CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript> regulatory T cells in human lupus erythematosus

Natural CD4⁺CD25⁺ regulatory T cells (T_reg) show a potent immunosuppressive function and contribute to immunologic self-tolerance by suppressing potentially auto-reactive T cells. Depletion of these cells leads to the induction of severe autoimmune diseases in animal models; more recently, several studies have also reported an impairment of T_reg number and/or function in various human autoimmune diseases. For example, aberrant numbers of circulating CD4⁺CD25⁺ T_reg have been seen in patients with type I diabetes, mycosis fungoides, graft-versus-host-reaction, and rheumatoid arthritis. Moreover, increased numbers of functionally active CD4⁺CD25⁺ T_reg have been detected in the synovial fluid of patients with rheumatoid arthritis. In systemic lupus erythematosus (SLE), conflicting data on the role of CD4⁺CD25⁺ T_reg in human autoimmune diseases have been presented in the literature. Decreased numbers of peripheral blood T_reg have been reported by most studies on SLE patients with active disease, but non-impaired or even increased CD4⁺CD25⁺ T_reg numbers have also been described. In addition, both deficient and normal suppressive capacity of isolated T_reg have been observed in SLE. Analysis of CD4⁺FoxP3⁺ T_reg in skin lesions of patients with a primarily cutaneous manifestation of the disease showed a significant reduction in cell numbers as compared to other inflammatory skin diseases, suggesting the importance of analyzing T_reg numbers in the affected tissue. In this review, we discuss the role of CD4⁺CD25⁺ T_reg in autoimmunity and recent published data on SLE. Furthermore, we highlight the need for additional studies that address specific gaps of knowledge regarding the pathophysiological mechanisms as well as the identification of future therapeutic strategies for autoimmune diseases.     

寻常型银屑病患者外周血CD4~+CD25~+及CD8~+CD25~+细胞的检测

目的研究进展期寻常型银屑病患者外周血CD4+CD25+和CD8+CD25+调节性T细胞的数量变化及其在银屑病免疫病理学发病机制中的作用。方法应用流式细胞术对进展期寻常型银屑病患者外周血CD4+CD25+和CD8+CD25+调节性T细胞进行检测。结果进展期寻常型银屑病外周血CD4+CD25+细胞及CD8+CD25+调节性T细胞数量与正常对照组相比,均显著降低(P<0.05,P<0.005),而CD4+CD25+/CD8+CD25+比值无显著性差异(P>0.05)。结论寻常型银屑病的发病与CD4+CD25+和CD8+CD25+调节性T细胞的同步降低有关,与二者的比值无关。     

Absence of CD4 or CD8 lymphocytes changes infiltration of inflammatory cells and profiles of cytokine expression in skin wounds,but does not impair healing

The involvement of lymphocytes in skin wound healing has not been studied extensively. This study shows that CD4 and CD8 cells are present in significant numbers in skin wounds with peak levels at days 5–10 and 7–10, respectively. Both subsets expressed inflammatory and/or regulatory cytokines. To examine the function of CD4 and CD8 lymphocytes in tissue repair, wound healing was examined in mice deficient for either CD4 or CD8 cells. Wounds in CD4 deficient mice exhibited an initial delayed infiltration of CD8 cells followed by a relative increase in CD8 cells at day 10 and thereafter. Wounds in CD4 deficient mice also displayed up‐regulated expression of IL1β, IL‐6, IL‐17, IFN‐γ, CXCL‐1 and down‐regulated expression of IL‐4 as compared to wild‐type mice. In contrast, wounds in CD8 deficient mice showed significantly decreased infiltration of CD4+ cells, neutrophils, and macrophages along with down‐regulated expression of IL1β, IL‐6, TNF‐α, CXCL‐1, CCL‐2 and up‐regulated expression of IL‐4 as compared to wild‐type mice. Despite these significant changes in cytokine expression and inflammatory cell infiltrate, the rate of wound closure, wound breaking strength, collagen content and angiogenesis in either CD4 or CD8 deficiency showed no significant difference from that of wild‐type mice. The results suggest that, despite being present and involved in wound inflammation, neither CD4+ nor CD8+ cells play critical roles in the healing process of skin wounds. Further studies are needed to investigate whether these cells might play critical roles in wounds that experience stress such as ischemia or infection.     

银屑病患者体外系统血液固有免疫反应中CD4~+ CD25~+ T细胞及CD4~+ CD25~(high) T细胞的变化与意义

目的用体外系统血液固有免疫反应体系研究银屑病患者外周血CD4+ CD25+T细胞及CD4+ CD25highT细胞的变化,并探讨其在银屑病发病机制中的作用。方法将灭活大肠杆菌悬液(3×108/mL)0.2mL作为免疫原激活剂加入枸橼酸抗凝的全血细胞悬液0.2mL和血浆0.3mL中,37℃水浴1h,用流式细胞仪测定CD4+ CD25+T细胞及CD4+ CD25highT细胞的比例。结果在加入大肠杆菌的银屑病全血细胞组(银屑病实验组)CD4+ CD25highT细胞比例(1.88%)明显高于银屑病对照组(1.41%)(P﹤0.01),CD4+ CD25+T细胞及CD4+ CD25highT细胞的比例(16.86%,1.88%)明显低于加入大肠杆菌的健康实验组(24.26%,2.81%)(P﹤0.01);银屑病对照组CD4+ CD25+T细胞及CD4+ CD25highT细胞的比例(15.97%,1.41%)较健康对照组明显降低(21.75%,2.17%)(P﹤0.01);健康实验组CD4+ CD25+T细胞及CD4+ CD25highT细胞的比例群(24.26%,2.81%)均明显高于健康对照组(21.75%,2.17%),(P﹤0.05)。结论银屑病患者CD4+ CD25+T细胞及CD4+ CD25highT细胞比例降低,外来抗原刺激后比例升高,但与健康正常人存在差异。这可能与其复杂的系统免疫学发病机制相关。     

细胞间黏附分子CD146在皮肤病中的研究进展

CD146是一种黏附分子,主要表达于血管内皮细胞.最近研究表明,CD146在多种皮肤病中发挥重要作用.CD146有三种形式,包括两种膜型异构体和一种可溶型分子.CD146分子通过与不同的配体结合可以介导不同的生物学功能.本文综述了CD146分子的结构、定位、调节和功能及在皮肤病中的研究进展.     

CD4~+CD25~+调节性T细胞及其细胞因子在寻常型银屑病患者的改变

目的探讨寻常型银屑病患者CD4~+CD25~+调节性T细胞及其细胞因子的改变。方法用流氏细胞仪直接免疫荧光法检测寻常型银屑病患者外周血CD4~+CD25~+T细胞的百分率、FoxP3+分子表达、细胞因子白细胞介素(IL)-10、转化生长因子(TGF)-β的表达。结果寻常型银屑病患者CD4~+CD25~+T细胞在进行期组、静止期组、健康对照组结果分别是4.55±1.11、5.26±1.38、6.03±1.96,CD4~+CD25~+FoxP3+T细胞在进行期组、静止期组、健康对照组结果分别是3.85±0.89、4.31±1.26、4.95±1.37。进行期患者明显低于静止期患者和健康对照组(P0.05);而静止期患者与健康对照组比较差异无统计学意义(P0.05)。CD4~+CD25~+IL-10+细胞、CD4~+CD25~+TGF-β+T细胞在进行期组、静止期组、健康对照组结果分别是11.57±5.64、14.49±8.26、16.35±9.98;2.65±0.97、4.23±1.55、4.83±1.84;进行期患者明显低于静止期患者和健康对照组(P0.05);而静止期患者与健康对照组比较差异无统计学意义(P0.05)。CD4~+CD25~+FoxP3+T细胞与PASI呈负相关(r=-0.659,P0.05);CD4~+CD25~+IL-10+T与PASI呈负相关(r=-0.537,P0.05);而CD4~+CD25~+TGF-β+T细胞与PASI直线相关(r=-0.184,P0.05)。结论 CD4~+CD25~+调节性T细胞的比例以及Foxp3的表达、IL-10、TGF-β的表达明显下降,导致调节性T细胞的抑制功能缺陷,进而影响银屑病病情的发展。可以推测,调节性T细胞的数量或功能异常,均将影响银屑病的发病。     

Increased expression of PD1 and CD39 on CD3+CD4+ skin T cells in the elderly

Normal ageing is associated with an impaired systemic immune response contributing to an increased susceptibility to infectious diseases. The aim of this study was to compare the lymphocyte phenotype in human skin from old and young healthy subjects. Skin samples from donors were used for explant cultures before flow cytometric analysis. Our results depicted a higher proportion of CD4⁺ and a lower proportion of CD8⁺ among CD3⁺ T cells, a decreased proportion of CD45RA⁺ naive T cells (3.5 ± 1.9% vs 22.9 ± 11.1%, P ≤ 0.007) and an upregulation of the expression of CD39 and PD1 on CD3⁺CD4⁺ T cells (25.1 ± 8.5% vs 12.5 ± 8.5%, P ≤ 0.003, 68.8 ± 11.6% vs 50.0 ± 11.3%, P ≤ 0.01, respectively) in the skin of old subjects. These findings could explain a reduced generation of long‐lived memory T cells and an impaired antitumoral response in the skin of the elderly.     

Administration of substance P during a primary immune response amplifies the secondary immune response via a long-lasting effect on CD8<Superscript>+</Superscript> T lymphocytes

Atopic dermatitis can be exacerbated or induced by scratching or psychological stress; both cause the release of substance P (SP) from sensory nerves. Therefore, SP may have an etiological role in mechanisms underlying AD. Here, we show that administration of SP during the primary immune response (PIR) imprinted long-lasting pro-inflammatory immunity, resulting in exacerbation of the secondary immune response (SIR) in the absence of further SP. Five days after sensitization with dinitrofluorobenzene (DNFB), challenge with DNFB together with SP (“SP-Group”) resulted in an increased PIR (as evaluated by ear swelling and granulocyte infiltration) compared to DNFB only (“Control-Group”). On day 26, after inflammation completely subsided, a second challenge with DNFB only (without SP) caused an increased SIR in the “SP-Group” compared to controls. Pretreatment on day 5 with spantide, an SP receptor antagonist, prevented increased ear swelling in the “SP-Group” not only on day 5 (PIR) but also on day 26 (SIR). In contrast, spantide treatment on day 26 did not affect the SIR. Adoptive transfer experiments suggested that CD8⁺ T cells were involved in mediating enhanced SIR in animals pretreated on day 5 with SP. The present study offers a novel experimental approach to an uninvestigated facet of the pro-inflammatory effect of SP, i.e., exacerbation of inflammation via a long-term and indirect influence on CD8⁺ T lymphocytes.     

外周血及蜕膜组织中CD4~+ CD25~+调节性T细胞比例和炎症因子原因不明复发性流产的关系研究

目的:探究外周血及蜕膜组织中CD4~+CD25~+调节性T细胞比例以及相关炎症因子对原因不明复发性流产的影响。方法:选取2014年5月至2015年5月就诊于我院门诊的原因不明复发性流产(URSA)患者90例为观察组,并选取同期在妇产科门诊手术室的行人工流产手术的正常患者90例为对照组;分析两组患者的一般资料、外周血及蜕膜组织中CD4~+CD25~+调节性T细胞比例、调节性T细胞特异调节因子Foxp3和EBi3的表达以及血清炎症因子(包括TNF-α、IL-2、IL-6、IL-10)水平,研究其相关性。结果:与正常妊娠组相比,反复流产组外周血及蜕膜组织中Treg细胞比例明显降低,Foxp3和EBi3因子mRNA的表达水平明显降低,且无论URSA患者或者是正常对照组,蜕膜中各因子的表达均高于外周血中的表达,外周血TNF-α、IL-2水平明显升高,而IL-6和IL-10水平要明显降低,差异有统计学意义(P0.05)。结论:蜕膜中各因子的表达均高于外周血中的表达提示妊娠过程的主要免疫反应部位是"母-胎界面",Treg细胞比例、Treg细胞因子和Th2型因子IL-6、IL-10水平可能参与妊娠的维持,调控"母-胎界面"局部免疫耐受。对于复发性流产的发病过程具有一定的影响作用。     

A possible mechanism in the recruitment of eosinophils and Th2 cells through CD163<Superscript>+</Superscript> M2 macrophages in the lesional skin of eosinophilic cellulitis

Background

M2 macrophages play a critical role in the recruitment of T helper 2 (Th2) regulatory T cells (Treg).

Objectives

To study the role of M2 macrophages and Treg cells in eosinophilic celulitis.

Material and Methods

We employed immunohistochemical staining for CD163 and CD206 (macrophages) as well as FoxP3 (Treg), in lesional skin of four cases of eosinophilic cellulitis.

Results

CD163⁺ CD206⁺ M2 macrophages, which were previously reported to produce CCL17 to induce Th2 cells and Treg cells, were predominantly infiltrating the subcutaneous tissues and interstitial area of the dermis. M2 macrophages derived from PBMC showed significantly increased expression of CCL11, CCL17, CCL24 and CCL26 mRNA and production of CCL17 and CCL24, when stimulated by IL-4 or IL-13. In addition, CCL17-producing cells and CCL24-producing cells were prominent in the lesional skin of EC.

Conclusion

Our study sheds light on one of the possible immunological mechanisms of eosinophilic cellulitis.

     

系统性硬皮病CD4+T细胞中CD70mRNA及蛋白表达水平的观察

目的:研究系统性硬皮病(SSc)患者外周血CD4+T细胞中CD70的表达水平.方法:应用密度梯度离心法分离17例SSc患者(女性12例,男性5例)和13例对照者(女性8例,男性5例)的外周血单个核细胞,磁珠分选CD4+T细胞.RT-PCR检测CD4+T细胞中CD70 mRNA的表达水平;流式细胞术检测CD70蛋白在CD4+T细胞的表达水平.结果:与对照组相比,SSc患者CD4+T细胞中CD70 mRNA和CD70蛋白表达均明显升高(P=0.001;P=0.007).结论:CD70在SSc的发生发展中可能起着重要作用.     

Skin disorders in Korean patients infected with human immunodeficiency virus and their association with a CD4 lymphocyte count: a preliminary study

Background Dermatological disorders are quite common in human immunodeficiency virus (HIV)‐infected patients. However, cutaneous findings in Korean HIV‐infected patients have not been properly investigated. Objective To investigate the spectrum of dermatological disorders in Korean HIV‐infected individuals according to a CD4 lymphocyte count. Methods A retrospective clinical study was carried out from June 2002 to January 2008. We comprehensively collected information regarding HIV‐associated skin problems, laboratory data and the history of highly active antiretroviral therapy (HAART). Results Ninety‐nine HIV‐seropositive patients (mean age: 39.6 ± 11.3 years, males: 94.9%) were included in this study. Of them, 55 patients (55.6%) presented with at least one skin problem. The four most common dermatological disorders were eosinophilic pustular folliculitis (18.6%), symptomatic syphilis (comprising of primary and secondary syphilis) (17.1%), seborrhoeic dermatitis (17.1%) and condyloma acuminatum (12.8%). The group with a CD4 lymphocyte count < 200 × 10⁶ cells/L showed a significantly higher prevalence of Kaposi sarcoma compared with the group with a CD4 lymphocyte count > 200 × 10⁶ cells/L (P = 0.014). Condyloma was more prevalent in the group with a CD4 count > 200 × 10⁶ cells/L (P = 0.022). The patients treated with HAART had a lower prevalence of neurosyphilis compared with the non‐treated group (P = 0.018). Conclusions Diverse dermatological conditions were demonstrated in Korean HIV‐infected patients. Kaposi sarcoma was associated with a low CD4 lymphocyte count, but condyloma was associated with a high CD4 lymphocyte count. The prevalence of syphilis in our study was higher than that of Western countries. HAART seemed to be associated with the low prevalence of neurosyphilis.     

系统性硬皮病CD4~+ T细胞中CD70 mRNA及蛋白表达水平的观察

目的:研究系统性硬皮病(SSc)患者外周血CD4+ T细胞中CD70的表达水平。方法:应用密度梯度离心法分离17例SSc患者(女性12例,男性5例)和13例对照者(女性8例,男性5例)的外周血单个核细胞,磁珠分选CD4+ T细胞。RT-PCR检测CD4+ T细胞中CD70 mRNA的表达水平;流式细胞术检测CD70蛋白在CD4+ T细胞的表达水平。结果:与对照组相比,SSc患者CD4+ T细胞中CD70mRNA和CD70蛋白表达均明显升高(P=0.001;P=0.007)。结论:CD70在SSc的发生发展中可能起着重要作用。     

银屑病外周血CD4+CD25+Foxp3+调节性T细胞的表达

目的: 检测CD4+CD25+Foxp3+调节性T细胞在不同类型银屑病患者中的表达.方法: 应用流式细胞仪检测外周血中CD4+CD25+Foxp3+调节性T细胞的表达.结果: 红皮病型银屑病患者外周血中CD4+CD25+Foxp3+调节性T细胞明显高于其他类型银屑病和正常对照组(P<0.05);斑块状银屑病CD4+CD25+Foxp3+T细胞比例高于点滴状患者(P<0.05);脓疱型银屑病患者中脓疱存在患者调节性T细胞比例明显低于脓疱消退患者(P<0.05).结论: CD4+CD25+Foxp3+调节性T细胞通过抑制效应T细胞在银屑病的病情活动中可能发挥重要作用.     

The immunomodulatory effects of regulatory T cells: implications for immune regulation in the skin

Regulatory T cells are thought to have a critical role in the suppression of immune responses. In addition to the prevention of the development of autoimmunity, they are also thought to have a role in the prevention of allergic responses to environmental allergens, immune responses to tumours and the development of memory responses to chronic infections. They have been isolated within the skin and have been shown to express surface markers that enable skin-specific migration, suggesting that regulatory T cells have a functional role in the skin. There is accumulating evidence to suggest that regulatory T cells may be involved in numerous skin disorders and may also be modified by various therapeutic agents used to treat these disorders. We review the evidence for the presence of this T-cell subset in humans, the suppressive effects of regulatory T cells, and their role in the skin.     

In situ demonstration of T cells in alopecia areata

Summary Local application of alpha-l-fucose on the ear before elicitation of contact allergy to dinitrofluorobenzene (DNFB) in BALB/c mice results in a suppression of the contact allergic response. However, local application of alpha-l-fucose at the sensitization site on the abdominal wall before sensitizing the animals with DNFB had no inhibitory effect on contact allergy. Alpha-l-fucose has been demonstrated to inhibit lymphokine activity in vitro and manifestation of cellular immunity in vivo. Our results suggest that alpha-l-fucose suppresses contact allergy by locally inhibiting the efferent phase of the cellular immune response.     

CD+4 CD+25调节性T细胞在自身免疫病中的意义

阐明CD4 CD2 5调节性T细胞作用机制及其自身免疫病的关系。     

斑秃患者外周血CD4+CD25+Foxp3调节性T细胞及T淋巴细胞亚群的测定

目的 研究斑秃患者外周血中CD4+CD25+调节性T细胞数量及CD4+、CD8+ T淋巴细胞亚群数量与斑秃疾病严重程度的关系。方法 对斑秃进行病情分组，以流式细胞仪检测17例重度、15例局限型斑秃患者和25例正常人对照者外周血中有功能活性的CD4+CD25+调节性T细胞（即CD4+CD25+ Foxp 3 T 细胞）在CD4+ T淋巴细胞中的比率，CD4+和CD8+占T淋巴细胞的比率。 结果 重度斑秃患者外周血中有功能活性的CD4+CD25+ Foxp 3 T细胞占CD4+ T细胞比率为0.54% ± 0.31%，显著低于正常人对照组（3.21% ± 0.76%）及局限型斑秃患者（2.71% ± 0.37%，P ＜ 0.001）；与正常人对照组比较，差异无统计学意义（P ＞ 0.05）。重度斑秃患者的CD4+占T淋巴细胞的比率为32.61% ± 3.48%，显著低于正常人对照组（43.0% ± 3.63%，P ＜ 0.001），而CD8+占T淋巴细胞的比率为40.96% ± 8.54%，显著高于正常人对照组（25.23% ± 2.14%，P ＜ 0.001）。局限型斑秃患者的此两项指标分别为41.25% ± 4.27%和26.6% ± 2.28%，与对照组差异无统计学意义（P ＞ 0.05）。重度斑秃患者的CD8+占T淋巴细胞的比率与CD4+CD25+ Foxp 3调节性 T 细胞占CD4+ T细胞的比率有负相关关系（r ＝ －0.94，P ＜ 0.001）。结论 重度斑秃可能与外周血中CD4+CD25+ T细胞数量的减少和功能活性的降低有关。