T cell receptor rearrangement excision circles (TRECs) and CD31+ regulatory T cells for assessing recent thymic output in patients with chronic hepatitis B
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Abstract:
Objective
To evaluate the clinical value of combined detection of T cell receptor rearrangement excision circles (TRECs) and CD31+ regulatory T (Treg) cells for accessing the recent thymic output in patients with chronic hepatitis B.
Methods
Four groups involving 135 subjects were set up in this study as follows: mild chronic hepatitis B (Mild CHB, n=35), moderate chronic hepatitis B (Moderate CHB, n=35), severe chronic hepatitis B (Severe CHB, n=35) and healthy control (HCs, n=30) groups. CD4+ CD25+ Treg cells in these subjects were sorted out using magnetic cell separation. The ratio of peripheral CD31+ Treg cells to Treg cells in each group was analyzed by flow cytometry. Real-time PCR was performed to detect TRECs in CD4+ CD25+ Treg cells. The percentages of CD3+ , CD4+ and CD8+ T cell subsets were also measured.
Results
The ratios of CD31+ Treg/Treg cells and the numbers of TRECs in peripheral blood of the Moderate CHB and Severe CHB groups were significantly lower than those of the Mild CHB and HCs groups (P 0.05). No significant difference in the percentages of CD3+ , CD4+ or CD8+ T cell subsets was observed between the four groups (P>0.05). CD31+ Treg/Treg cell ratio had a positive correlation with the number of TRECs (r=0.551, P=0.014).
Conclusions
Both CD31+ Treg/Treg cell ratio and the number of TRECs were reduced in the peripheral blood of patients with moderate or severe CHB. CD31+ Treg/Treg cell ratio and the number of TRECs were positively correlated and could be used as new indices to evaluate recent thymus output.
Key words:
Chronic hepatitis B; CD4+ CD25+ regulatory T cell; CD31+ regulatory T cell; T cell receptor rearrangement excision circlesKeywords:
CD31
Objective:To investigate the quantification of CD4+CD25+ regulatory T cells and distribution of CD4+CD8+ T lymphocyte subgroup in peripheral blood of patients in chronic hepatitis B(CHB),and to reveal relationship between CD4+CD25+ regulatory T cells,CD4+CD8+ T lymphocyte subgroup and HBV infetion as well.Methods:CD4+CD25high,CD4+CD25+Foxp3+Treg and CD3+CD4+CD8+T lymphocyte subgroup in peripheral blood from 50 patients with CHB and 20 healthy controls was analyzed using flow cytometry.HBV DNA was detected by fluorescence quantitative PCR.Results:The number of CD4+CD25highTregs in patients with CHB was obviously higher than that in healthy controls(P0.01)and increased with copies of HBV DNA.The same with the change of CD4+CD25+Foxp3+Tregs in patients with CHB and there was a positive correlation between CD4+CD25highTregs and CD4+CD25+Foxp3+Tregs(r=0.890,P0.001).Compared with healthy controls,the frequency of CD4+T cells and the ratio of CD4+/CD8+ in patients with CHB was declined,but there was no significant difference in the frequency of CD3+T cells and CD8+T cells between them(P0.05).The variation in the number of CD4+CD25highTregs was correlated positively with the copies of HBV DNA(r=0.782,P0.001)and glutamic-pyruvic transaminase(ALT)(r=0.432,P0.005)separately,but negatively with the frequency of CD3+,CD4+,CD8+T cells and the ratio of CD4+/CD8+(P0.05).The variation in the frequency of CD3+,CD4+,CD8+T cells and the ratio of CD4+/CD8+ was also correlated negatively with the copies of HBV DNA(P0.05).Conclusion:The number of CD4+CD25highTregs increases in patients with CHB and is in accordance with the copies of HBV DNA and increased level of ALT.Further studies should be done to investigate weather CD4+CD8+ T lymphocyte subgroup could be used to monitor the state of community.
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To evaluate the inhibition of CD4+ CD25+ regulatory T cells (Treg) in the chronic hepatitis B patients.Peripheral blood samples were collected from 22 patients with chronic hepatitis B (CHB) and 18 healthy blood donors to isolate the peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze the proportion of CD4+ CD127(lo)CD25(hi-int) Tregs in the CD4+ T cells so as to calculate the proportion of CD4+ CD25+ Tregs in the CD4+ T cells. BrdU incorporation method was used to evaluate the immune inhibition of the CD4+ CD25+ Tregs. CD4+ CD25- cells were isolated by magnetic bead sorting technique. The CD4- T cells and CD4+ CD25- T cells ere mixed and stimulated by HBVcore 18-27 peptide. The PBMCs of the CHB patients with the Treg depleted and Treg not depleted underwent detection of HBVcore18-27 specific cytotoxic T lymphocytes (CTLs). The IFN-gamma secretion of the CTLs in the PBMCs of CHB patients with Treg depleted and Treg not depleted was detected by HLA-pentamer and enzyme-linked immunospot assay (Elispot).The proportion of CD4+ CD127(lo)CD25(hi-int) Treg in the CD4+ T cells used to reflect the percentage of CD4+CD25+ Tregs in the CD4+ T cells of the CHB patients was 4.3% +/- 2.4%, significantly higher than that of the healthy controls (2.1% +/- 1.3%, t = 3.74, P <0.01). There was no significant difference in the inhibition of CD4+ CD25- T cells by autogenous CD4+ CD25+ T cells between the CHB patients and healthy controls. The frequency of CTLs induced by HBV core 18-27 of the CHB patients with their CD4+ CD25+ cells in circulation depleted was 0.74% +/- 0.31%, significantly higher than that of the patients whose CD4+ CD25+ cells in circulation were not depleted (0.17% +/- 0.08%, t = 4.75, P <0.01). The frequency of IFN-gamma secreting spots of HBVcore18-27-specific CD8+ T cells of the CHB patients with their CD4+ CD25+ cells depleted was (112 +/- 33), significantly higher than that of the CHB patients whose CD4+ CD25+ cells in circulation were not depleted [(23 +/- 14), t =7.828, P<0.01)].The proportion of CD4+ CD25+ Treg in CHB patients is increased compared to the healthy blood donor. The proliferative capacity of CD4+ CD25- T cells is inhibited by the presence of CD4+ CD25+ Treg dose-dependently, and the inhibition of CD4+ CD25+ Tregs in the CHB patients is similar to the inhibition of CD4+ CD25+ Tregs in healthy donors. The elimination of Treg cells followed by stimulation with HBVcore18-27 peptide significantly improves the antivirus CTL responses in CHB patients.
ELISPOT
Interleukin-7 receptor
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Objective:The current study was designed to investigate the changes in peripheral lymphocyte subsets and CD4~+CD25~+ regulatory T cells(CD4~+CD25~+ Treg) in malignancies.Methods:From 53 malignancies, 4 ml venous blood was obtained. By using monoclonal antibodies, the blood samples were evaluated with the flow cytometry for lymphocyte subsets and Treg cells. At the same time the expressive rates of CD4,CD16 and the ratio of CD4/CD8 in malignancies were also investigated.Results:Compared with healthy volunteers, the expressive rates of CD4,CD16 in peripheral blood in early stage of malignancies were lower than that in normal volunteers, but differences were no significant (P0.05); the ratio of CD4/CD8 was also lower than that in normal volunteers,the difference was significant (P0.05). while in the advanced stages, the expressive rates of CD4,CD16 and the ratio of CD4/CD8 in peripheral blood were lower significantly than that in normal volunteers (P0.05). On the other hand, Cancer patients had a higher proportion of CD4~+CD25~+ Treg cells(19.61±8.17)% than those of the healthy volunteers(14.49±4.69)%, (P0.05).Conclusion:The relative increase in CD4~+CD25~+ regulatory T cells may be related to immunosuppression and tumor progression in patients with malignancies. This finding suggests that the deletion of the CD4~+CD25~+ Treg cells to treat cancer patients may be an effective strategy.
Immunosuppression
CD16
Venous blood
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Objective: To analyze the expression levels of CD 4 +CD 25 +Treg and CD 4 +CD 25 +Foxp 3 +Treg in peripheral blood of school-age children with metabolism syndrome( MS). Methods: A total of 25 MS children treated in the hospital recently were selected as MS group,and 24 healthy children who received physical examination during the same period were selected as control group; regulatory T cells detection( CD 4 +CD 25 +Treg and CD 4 +CD 25 +Foxp 3 +Treg) and helper T cells detection( CD+ 3,CD+ 4,CD+ 8,CD 4 +/ CD 8 +) in peripheral blood of the children in the two groups were conducted. Results: The levels of CD 4 +CD 25 +Treg and CD 4 +CD 25 +Foxp 3 +Treg in peripheral blood of MS group were statistically significantly lower than those of control group( P 0. 05); meanwhile,the expression level of CD 8 +in peripheral blood of MS group was statistically significantly higher than that of control group( P 0. 05),but the ratio of CD 4 +/ CD 8 +in MS group was statistically significantly lower than that in control group( P 0. 05). Conclusion: Down-regulation of regulatory T cells in peripheral blood of MS children can be detected definitely.
Treg cell
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To explore the percentage of CD4(+);CD25(+);Foxp3(+); regulatory T cells (Treg) in peripheral blood of chronic lymphocytic leukemia (CLL) patients and the correlations with clinical prognosis.The study enrolled 30 healthy individuals and 28 CLL patients. The CD4(+);CD25(+); Treg and CD4(+);CD25(+);Foxp3(+); Treg were detected by the flow cytometry in their peripheral blood. Of the 28 CLL patients, 19 received treatment and follow-up.The number of CD4(+);CD25(+); Treg in the pre-treated cases (n = 28) was higher than that in the healthy controls (n = 30) with significant statistical difference (P < 0.05). The number of CD4(+);CD25(+);Foxp3(+); Treg was higher in the pre-treated cases (n = 28) than that in the treated cases (n = 19) and in the healthy controls (n = 30) (P < 0.05). Compared with the healthy controls, the treated cases (n = 19) had the higher level of CD4(+);CD25(+);Foxp3(+); Treg (P < 0.05). The CD4(+);CD25(+);Foxp3(+); Treg was positively correlated with the expressions of CD38, β2-microglobulin (β(2);-MG), zeta-associated protein 70(ZAP-70) and the clinical Binet and Rai stages.The CD4(+);CD25(+);Foxp3(+); Treg might be a valuable indicator for assessing the therapeutic efficacy, disease progression and prognosis of the CLL patients.
Regulatory T cell
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To explore the subpopulation of CD4(+); CD25(+); Foxp3(+); regulatory T cells (Treg), CD4(+); CD25(+); CD127(low/-); Treg in peripheral blood of HIV-infected patients and study its correlation with other immune indicators.We enrolled 68 cases of HIV/AIDS patients without anti-HIV treatment [29 cases of long-term non-progressive (LTNP) group, 27 cases of typical progressive HIV infection group and 12 cases of AIDS group] and 20 healthy individuals as a control group. Blood samples of these cases were analyzed by flow cytometry after immunofluorescent staining to determine the levels of CD4(+); T cells, CD8(+); T cells, NK cells and CD4(+); CD25(+); Foxp3(+);/CD127(low/-); Treg.Except CD8(+); T cells, the levels of CD4(+); T, NK cells and CD4(+);/CD8(+); in peripheral blood of HIV/AIDS patients were significantly lower than those in the control group (P<0.05); With the progression of disease, the percentage and absolute count of CD4(+);T cells, the absolute counts of CD8(+);T cells and NK cells, and CD4(+);/CD8(+); T cell ratio in the LTNP group, HIV group and AIDS group decreased gradually, while the percentage of CD8(+);T cells increased gradually. Our multiple comparison analysis revealed that the percentages of CD4(+); CD25(+); Foxp3(+); Treg and CD4(+); CD25(+); CD127(low/-); Treg in CD4(+); T cells were significantly different among groups (P<0.05). With the progression of disease, the percentages of CD4(+); CD25(+); Foxp3(+); Treg and CD4(+); CD25(+); CD127(low/-); Treg increased gradually; in addition, the difference in the absolute count of CD4(+); CD25(+); Foxp3(+);/CD127(low/-); Treg was not statistically significant between LTNP group and healthy control group(P>0.05), so was between HIV and AIDS groups (P>0.05); no significant difference was found in every other two groups (P<0.05); the absolute count of CD4(+); CD25(+); Foxp3(+);/CD127(low/-); Treg decreased gradually.CD4(+); CD25(+); Foxp3(+);/CD127(low/-); Treg may play a role in the immunopathogenesis of persistent HIV infection.
Interleukin-7 receptor
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Objective To investigate the frequency of CD4+CD25+Foxp3+ regulatory T cells( Treg) in peripheral blood of patients with chronic hepatitis B( CHB) and its significance in the hepatitis B virus( HBV) infection. Methods The frequencies of CD4+CD25+Foxp3+ Treg in peripheral blood from 86 CHB patients,30 acute hepatitis B( AHB)patients and 30 healthy subjects were determined by flow cytometry. The correlations of HBV DNA loads with CD4+CD25+Foxp3+Treg frequency and the frequency of CD4+CD25+Foxp3+ Treg after therapy with different therapeutic effects were analyzed respectively. CD4+CD25+Foxp3+Treg frequencies among mild,moderate and severe active CHB patients were compared respectively. Results The percentages of CD4+CD25+Foxp3+ Treg in CHB patients,AHB patients and healthy subjects were 2. 56% ± 1. 12%,1. 39% ± 0. 68% and 1. 45% ± 0. 76%,respectively. The percentage in CHB patients was higher than those in AHB patients and healthy subjects( P 0. 05),and there was no statistical significance between the percentages of AHB patients and healthy subjects( P 0. 05). The percentages of CD4+CD25+Foxp3+ Treg among mild,moderate and severe active CHB patients had no statistical significance( P 0. 05). The levels of alanine aminotransferase( ALT) in CHB patients,AHB patients and healthy subjects were 285. 6 ±168. 3,( 780. 9 ± 432. 6) and( 23. 2 ± 6. 7) U / L,respectively. The levels of ALT in CHB patients and AHB patients were higher than that in healthy subjects( P 0. 05). The level of ALT in CHB patients was lower than that in AHB patients( P 0. 05). The frequency of CD4+CD25+Foxp3+ Treg was not correlated with the level of ALT( r = 0. 11,P 0. 05). The HBV DNA loads in CHB patients,AHB patients and healthy subjects were( 5. 2 ± 1. 8) log10 copies / mL,( 7. 2 ±1. 8) log10 copies / mL and negative respectively. The HBV DNA load in AHB patients was higher than that in CHB patients( P 0. 05). There was a positive correlation between CD4+CD25+Foxp3+ Treg frequency and HBV DNA logarithm( r = 0. 30,P 0. 05). CD4+CD25+Foxp3+ Treg frequency decreased obviously after anti-viral therapy in the patients with obvious good therapeutic effect,and it was lower than that in the patients with poor therapeutic effect( P 0. 05). Conclusions The increase of CD4+CD25+Foxp3+ Treg in CHB patients plays an active role in chronic HBV.The regulation and control of function and amount of CD4+CD25+Foxp3+ Treg may provide a new therapy for CHB.
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Objective:To observe the changes of CD4+CD25+FOXP3+ regulatory T cells(Treg cells) in peripheral blood of patients with acute myelogenous leukemia(AML) in order to reveal the role of Treg cells in the pathogenesis of AML and to evaluate its clinical significance.Methods:The flow cytometry was used to evaluate the proportion of CD4+CD25highFOXP3+ Treg cells and CD4+ FOXP3+ T cells in the peripheral blood of 31 patients with AML who were newly diagnosed(newly diagnosed group),23 patients with AML who achieved complete remission(CR group) and 20 healthy donors(control group).CD4+/CD8+ ratio,the proportion of NK cells and the level of lactate dehydrogenase(LDH) were also analyzed.Results:Compared with that of control group,the proportion of CD4+CD25highFOXP3+ Treg cells and CD4+ FOXP3+ T cells in newly diagnosed group were significantly increased(P0.01).Compared with that of the newly diagnosed group,the proportion of CD4+CD25highFOXP3+ Treg cells in CR group was not significantly decreased(P0.05),while that of CD4+ FOXP3+ T cells was decreased(P0.01).The proportion of CD4+CD25highFOXP3+ Treg cells was positively correlated with the proportion of CD4+ FOXP3+ T cells(r=0.86;P0.01).The proportion of CD4+CD25highFOXP3+ Treg cells and CD4+ FOXP3+ T cells was negatively correlated with CD4+/CD8+ ratio(r=-0.54,-0.52,respectively;P0.01) and the proportion of NK cells(r=-0.41,-0.43,respectively;P0.05),positively correlated with the level of LDH(r=0.51,0.57,respectively;P0.05).Conclusion:The increased number of CD4+CD25highFOXP3+ Treg cells might be one of the important reasons of immunosuppression in AML.Analysis of its changes may be helpful on judgement of prognosis of AML.The function of CD4+ FOXP3+ Treg cells is similar to CD4+CD25highFOXP3+ Treg cells.Measurement of its proportion may be more value on evaluation of therapeutic effect.
Pathogenesis
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Objective:To investigate the significance of regulatory T cells in peripheral blood of chronic renal insufficientce.Methods:The peripheral blood samples were collected from 40 patients with chronic renal insufficient.The ratios ot CD4+T cell in lymphocyte and CD4+CD127-Treg and CD4+CD25+CD127-Treg in CD4+T were detected by flow cytometry.Results:The number of CD4+T in lymphocyte of chronic renal insufficient was higher than in healthy control group and there wasn’t significantly difference of the CD4+CD25+CD127-Treg ratios in CD4+T between chronic renal insufficience and healthy central.The ratio of CD4+T cells in lymphocytes of chronic renal insufficience was lower than in healthy control group except compensatory stage.There was no correlation between CD4+T cell ratios in lymphocytes,CD4+CD127-Treg or CD4+CD25+CD127-Treg ratios in CD4+T cells and the values of BUN,Cr among the hypertension patients.Conclusion:The number of CD4+T cells increases,and CD4+CD127-Treg decreases in the patients with chronic renal insufficience and their immune functions are shown in disoroler .
Interleukin-7 receptor
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Objective To compare the effects of CD4+CD25+FoxP3+ and CD4+CD25+CD127-/low gating on CD4+CD25+Treg and explore the expression and dinical significance of CD4+CD25+Treg in patients with chronic hepatitis B virus infection.Methods The frequency of CD4+CD25+CD127-/low Treg in the peripheral blood from 52 chronic hepatitis B patients,24 chronic asymptomatic HBV carriers,24 inactive HBsAg carriers and 25 healthy controls were measured by flow cytometry with CD4+CD25+CD127-/low gating.Furthermore,healthy controls and 21 chronic hepatitis B were measured by flow cytometry with CD4+CD25+FoxP3+.HBV DNA levels were measured by real-time PCR.Results There was a significant positive correlation between the results of CD4+CD25+CD127-/low gating and CD4+CD25+FoxP3+ gating(r=0.506,P0.05;r=0.556,P0.01).There was significant difference in the frequency of CD4+CD25+CD127-/lowTreg between chronic hepatitis B patients(10.65±2.86)and the other groups(P0.01).The level of Treg in chronic asymptomatic HBV carriers(8.56±2.01)was higher than that in healthy controls(7.33±1.17).There was no correlation between serum HBV DNA levels and the frequency of Treg in chronic hepatitis B patients and chronic asymptomatic HBV carriers;No statistical was difference in the frequency of Treg between chronic hepatitis B patients of HBeAg positive and negative.Conclusion It suggested that there was a significant positive correlation between the results of CD4+CD25+CD127-/low gating and CD4+CD25+FoxP3+ gating,and the former was more easily performed and practicable.The level of Treg in CHB patients and chronic asymptomatic HBV carriers is higher than that in health controls.The finding suggested that Treg plays an important role in chronic hepatitis B virus infection.
Interleukin-7 receptor
Asymptomatic carrier
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