatory cytokines, including IL-1b, IL-6, IL-8, IL-10, TNF-a, and TGF-b (Allen et al 1997;Barak et al 1999;Michelakakis et al 1996;Deegan et al 2005;Pérez Calvo et al 2000). These findings imply that chronic inflammatory status possibly reflects a chronic stimulation of the immune system.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease

Cited by 112 publications

References 36 publications

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

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

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