摘要
第一部分:银屑病患者外周血调节性T细胞的表达
目的:探讨不同方法标记的银屑病患者外周血中调节性T细胞(Treg)的表达及其在银屑病免疫学变化中的作用。方法:利用流式细胞仪检测45例银屑病患者外周血中CD4~+CD25~(high)Foxp3~+调节性T细胞在CD4~+T细胞中的比例;用流式细胞仪和单克隆荧光抗体检测45例银屑病患者外周血中CD4~+CD25~(high)调节性T细胞百分率,对10例银屑病患者进行了CD4~+CD25~(hi-int)CD127~(low/-)调节性T细胞百分率的检测。结果:红皮病型银屑病患者外周血中CD4~+CD25~(bright)Treg、CD4~+CD25h~(high)Foxp3~+Treg细胞比例均较正常人对照组显著增高,分别为5.37±1.99vs1.77±1.20(P＜0.01)和12.56±2.68vs7.09±2.2(P＜0.05)。寻常型银屑病患者中点滴型组银屑病患者CD4~+CD25~(high)Foxp3~+Treg细胞比例低于斑块型(6.31±1.28vs8.18±1.55,P＜0.05);脓疱型银屑病患者中脓疱存在患者CD4~+CD25~(high)Foxp3~+Treg细胞比例明显低于脓疱消退患者(4.75±2.06vs8.25±11.5,P＜0.05)。银屑病和正常对照组CD4~+CD25~(hi-int)CD127~(low/-)调节性T细胞在CD4~+T细胞中比例同CD4~+CD25~(high)调节性T细胞比例相比,差异均有统计学意义(P＜0.05);但两组之间相比无差异(P＞0.05)。结论:红皮病型银屑病外周血CD4~+CD25~(high)Treg、CD4~+CD25~(high)Foxp3~+Treg细胞比例均增高,可能与红皮病型银屑病特殊的发病机制有关;Treg细胞比例的改变,可能参与了不同类型银屑病不同阶段的发病;结合CD127可纯化调节性T细胞。
第二部分:银屑病患者外周血CD4~+CD25~+调节性T细胞的功能分析
目的:探讨银屑病患者外周血中CD4~+CD25~+调节性T细胞的功能改变及其在银屑病发病中的作用。方法:磁珠分离8例寻常型银屑病患者、6例正常健康对照外周血CD4~+CD25~+Treg细胞、CD4~+CD25~-Tresp细胞,1:1混合培养72小时,3H-thymidine掺入法测定两组混合培养后Treg细胞对Tresp细胞增殖的抑制及Treg细胞、Tresp细胞分别培养后的增殖能力;收集培养的上清液,ELISA法检测两组CD4~+CD25~+Treg细胞对CD4~+CD25~-T细胞分泌功能的影响;ReaL-time PCR检测两组CD4~+CD25~+Treg细胞、CD4~+CD25~-T细胞(Tresp)Foxp3的表达。结果:Tresp细胞、Treg细胞的增殖能力,银屑病患者和健康对照组相比,无统计学意义;银屑病患者Treg细胞对Tresp细胞增殖的抑制明显下降(19.5%vs60%,P＜0.01);两者共培养后,银屑病患者Tresp细胞分泌高水平的IFN-γ(179.66±48.97vs87.36±33.36,P＜0.05);较正常对照组相比,银屑病组Treg细胞对Tresp细胞分泌IFN-γ的抑制减弱(40%vs63%,P＜0.05);两组IL-10与TGF-β分泌改变均无统计学意义;Treg细胞较Tresp细胞相比,表达高水平的Foxp3,银屑病患者Treg细胞Foxp3mRNA的表达同健康对照组相比无统计学意义。
结论:寻常型银屑病患者外周血中CD4~+CD25~+Treg细胞对CD4~+CD25~-T细胞(Trep)增殖的抑制功能的降低可能参与了该病的发病过程。
第三部分:细胞外腺苷代谢途径在寻常型银屑病患者外周血调节性T细胞发挥功能中的作用
目的:探讨细胞胞外腺苷代谢途径(CD39、CD73分子、A2A受体)在银屑病患者外周血CD4~+CD25~+Treg细胞抑制功能中的作用。方法:利用流式细胞仪、单克隆抗体检测寻常型银屑病患者、正常健康对照组外周血中CD39、CD73及A2A受体在Treg细胞、Teff细胞表面的表达。结果:寻常型银屑病患者外周血中CD4~+CD25~(high)Treg细胞中,CD39、CD73双染(2.41±0.42vs6.11±1.27)及CD73单染比例(6.48±1.53vs14.28±2.46)均低于正常对照组(P＜0.01),CD4~+CD25~(med)T细胞、CD4~+CD25~-Teff细胞中,银屑病患者CD73单染比例亦降低(14.34±1.63vs23.34±3.85,15.42±4.46vs28.58±6.42,P＜0.05);加入Foxp3染色后,CD4℃D25~(high)Foxp3~+Treg部分,CD39/CD73双染(2.89±0.55vs5.97±1.09)及CD73单染比例在银屑病患者外周血中亦明显减少(7.69±1.49vs12.65±1.98(P＜0.01),而CD4~+CD25~(med)、CD4~+CD25~-部分,CD39和CD73的表达无异常;寻常型银屑病患者外周血CD4~+CD25_(high)Foxp3~+Treg细胞表面A2AR表达增加(43.7±9.55 vs 70.4±7.86,P＜0.05),而CD4~+CD25 Teff细胞表面A2AR表达同正常对照相比无统计学意义。结论:寻常型银屑病患者外周血Treg细胞表面胞外酶CD73表达降低,A2AR表达增加,这可能是导致银屑病患者外周血Treg细胞抑制功能减弱的机制之,参与了银屑病的发病。
PartⅠThe expression of CD4~+CD25~+regulatory T cells in peripheral blood of patients with psoriasis
Objective:To study the level of regulatory T cells labeled by different antibody in peripheral blood of patients with psoriasis and its role in the pathogenesis.Methods:Flow cytometric analysis was employed to study the CD4~+CD25~(high)Foxp3~+regulatory T cells in the peripheral blood of 45 patients with psoriasis.The expression of CD4~+CD25~(high)cells in 45 patients with psoriasis and the surface antigens(CD4,CD25,CD127) of T cells in the peripheral blood of 10 psoriasis vulgaris were also detected by Flow cytometric analysis.Results: The proportion of CD4~+CD25~(high)、CD4~+CD25~(high)Foxp3~+regulatory T cells were both significant higher in patients with psoriatic erythroderma than healthy control and other types(P＜0.01,P＜0.05);In psoriasis vulgaris,the CD4~+CD25~(high)Foxp3~+regulatory T cells population demonstrated elevated ratio in guttate psoriasis group,compared to chronic plaque psoriasis;Same change happened to pustule remained pustular psoriasis patients versus pustule faded pustular psoriasis.There was big difference of the percentage of CD4~+CD25~(hi-int) CD127~(low/-) regulatory T cells compared to CD4~+CD25~(high)regulatory T cells in both psoriasis and normal,while the psoriatic group has the same level of CD4~+CD25~(hi-int)CD127~(low/-)regulatory T cells as normal one.Conclusion:CD4~+CD25~(high)、CD4~+CD25~(high)Foxp3~+regulatory T cells may play an important role in the special pathogenesis of erythrodermic psoriasis;Less number of CD4~+CD25~(high) Foxp3~+ regulatory T cells may not work properly in early stage of the different psoriasis,leading the disease progression.Treg cells can be purified better by CD127 to further study its number in peripheral blood.
PartⅡThe function change of CD4~+CD25~(high)regulatory T cell in peripheral blood of patients with psoriasis
Objective:To analysis the function change of CD4~+CD25~(high)regulatory T cells in patients with psoriasis vulgaris compared to normal group.Methods:Using the immunomagnetic beads isolate the CD4~+CD25~(high)Treg cells and CD4~+CD25~-Tresp cells(T effector).Sixteen hours before finish culture,[3~H]-thymidine was added to analyze alloantigen-specific T cell proliferation of CD4~+CD25~-Tresp cell in the presence or the absence of Treg cells.The secretive function of Tresp cells、Treg cells co-cultured and cultured separately were measured by ELISA.Foxp3 mRNA level of Treg and Teff cells were also detected by real-time quantitative RT-PCR.Results:The proliferation ability of the CD4~+CD25~(high) Tregs and CD4~+CD25~-Tresp cells in control and psoriatic group have no difference. The CD4~+CD25~(high)Treg cell population demonstrated significant decreased suppression to effector T cells(P＜0.01).As secretive function,the level of IFN-γin Tresp cell of psoriasis were much higher than normal group,the suppression of Treg cells to co-cultured IFN-γsecreting of Tresp cells in psoriasis were decreased compared to normal(P＜0.05);While there was no change in IL-10 and TGF-βsecretion level of Treg cells co-cultured in two group.In both psoriatic and normal patient,Treg population contain high level Foxp3 mRNA compared to Tresp.Conclusion:Dysfunction of CD4~+CD25~(high)Treg cell may be a potential explanation for unrestrained effector T cell proliferation in psoriasis and play an important role in the pathogenesis of psoriasis.
PartⅢExtracellular adenosine generation in psoriatic patient' s peripheral blood CD4~+CD25~+regulatory T cell
Objective:To study CD4~+CD25~+Treg cell surface ectoenzyme CD39/CD73 and adenosine receptor A2A expression level on CD4~+CD25~+Treg cell and CD4~+CD25~-Teff.
Methods:Flow cytometric analysis was employed to study the CD39,CD73 level on CD4~+CD25~(high)Treg cell and CD4~+CD25~(high)Foxp3~+Treg cell in peripheral blood of psoriasis vulgaris and normal patients.The expression of A2A receptor in Treg cell and Teff cell was also detected by Flow cytometric analysis in psoriatic and normal patient.Results:The double positive of CD39/CD73 and single CD73 positive expression in CD4~+CD25~(high)regulatory T cell were both significant lower in patients with vulgaris psoriasis,compared to normal control,2.41±0.42vs6.11±1.27(P＜0.01) and 6.48±1.53vs14.28±2.46 respectively(P＜0.01), while in CD4~+CD25~(mde) and CD4~+CD25~-T cell,the psoriatic single CD73 level also decreased(14.34±1.63vs23.34±3.85,15.42±4.46vs28.58±6.42,P＜0.05);After Foxp3 staining,the CD4~+CD25~(high)Foxp3~+regulatory T cell population in psoriasis vulgaris patients still demonstrated obvious decrease ratio in double CD39/CD73 and single CD73 level compared to normal patient(2.89±0.55vs5.97±1.09,7.69±1.49vs12.65±1.98,P＜0.01):No difference of CD39、CD73 level in CD4~+CD25~(med) and CD4~+CD25~-T cell part after Foxp3 staining.The A2A receptor level in CD4~+CD25~(high)Foxp3~+regulatory T cells was significant higher in patients with psoriasis vulgaris than healthy controls,43.7±9.55 and 70.4±7.86 respectively(P＜0.01);No expression difference of A2AR on CD4~+CD25~-Teff cell in psoriatic patient and normal one.Conclusion:Extracelluar adenosine generated by Treg cell marker CD73 and adenosine receptor A2A may impart the attenuated suppression capacity of peripheral blood Treg cells in psoriatic patient and play an important role in the pathogenesis of psoriasis.
引文
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