Th 1 cytokine production by peripheral blood mononuclear cells in X-linked adrenoleukodystrophy

Biase, Antonella Di; Merendino, Nicolò; Avellino, C.; Cappa, Marco; Salvati, Serafina

doi:10.1016/s0022-510x(00)00469-x

Cited by 21 publications

(23 citation statements)

References 17 publications

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“…In addition, western blot analysis also indicates that a fraction of the other two cytoplasmic subunits of the NADPH oxidase (p47 PHOX and p67 PHOX ) was found associated with the membranes at similar levels in control and X-ALD lymphoblasts, suggesting that the higher levels of synthesis of free radicals observed in X-ALD lymphoblasts under basal conditions, may be a consequence of the higher levels of the catalytic subunit gp91 PHOX . The results also indicate that X-ALD lymphoblasts produce higher levels of NO and TNFα and IL-1β cytokines, suggesting additional alterations of other membrane proteins, and support previous studies reporting that cells derived from X-ALD patients have an increased proinflammatory response (20-22). Taken together, the data suggest that NADPH oxidase-produced free radicals may play an important role as a modulator of the development/progression of neuroinflammation in X-ALD disease.…”

Section: Discussionsupporting

confidence: 89%

“…As reported earlier, peripheral blood mononuclear cells from X-linked adrenoleukodystrophy patients synthesize excessive levels of the proinflammatory cytokine Tumor Necrosis Factor alpha (TNF-α) when stimulated with bacterial lipopolysaccharide (LPS) (20, 21). Therefore, we investigated whether lymphoblasts are able to synthesize cytokines under non-stimulated conditions.…”

Section: Resultsmentioning

confidence: 87%

“…For example, peripheral blood mononuclear cells from X-ALD patients, when stimulated with bacterial lipopolysaccharide (LPS), produce increased levels of cytokines typical of a Th1 cell response (IL-12, TNFα) as compared to cells from control patients (20, 21); skin fibroblasts derived from peroxisomal metabolic disorder patients (including X-ALD) have an increased basal as well as IL-1β stimulated arachidonic acid metabolism (22); and C6 cells enriched in the VLC fatty acid hexacosanoic acid (C26:0) and stimulated with oxidative stressors (LPS, oxidized LDL) produce higher levels of nitric oxide and superoxide products as compared to those by untreated cells (23). These reports support the hypothesis that accumulation of VLC fatty acids alters the plasma membrane properties (24, 25), and hence cell signaling functions in those cells (26).…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Imbalance in Nonstimulated X-Adrenoleukodystrophy-Derived Lymphoblasts

et al. 2008

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X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very long chain (VLC) fatty acids, which induces alterations in cellular redox and induction of inflammatory disease, both of which are reported to play a role in pathogenesis of the severe form of the disease (childhood ALD). Here we report on the status of oxidative stress (NADPH oxidase activity) and inflammatory mediators in a X-ALD lymphoblast cell line under non-stimulated conditions. X-ALD lymphoblasts contain near 7 fold higher levels of the C26:0 fatty acid, as compared to controls; levels that were down regulated by treatment with Sodium Phenylacetate (NaPA), lovastatin or combination of both drugs. In addition, free radical synthesis was elevated in X-ALD lymphoblasts, and protein levels of the NADPH oxidase gp91 PHOX membrane subunit were significantly upregulated, but no changes were observed in the p47 PHOX and p67 PHOX cytoplasmic subunits. Unexpectedly, there was no increase in gp91 PHOX mRNA levels in X-ALD lymphoblasts. Furthermore, X-ALD lymphoblasts produced higher levels of nitric oxide (NO) and cytokines (TNF-α and IL-1β); and treatment with NaPA, or lovastatin decreased the synthesis of NO. Our data indicates that X-ALD lymphoblasts are significantly affected by the accumulation of VLC fatty acids, which in turn induces changes in the cell membrane properties/functions that may play a role in the development/progression of the pathogenesis of X-ALD disease.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Oxidative Imbalance in Nonstimulated X-Adrenoleukodystrophy-Derived Lymphoblasts

et al. 2008

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“…In particular, we found amplified V families in cases of CALD as well as in cases of AMN. Di Biase et al (2001) also showed that stimulated peripheral blood mononuclear cells from both asymptomatic and symptomatic (CALD or …”

Section: Usage In Csf T Cells 257mentioning

confidence: 98%

T-cell receptor Vβ gene usage in CSF lymphocytes in X-linked adrenoleukodystrophy

Picard¹,

Guidoux²,

Martin³

et al. 2005

J. Mol. Recognit.

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X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid (VLCFA) metabolism that produces a neurological disease with significant variability of clinical phenotypes even within kindred. The two most common forms are the cerebral form (CALD) with an important inflammatory reaction at the active edge of demyelinating lesions, resembling some aspects of multiple sclerosis pathology, and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. One hypothesis is that the phenotypic variability is related to T cell-mediated immune mechanisms playing a primary role in the demyelinating pathogenic process of CALD. The present study aims to test the hypothesis that CSF of patients with the CALD form contains highly restricted T cell populations. The variable regions of the T cell receptor beta chains (TCR Vbeta) were studied in CSF from 29 ALD patients with different phenotypes. RNA was extracted and cDNA synthesized from CSF lymphocytes; TCR Vbeta gene segments were amplified from the cDNA by polymerase chain reaction (PCR) using 20 family-specific primers. PCR products were analyzed by Southern blot. Some amplified Vbeta products were sequenced. The majority of ALD patients (21/29), whatever their phenotype, exhibited oligoclonal T cell expansion. However the overexpression of some TCR Vbeta families was heterogeneous among the different patients without any preponderance of specific Vbeta families or any clustering according to clinical phenotype. In particular a dominant TCR Vbeta utilization was not found in patients with CALD.

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“…Proinflammatory cytokines such as TNFα, IL-1 and IL-6 are also increased in ALD patients and are possibly involved in the pathophysiology of the disease. They are able to promote the inflammatory process in the central nervous system [13] and may also have direct and differential effects on the steroid synthesis of the adrenal cortex [18].…”

Section: Discussionmentioning

confidence: 99%

Adrenal steroids in adrenomyeloneuropathy

Wichers-Rother¹,

Grigull²,

Sokolowski

et al. 2005

J Neurol

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Adrenoleukodystrophy (ALD) and its adult variant adrenomyeloneuropathy (AMN) are X-linked diseases associated with a deficiency in the peroxisomal degradation of saturated very long chain fatty acids (VLCFA) resulting in an accumulation of VLCFA in the central and peripheral myelin, the adrenal cortex and the testis. Adrenal insufficiency with clinical hypocortisolism occurs in approximately two thirds of the patients with AMN. We studied the circulating adrenal hormones 17alpha-hydroxyprogesterone (17alpha-OHP), androstenedione and dehydroepiandrosterone sulphate (DHEAS) in 63 male AMN patients (age 17-65 years) and the DHEAS serum levels in 95 healthy male controls (age 30-65 years). 34 of the patients presented with the phenotype of only spinal cord and peripheral nerve disability without hypocortisolism, 29 of the patients presented with the phenotype of either additional hypocortisolism or Addison's syndrome only. Normal 17alpha-OHP concentrations were found in all patients with no significant difference between patients without and with hypocortisolism (6.07 +/- 0.61 nmol/l and 4.76 +/- 0.37 nmol/l). Androstenedione concentration was significantly (p < 0.01) lower in patients with hypocortisolism (2.99 +/- 0.65 pmol/l versus 5.71 +/- 0.68 pmol/l). As serum levels of DHEAS are agedependent we divided the two groups into two subgroups each (subgroup one: age 17-40 years, subgroup two: age 41-65 years). The DHEAS concentration of patients without and with hypocortisolism was significantly (p < 0.01) lower in both subgroups (1. 4.35 +/- 0.84 micromol/l, n = 15, 2. 15 +/- 0.28 micromol/l, n = 19; 1. 1.90 +/- 0.57 micromol/, n = 21, 2. 0.96 +/- 0.29 micromol/l, n = 8) compared to controls (1. 9.0 +/- 0.96 micromol/l; 2. 5.21 +/- 0.25 micromol/l). In conclusion, androstenedione and DHEAS serum concentrations are subnormal in all AMN patients and may therefore serve as sensitive markers of the adrenal function in adrenomyeloneuropathy.

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Th 1 cytokine production by peripheral blood mononuclear cells in X-linked adrenoleukodystrophy

Cited by 21 publications

References 17 publications

Oxidative Imbalance in Nonstimulated X-Adrenoleukodystrophy-Derived Lymphoblasts

Oxidative Imbalance in Nonstimulated X-Adrenoleukodystrophy-Derived Lymphoblasts

T-cell receptor Vβ gene usage in CSF lymphocytes in X-linked adrenoleukodystrophy

Adrenal steroids in adrenomyeloneuropathy

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