Limits...
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

Show MeSH

Related in: MedlinePlus

CD4+CD25High regulatory T-lymphocytes (Tregs) are reduced in rapidly progressing ALS patientsShown are flow cytometric analyses of leukocytes from 54 ALS patients through all stages of disease and 33 control volunteers.Representative flow diagrams showing CD4+CD25High Tregs from a rapidly progressing ALS patient, a slowly progressing ALS patient, and a control volunteer.Box and whisker plots indicating that percent of CD4+CD25High Tregs in total leukocytes from ALS patients (mean = 0.692%, median = 0.610%) were not different when compared with control volunteers using the t-test (mean = 0.845%, median = 0.800%).When the ALS patients were separated based on the rate of disease progression into rapidly (AALS points per month ≥1.5; 26 patients) versus slowly (AALS points per month <1.5; 28 patients) progressing ALS patients, the percent of CD4+CD25High Tregs were reduced in rapidly progressing patients (mean = 0.573%, median = 0.495%) compared with slowly progressing patients (mean = 0.825%, median = 0.660%) and reduced compared with control volunteers (mean = 0.845%, median = 0.800%); slowly progressing patients were not different than controls. #p = 0.018 versus slowly progressing ALS patients; **p = 0.003 versus controls.Scatter plot with regression line demonstrating that the percent of CD4+CD25High T cells were inversely correlated with rate of ALS progression (R = 0.301; linear regression). Slowly progressing ALS patients = AALS points/month <1.5; rapidly progressing ALS patients = AALS points/month >1.5, at the time of collection. ALS patients early in disease = AALS score < 100; ALS patients late in disease = AALS score ≥100, at the time of collection. &p = 0.028.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3569654&req=5

fig01: CD4+CD25High regulatory T-lymphocytes (Tregs) are reduced in rapidly progressing ALS patientsShown are flow cytometric analyses of leukocytes from 54 ALS patients through all stages of disease and 33 control volunteers.Representative flow diagrams showing CD4+CD25High Tregs from a rapidly progressing ALS patient, a slowly progressing ALS patient, and a control volunteer.Box and whisker plots indicating that percent of CD4+CD25High Tregs in total leukocytes from ALS patients (mean = 0.692%, median = 0.610%) were not different when compared with control volunteers using the t-test (mean = 0.845%, median = 0.800%).When the ALS patients were separated based on the rate of disease progression into rapidly (AALS points per month ≥1.5; 26 patients) versus slowly (AALS points per month <1.5; 28 patients) progressing ALS patients, the percent of CD4+CD25High Tregs were reduced in rapidly progressing patients (mean = 0.573%, median = 0.495%) compared with slowly progressing patients (mean = 0.825%, median = 0.660%) and reduced compared with control volunteers (mean = 0.845%, median = 0.800%); slowly progressing patients were not different than controls. #p = 0.018 versus slowly progressing ALS patients; **p = 0.003 versus controls.Scatter plot with regression line demonstrating that the percent of CD4+CD25High T cells were inversely correlated with rate of ALS progression (R = 0.301; linear regression). Slowly progressing ALS patients = AALS points/month <1.5; rapidly progressing ALS patients = AALS points/month >1.5, at the time of collection. ALS patients early in disease = AALS score < 100; ALS patients late in disease = AALS score ≥100, at the time of collection. &p = 0.028.

Mentions: CD4+CD25High Tregs were evaluated to determine whether they are associated with disease progression in ALS patients, as in mSOD1 mice. Single blood samples from 54 ALS patients from all stages of disease and control volunteers were examined by flow cytometry (Fig 1A). The percentages of CD3+, CD4+ or CD8+ lymphocytes (data not shown), or CD4+CD25High Tregs (Fig 1B) of total leukocytes from ALS patients and controls were not different. However, differences were noted when the patients were separated and grouped based on their rate of disease progression at the time of blood collection [rate was determined as the change in AALS score, change in time (months), comparing the initial clinical evaluation with the evaluation performed at the time of blood collection]. Patients were grouped into slowly (<1.5 AALS points/month, 28 patients) versus rapidly (≥1.5 AALS points/month, 26 patients) progressing patients using the Appel ALS (AALS) score (Fig 1C; Haverkamp et al, 1995), as this rate separated the patients surviving only a year or two after diagnosis from those that survive up to 6 years or more after diagnosis and also divided these patients approximately in half. Leukocytes from blood of rapidly progressing patients consisted of 31% fewer CD4+CD25High Tregs compared with slowly progressing patients (p = 0.018) and 32% fewer CD4+CD25High Tregs compared with controls (p = 0.003). CD4+CD25High Tregs from slowly progressing patients were not different than controls (p = 0.846). No correlation with age (p = 0.689) nor difference between limb versus bulbar onsets (p = 0.684) were found. The percent of CD4+CD25High Tregs in ALS patients were inversely correlated with rate of disease progression; the greater the number of Tregs, the slower the disease progression rate (p = 0.028; Fig 1D). These results indicate an association between numbers of CD4+CD25High Tregs in blood with the rate at which disease progresses in ALS patients.


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)

CD4+CD25High regulatory T-lymphocytes (Tregs) are reduced in rapidly progressing ALS patientsShown are flow cytometric analyses of leukocytes from 54 ALS patients through all stages of disease and 33 control volunteers.Representative flow diagrams showing CD4+CD25High Tregs from a rapidly progressing ALS patient, a slowly progressing ALS patient, and a control volunteer.Box and whisker plots indicating that percent of CD4+CD25High Tregs in total leukocytes from ALS patients (mean = 0.692%, median = 0.610%) were not different when compared with control volunteers using the t-test (mean = 0.845%, median = 0.800%).When the ALS patients were separated based on the rate of disease progression into rapidly (AALS points per month ≥1.5; 26 patients) versus slowly (AALS points per month <1.5; 28 patients) progressing ALS patients, the percent of CD4+CD25High Tregs were reduced in rapidly progressing patients (mean = 0.573%, median = 0.495%) compared with slowly progressing patients (mean = 0.825%, median = 0.660%) and reduced compared with control volunteers (mean = 0.845%, median = 0.800%); slowly progressing patients were not different than controls. #p = 0.018 versus slowly progressing ALS patients; **p = 0.003 versus controls.Scatter plot with regression line demonstrating that the percent of CD4+CD25High T cells were inversely correlated with rate of ALS progression (R = 0.301; linear regression). Slowly progressing ALS patients = AALS points/month <1.5; rapidly progressing ALS patients = AALS points/month >1.5, at the time of collection. ALS patients early in disease = AALS score < 100; ALS patients late in disease = AALS score ≥100, at the time of collection. &p = 0.028.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: CD4+CD25High regulatory T-lymphocytes (Tregs) are reduced in rapidly progressing ALS patientsShown are flow cytometric analyses of leukocytes from 54 ALS patients through all stages of disease and 33 control volunteers.Representative flow diagrams showing CD4+CD25High Tregs from a rapidly progressing ALS patient, a slowly progressing ALS patient, and a control volunteer.Box and whisker plots indicating that percent of CD4+CD25High Tregs in total leukocytes from ALS patients (mean = 0.692%, median = 0.610%) were not different when compared with control volunteers using the t-test (mean = 0.845%, median = 0.800%).When the ALS patients were separated based on the rate of disease progression into rapidly (AALS points per month ≥1.5; 26 patients) versus slowly (AALS points per month <1.5; 28 patients) progressing ALS patients, the percent of CD4+CD25High Tregs were reduced in rapidly progressing patients (mean = 0.573%, median = 0.495%) compared with slowly progressing patients (mean = 0.825%, median = 0.660%) and reduced compared with control volunteers (mean = 0.845%, median = 0.800%); slowly progressing patients were not different than controls. #p = 0.018 versus slowly progressing ALS patients; **p = 0.003 versus controls.Scatter plot with regression line demonstrating that the percent of CD4+CD25High T cells were inversely correlated with rate of ALS progression (R = 0.301; linear regression). Slowly progressing ALS patients = AALS points/month <1.5; rapidly progressing ALS patients = AALS points/month >1.5, at the time of collection. ALS patients early in disease = AALS score < 100; ALS patients late in disease = AALS score ≥100, at the time of collection. &p = 0.028.
Mentions: CD4+CD25High Tregs were evaluated to determine whether they are associated with disease progression in ALS patients, as in mSOD1 mice. Single blood samples from 54 ALS patients from all stages of disease and control volunteers were examined by flow cytometry (Fig 1A). The percentages of CD3+, CD4+ or CD8+ lymphocytes (data not shown), or CD4+CD25High Tregs (Fig 1B) of total leukocytes from ALS patients and controls were not different. However, differences were noted when the patients were separated and grouped based on their rate of disease progression at the time of blood collection [rate was determined as the change in AALS score, change in time (months), comparing the initial clinical evaluation with the evaluation performed at the time of blood collection]. Patients were grouped into slowly (<1.5 AALS points/month, 28 patients) versus rapidly (≥1.5 AALS points/month, 26 patients) progressing patients using the Appel ALS (AALS) score (Fig 1C; Haverkamp et al, 1995), as this rate separated the patients surviving only a year or two after diagnosis from those that survive up to 6 years or more after diagnosis and also divided these patients approximately in half. Leukocytes from blood of rapidly progressing patients consisted of 31% fewer CD4+CD25High Tregs compared with slowly progressing patients (p = 0.018) and 32% fewer CD4+CD25High Tregs compared with controls (p = 0.003). CD4+CD25High Tregs from slowly progressing patients were not different than controls (p = 0.846). No correlation with age (p = 0.689) nor difference between limb versus bulbar onsets (p = 0.684) were found. The percent of CD4+CD25High Tregs in ALS patients were inversely correlated with rate of disease progression; the greater the number of Tregs, the slower the disease progression rate (p = 0.028; Fig 1D). These results indicate an association between numbers of CD4+CD25High Tregs in blood with the rate at which disease progresses in ALS patients.

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