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Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.

Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH - EMBO Mol Med (2012)

Bottom Line: The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates.No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients.Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Methodist Hospital Research Institute, Houston, TX, USA. jhenkel@tmhs.org

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FoxP3, CD25, Gata3, TGF-β, IL4, IL10, Tbx21 (Tbet), IFN-γ and NOX2 mRNA expression levels in spinal cord autopsy tissue from ALS patientsqRT-PCR was utilized to evaluate mRNA expression levels of CD25, FoxP3, Gata3 (Th2 transcription factor), Tbx21 (Th1 transcription factor), IFN-γ and NOX2 in spinal cord autopsy tissue obtained from 34 ALS patients and 14 disease control. Spinal cord FoxP3 mRNA expression levels were reduced in ALS patients who had progressed rapidly, CD25 mRNA expression levels were not significantly reduced, and Gata3 mRNA expression levels of ALS patients were increased in ALS patients who had progressed slowly. Spinal cord Tbx21 mRNA expression levels were increased in ALS patients who had progressed slowly or rapidly, IFN-γ levels were upregulated in patients who had progressed rapidly, and NOX2 levels were increased in patients who had progressed rapidly (t-test). Therefore, while Tbx21 levels in spinal cord were upregulated in patients who had progressed either rapidly or slowly versus controls, IFN-γ and NOX2 levels were upregulated only in patients who had progressed rapidly, suggesting an active suppression as observed in the mSOD1 mouse. *p ≤ 0.05 versus controls, **p ≤ 0.01 versus controls, #p ≤ 0.05 versus slowly progressing.
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fig06: FoxP3, CD25, Gata3, TGF-β, IL4, IL10, Tbx21 (Tbet), IFN-γ and NOX2 mRNA expression levels in spinal cord autopsy tissue from ALS patientsqRT-PCR was utilized to evaluate mRNA expression levels of CD25, FoxP3, Gata3 (Th2 transcription factor), Tbx21 (Th1 transcription factor), IFN-γ and NOX2 in spinal cord autopsy tissue obtained from 34 ALS patients and 14 disease control. Spinal cord FoxP3 mRNA expression levels were reduced in ALS patients who had progressed rapidly, CD25 mRNA expression levels were not significantly reduced, and Gata3 mRNA expression levels of ALS patients were increased in ALS patients who had progressed slowly. Spinal cord Tbx21 mRNA expression levels were increased in ALS patients who had progressed slowly or rapidly, IFN-γ levels were upregulated in patients who had progressed rapidly, and NOX2 levels were increased in patients who had progressed rapidly (t-test). Therefore, while Tbx21 levels in spinal cord were upregulated in patients who had progressed either rapidly or slowly versus controls, IFN-γ and NOX2 levels were upregulated only in patients who had progressed rapidly, suggesting an active suppression as observed in the mSOD1 mouse. *p ≤ 0.05 versus controls, **p ≤ 0.01 versus controls, #p ≤ 0.05 versus slowly progressing.

Mentions: To address whether the low FoxP3 and Gata3 expressions in the peripheral leukocytes of rapidly progressing patients might be due to enhanced infiltration of Treg and Th2 lymphocytes from the periphery into the spinal cord tissue and address whether the infiltrating T-lymphocytes could potentially influence disease progression rates, mRNA levels were examined in postmortem spinal cord from 15 patients who had progressed rapidly, 19 patients who had progressed slowly and 14 controls and compared with the patients' prior progression rates (Fig 6). FoxP3 mRNA levels were reduced 56.2% in patients who had progressed rapidly compared with disease controls (p = 0.042), and Gata3 levels were enhanced 108.7% in patients who had progressed slowly (p = 0.045) compared with controls. Therefore, while these analyses were performed on tissues from patients after death, the reduced FoxP3 and Gata3 expressions in peripheral leukocytes of patients who had progressed rapidly do not appear to be due to an enhanced influx of Tregs and Th2 lymphocytes into the CNS. Additionally, Tbx21 mRNA levels in spinal cord were similarly increased in patients who had progressed rapidly (113.2%) or slowly (112.1%) versus controls (p = 0.0084, p = 0.0079, respectively). IFN-γ levels were upregulated 212.0% in patients who had progressed rapidly compared with controls (p = 0.024) and compared with slowly progressing patients (p = 0.036). There was no difference in IFN-γ levels between slowly progressing patients and controls (p = 0.724). NOX2 levels were upregulated 72.5% in patients who had progressed rapidly compared with controls (p = 0.028). This similar increase in Tbx21 expression in patients who had progressed slowly and rapidly compared with controls, yet no corresponding upregulation of IFN-γ mRNA in the patients who had progressed slowly, suggest an active suppression of IFN-γ expression in Th1 cells in slowly progressing patients as was observed in the mSOD1 mouse during the slow phase (Beers et al, 2011a).


Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.

Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH - EMBO Mol Med (2012)

FoxP3, CD25, Gata3, TGF-β, IL4, IL10, Tbx21 (Tbet), IFN-γ and NOX2 mRNA expression levels in spinal cord autopsy tissue from ALS patientsqRT-PCR was utilized to evaluate mRNA expression levels of CD25, FoxP3, Gata3 (Th2 transcription factor), Tbx21 (Th1 transcription factor), IFN-γ and NOX2 in spinal cord autopsy tissue obtained from 34 ALS patients and 14 disease control. Spinal cord FoxP3 mRNA expression levels were reduced in ALS patients who had progressed rapidly, CD25 mRNA expression levels were not significantly reduced, and Gata3 mRNA expression levels of ALS patients were increased in ALS patients who had progressed slowly. Spinal cord Tbx21 mRNA expression levels were increased in ALS patients who had progressed slowly or rapidly, IFN-γ levels were upregulated in patients who had progressed rapidly, and NOX2 levels were increased in patients who had progressed rapidly (t-test). Therefore, while Tbx21 levels in spinal cord were upregulated in patients who had progressed either rapidly or slowly versus controls, IFN-γ and NOX2 levels were upregulated only in patients who had progressed rapidly, suggesting an active suppression as observed in the mSOD1 mouse. *p ≤ 0.05 versus controls, **p ≤ 0.01 versus controls, #p ≤ 0.05 versus slowly progressing.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3569654&req=5

fig06: FoxP3, CD25, Gata3, TGF-β, IL4, IL10, Tbx21 (Tbet), IFN-γ and NOX2 mRNA expression levels in spinal cord autopsy tissue from ALS patientsqRT-PCR was utilized to evaluate mRNA expression levels of CD25, FoxP3, Gata3 (Th2 transcription factor), Tbx21 (Th1 transcription factor), IFN-γ and NOX2 in spinal cord autopsy tissue obtained from 34 ALS patients and 14 disease control. Spinal cord FoxP3 mRNA expression levels were reduced in ALS patients who had progressed rapidly, CD25 mRNA expression levels were not significantly reduced, and Gata3 mRNA expression levels of ALS patients were increased in ALS patients who had progressed slowly. Spinal cord Tbx21 mRNA expression levels were increased in ALS patients who had progressed slowly or rapidly, IFN-γ levels were upregulated in patients who had progressed rapidly, and NOX2 levels were increased in patients who had progressed rapidly (t-test). Therefore, while Tbx21 levels in spinal cord were upregulated in patients who had progressed either rapidly or slowly versus controls, IFN-γ and NOX2 levels were upregulated only in patients who had progressed rapidly, suggesting an active suppression as observed in the mSOD1 mouse. *p ≤ 0.05 versus controls, **p ≤ 0.01 versus controls, #p ≤ 0.05 versus slowly progressing.
Mentions: To address whether the low FoxP3 and Gata3 expressions in the peripheral leukocytes of rapidly progressing patients might be due to enhanced infiltration of Treg and Th2 lymphocytes from the periphery into the spinal cord tissue and address whether the infiltrating T-lymphocytes could potentially influence disease progression rates, mRNA levels were examined in postmortem spinal cord from 15 patients who had progressed rapidly, 19 patients who had progressed slowly and 14 controls and compared with the patients' prior progression rates (Fig 6). FoxP3 mRNA levels were reduced 56.2% in patients who had progressed rapidly compared with disease controls (p = 0.042), and Gata3 levels were enhanced 108.7% in patients who had progressed slowly (p = 0.045) compared with controls. Therefore, while these analyses were performed on tissues from patients after death, the reduced FoxP3 and Gata3 expressions in peripheral leukocytes of patients who had progressed rapidly do not appear to be due to an enhanced influx of Tregs and Th2 lymphocytes into the CNS. Additionally, Tbx21 mRNA levels in spinal cord were similarly increased in patients who had progressed rapidly (113.2%) or slowly (112.1%) versus controls (p = 0.0084, p = 0.0079, respectively). IFN-γ levels were upregulated 212.0% in patients who had progressed rapidly compared with controls (p = 0.024) and compared with slowly progressing patients (p = 0.036). There was no difference in IFN-γ levels between slowly progressing patients and controls (p = 0.724). NOX2 levels were upregulated 72.5% in patients who had progressed rapidly compared with controls (p = 0.028). This similar increase in Tbx21 expression in patients who had progressed slowly and rapidly compared with controls, yet no corresponding upregulation of IFN-γ mRNA in the patients who had progressed slowly, suggest an active suppression of IFN-γ expression in Th1 cells in slowly progressing patients as was observed in the mSOD1 mouse during the slow phase (Beers et al, 2011a).

Bottom Line: The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates.No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients.Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Methodist Hospital Research Institute, Houston, TX, USA. jhenkel@tmhs.org

Show MeSH
Related in: MedlinePlus