系统性红斑狼疮患者外周血T淋巴细胞PD-1分子、单个核细胞PD-L1分子的表达
|
摘要
目的探讨程序性细胞死亡受体-1(programmed cell death-l,PD-1)在系统性红斑狼疮(systemic lupus eythematosu,SLE)患者外周血T淋巴细胞,程序性死亡配体-1(programmed death ligand-1,PD-L1)在外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)上的表达及意义。
方法收集SLE患者临床资料,根据SLE疾病活动指数(systemic lupus erythematosus disease activity ,SLEDAI)将患者分为活动组(SLEDAI≥10)、不活动组(SLEDAI<10分)。应用流式细胞仪检测33例SLE活动组、18例不活动组患者和38例健康对照者外周血T淋巴细胞亚群表面PD-1分子和单个核细胞表面PD-L1分子表达水平。比较活动组、不活动组和健康对照组外周血T细胞亚群表面PD-1,单个核细胞表面PD-L1表达水平,并分析其意义。
结果①SLE患者外周血CD4~+、CD8~+T淋巴细胞表面PD-1表达水平:活动组PD-1~+CD4~+T细胞百分率(14.39±3.76)%,高于健康对照组(4.89±2.56)%和不活动组(5.35±2.09)%(P均<0.05),不活动组与健康对照组之间差异无统计学意义。活动组PD-1~+CD8~+T细胞百分率(47.98±14.30)%,不活动组(24.85±6.41)%,均高于健康对照组(16.92±4.53)%(P均<0.05),且活动组又高于不活动组,差异有统计学意义(P<0.05)。②SLE患者外周血单个核细胞表面PD-L1表达水平:不活动组PD-L1~+T细胞百分率(23.72±3.47)%高于活动组(8.12±7.14)%和健康对照组(6.63±2.31)%,差异有统计学意义(P均<0.05),活动组和健康对照组比较差异无统计学意义。不活动组PD-L1~+B细胞百分率(1.70±0.68)%高于活动组(0.65±0.62)%和健康对照组(0.43±0.24)%,差异有统计学意义(P均<0.05),活动组和健康对照组之间差异无统计学意义。活动组PD-L1~+单核细胞百分率(39.48±7.01)%高于不活动组(20.26±5.46)%和健康对照组(10.21±4.50)%,差异有统计学意义(P均<0.05);且不活动组又高于健康对照组,差异有统计学意义(P<0.05)。③SLE患者中有、无狼疮肾炎组外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平:狼疮肾炎组PD-1~+CD4~+ T细胞百分率(13.40±5.05)%、PD-1~+CD8~+ T细胞百分率(46.46±15.70)%,分别高于其无狼疮肾炎组(8.04±4.39)%、(30.31±12.44)%(P=0.001、P=0.000);无狼疮肾炎组PD-L1~+T细胞百分率(18.95±9.00)%、PD-L1~+B细胞百分率(1.46±0.83)%均高于狼疮肾炎组(9.90±8.38)%、(0.71±0.66)%(P=0.002、P=0.000),而无狼疮肾炎组PD-L1~+单核细胞百分率(26.41±10.42)%低于其狼疮肾炎组(37.10±9.82)%(P=0.001)。④SLE患者中抗双链脱氧核糖核酸(double-stranded-DNA,ds-DNA)抗体阳性、阴性组外周血CD4~+、CD8~+T细胞PD-1和单个核细胞PD-L1表达水平:抗ds-DNA抗体阳性组CD4~+ PD-1~+ T淋巴细胞百分率(13.22±4.84)%、CD8~+PD-1~+ T细胞百分率(45.97±15.27)%分别高于其阴性组[(8.54±5.11)%、(31.71±14.47)%(P=0.002、P=0.001)];抗ds-DNA抗体阴性组PD-L1~+T细胞百分率(17.55±9.34)%、PD-L1~+ B细胞百分率(1.36±0.89)%高于其阳性组[(10.65±8.95)%、(0.76±0.66)%(P=0.016、P=0.037)],而抗ds-DNA抗体阴性组PD-L1~+单核细胞百分率(25.04±10.63)%,低于其阳性组(38.51±7.89)%(P=0.000)。⑤SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与SLE疾病活动指数(systemic lupuserythematosus disease activity index, SLEDAI)评分的相关性:PD-1~+ CD4~+T细胞百分率、PD-1~+ CD8~+ T细胞百分率与SLEDAI评分都呈正相关(r=0.830, P<0.01、r=0.804, P<0.01)。PD-L1~+ T细胞百分率、PD-L1~+ B细胞百分率与SLEDAI评分均呈负相关(r=-0.813, P<0.01、r=-0.643, P<0.01),而PD-L1~+单核细胞百分率与SLEDAI评分呈正相关(r=0.884, P<0.01)。⑥SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与24h尿蛋白定量的相关性:PD-1~+ CD4~+ T细胞百分率、PD-1~+ CD8~+ T细胞百分率与24h尿蛋白定量(r=0.475, P<0.01、r=0.358,P<0.05)均呈正相关,PD-L1~+ B细胞百分率与24h尿蛋白定量负相关(r=-0.524, P<0.01),PD-L1~+单核细胞百分率与24h尿蛋白定量正相关(r=0.436, P<0.01)。⑦SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与补体C3水平的相关性:PD-1~+ CD4~+ T细胞百分率、PD-1~+ CD8~+ T细胞百分率与补体C3均呈负相关(r=-0.403, P<0.01、r=-0.439, P<0.01)。PD-L1~+ T细胞百分率、PD-L1~+ B细胞百分率与补体C3均呈正相关(r=0.440, P<0.01、r=0.382,P<0.01);PD-L1~+单核细胞百分率与补体C3呈负相关(r=-0.574, P<0.01)。
结论⑴系统性红斑狼疮疾病状态下,CD4~+、CD8~+ T淋巴细胞表面PD-1表达增高,T淋巴细胞、B淋巴细胞和单核细胞表面PD-L1表达增高。⑵系统性红斑狼疮疾病状态下,PD-1~+ CD4~+、PD-1~+ CD8~+T淋巴细胞百分率、PD-L1~+单核细胞百分率与病情活动情况呈正相关。⑶系统性红斑狼疮疾病状态下,PD-L1~+T淋巴细胞、PD-L1~+B淋巴细胞百分率与病情活动情况呈负相关。
Objective To investigate the expression of PD-1 on T lymphocytes and PD-L1 on peripheral blood mononuclear cells (PBMCs)from the patients with systemic lupus erythematosus(SLE)and analyze the clinical relevance to disease severity.
Methods The expression of PD-1 on the subsets of T cells and PD-L1 on PBMCs were examined from 51 SLE patients ( included 33 active SLE,18 inactive SLE) and 38 healthy controls (HC) by the technique of the immunofluorescence and the flow cytometry.Clinical manifestations and laboratory findings of SLE were also collected.Patients were divided into two groups according to their SLE disease activity index(SLEDAI).SLEDAI score≥10 was defined as activity group and <10 as inactivity group .The percentage of PD-1 and PD-L1 was compared with inactive or active SLE patients and HC, and analyze its significance.
Results①The percentage of CD4~+ PD-1~+ T cells and CD8~+ PD-1~+ T cells : Proportions of CD4~+ PD-1~+ T cells were significantly increased in active SLE patients (14.39±3.76)% as compared with inactive SLE patients (5.35±2.09)% and HC (4.89±2.56)%(P<0.05). No significant difference was observed between inactive SLE patients and HC. Proportions of CD8~+ PD-1~+ T cells were significantly increased in active(47.98±14.30)% and inactive SLE patients (24.85±6.41)% as compared with HC (16.92±4.53)%(P<0.05). Proportions of CD8~+ PD-1~+ T cells in active SLE patients were higher than that in inactive patients(P<0.05).②The percentages of PD-L1~+ cells in PBMCs in patients with SLE: Proportions of CD19+ PD-L1~+ B cells were significantly increased in inactive SLE patients (11.70±0.68)% as compared with that in active SLE patients(0.65±0.62)% and HC(0.43±0.24)% (P<0.05). No significant difference was observed between active SLE patients and HC. Proportions of CD14+ PD-L1~+ monocytes were significantly increased in active SLE patients (39.48±7.01)% as compared with inactive SLE patients (20.26±5.46)% and HC (10.21±4.50)%(P<0.05). Proportions of CD14+ PD-L1~+ monocytes in inactive SLE patients were higher than that in HC(P<0.05).③The percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+T cells and PD-L1 cells in PBMCs in SLE patients with or without nephritis: Proportions of CD4~+PD-1~+ T cells (13.40±5.05)% and CD8~+ PD-1~+ T cells (46.46±15.70)% in SLE patients with nephritis were respectively higher than those in patients without nephritis [(30.31±12.44)%, P=0.001; (30.31±12.44)%, P=0.000]. Proportions of PD-L1~+ T cells(18.95±9.00)% and of PD-L1~+B cells (1.46±0.83)% were significantly increased in SLE patients with nephritis as compared those without nephritis [(9.90±8.38)%, P=0.002; (0.71±0.66)%, P=0.000, respectively]. Proportions of PD-L1 on monocytes (26.41±10.42)% in SLE patients without nephritis were lower than those in SLE patients with nephritis [ (37.10±9.82)%, P=0.001].④The percentages of CD4~+ PD-1~+T cells or CD8~+ PD-1~+T cells and PD-L1~+ cells in peripheral blood mononuclear cells in SLE patients with or without anti-dsDNA: Proportions of CD4~+ PD-1~+ (13.22±4.84) % and CD8~+ PD-1~+(45.97±15.27)% T cells in SLE patients with positive anti-dsDNA were respectively higher than those in SLE patients with negative anti-dsDNA[(8.54±5.11)%,P=0.002;(31.71±14.47)%,P=0.001 respectively].Proportions of PD-L1~+ B cells (17.55±9.34)% and PD-L1~+(1.36±0.89)% T cells in SLE patients without anti-dsDNA were respectively higher than those in SLE patients with anti-dsDNA[(10.65±8.95)%,P=0.016;(0.76±0.66)%,P=0.037, respectively]. Proportions of PD-L1~+ cells in monocytes (25.04±10.63)% in SLE patients without anti-dsDNA were lower than those in SLE patients with anti-dsDNA [(38.51±7.89)%, P=0.000.].⑤The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and SLEDAI: A positive correlation was observed for proportios of CD4~+ PD-1~+ and CD8~+ PD-1~+ T cells with the SLEDAI score(r=0.830, P<0.01; r=0.804, P<0.01,respectively). Proportios of PD-L1~+ B cells and PD-L1~+ T cells were inversely correlated with SLEDAI score(r=﹣0.813, P<0.01; r=﹣0.643, P<0.01, respectively). Proportios of PD-L1~+ cells in monocytes were positively correlated with SLEDAI score(r=0.884, P<0.01).⑥The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and amounts of proteinuria: A positive correlation was observed for proportios of CD4~+PD-1~+ or CD8~+ PD-1~+ T cells and PD-L1~+ cells in monocytes with the amounts of proteinuria(r=0.475, P<0.01; r=0.358, P<0.05; r=0.436, P<0.01, respectively). Proportios of PD-L1~+ B cells were inversely correlated with amounts of proteinuria(r=-0.524, P<0.01).⑦The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and complement 3(C3) levels: A negative correlation was observed for proportios of CD4~+ PD-1~+ or CD8~+ PD-1~+ T cells and PD-L1~+ cells in monocytes with the level of C3(r=-0.403, P<0.01; r=-0.439, P<0.01; r=-0.574, P<0.01, respectively). Proportions of PD-L1~+ T cells and PD-L1~+ B cells were positively correlated with C3 (r=0.440, P<0.01; r=0.382, P<0.01)
Conclusions⑴Systemic lupus erythematosus disease state, the expression of PD-1 on the surface of the CD4 +, CD8 + T lymphocytes were increased, the expression of PD-L1 on the surface of T lymphocytes, B lymphocytes and monocytes are increased.⑵Systemic lupus erythematosus disease state, PD-1~+ CD4~+, PD-1~+ CD8~+ T lymphocyte percentage, and PD-L1~+ monocyte percentage were positively correlated with disease activity.⑶Systemic lupus erythematosus disease state, PD-L1~+T lymphocytes, PD-L1~+ B lymphocyte percentage were negatively correlated with disease activity .
方法收集SLE患者临床资料,根据SLE疾病活动指数(systemic lupus erythematosus disease activity ,SLEDAI)将患者分为活动组(SLEDAI≥10)、不活动组(SLEDAI<10分)。应用流式细胞仪检测33例SLE活动组、18例不活动组患者和38例健康对照者外周血T淋巴细胞亚群表面PD-1分子和单个核细胞表面PD-L1分子表达水平。比较活动组、不活动组和健康对照组外周血T细胞亚群表面PD-1,单个核细胞表面PD-L1表达水平,并分析其意义。
结果①SLE患者外周血CD4~+、CD8~+T淋巴细胞表面PD-1表达水平:活动组PD-1~+CD4~+T细胞百分率(14.39±3.76)%,高于健康对照组(4.89±2.56)%和不活动组(5.35±2.09)%(P均<0.05),不活动组与健康对照组之间差异无统计学意义。活动组PD-1~+CD8~+T细胞百分率(47.98±14.30)%,不活动组(24.85±6.41)%,均高于健康对照组(16.92±4.53)%(P均<0.05),且活动组又高于不活动组,差异有统计学意义(P<0.05)。②SLE患者外周血单个核细胞表面PD-L1表达水平:不活动组PD-L1~+T细胞百分率(23.72±3.47)%高于活动组(8.12±7.14)%和健康对照组(6.63±2.31)%,差异有统计学意义(P均<0.05),活动组和健康对照组比较差异无统计学意义。不活动组PD-L1~+B细胞百分率(1.70±0.68)%高于活动组(0.65±0.62)%和健康对照组(0.43±0.24)%,差异有统计学意义(P均<0.05),活动组和健康对照组之间差异无统计学意义。活动组PD-L1~+单核细胞百分率(39.48±7.01)%高于不活动组(20.26±5.46)%和健康对照组(10.21±4.50)%,差异有统计学意义(P均<0.05);且不活动组又高于健康对照组,差异有统计学意义(P<0.05)。③SLE患者中有、无狼疮肾炎组外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平:狼疮肾炎组PD-1~+CD4~+ T细胞百分率(13.40±5.05)%、PD-1~+CD8~+ T细胞百分率(46.46±15.70)%,分别高于其无狼疮肾炎组(8.04±4.39)%、(30.31±12.44)%(P=0.001、P=0.000);无狼疮肾炎组PD-L1~+T细胞百分率(18.95±9.00)%、PD-L1~+B细胞百分率(1.46±0.83)%均高于狼疮肾炎组(9.90±8.38)%、(0.71±0.66)%(P=0.002、P=0.000),而无狼疮肾炎组PD-L1~+单核细胞百分率(26.41±10.42)%低于其狼疮肾炎组(37.10±9.82)%(P=0.001)。④SLE患者中抗双链脱氧核糖核酸(double-stranded-DNA,ds-DNA)抗体阳性、阴性组外周血CD4~+、CD8~+T细胞PD-1和单个核细胞PD-L1表达水平:抗ds-DNA抗体阳性组CD4~+ PD-1~+ T淋巴细胞百分率(13.22±4.84)%、CD8~+PD-1~+ T细胞百分率(45.97±15.27)%分别高于其阴性组[(8.54±5.11)%、(31.71±14.47)%(P=0.002、P=0.001)];抗ds-DNA抗体阴性组PD-L1~+T细胞百分率(17.55±9.34)%、PD-L1~+ B细胞百分率(1.36±0.89)%高于其阳性组[(10.65±8.95)%、(0.76±0.66)%(P=0.016、P=0.037)],而抗ds-DNA抗体阴性组PD-L1~+单核细胞百分率(25.04±10.63)%,低于其阳性组(38.51±7.89)%(P=0.000)。⑤SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与SLE疾病活动指数(systemic lupuserythematosus disease activity index, SLEDAI)评分的相关性:PD-1~+ CD4~+T细胞百分率、PD-1~+ CD8~+ T细胞百分率与SLEDAI评分都呈正相关(r=0.830, P<0.01、r=0.804, P<0.01)。PD-L1~+ T细胞百分率、PD-L1~+ B细胞百分率与SLEDAI评分均呈负相关(r=-0.813, P<0.01、r=-0.643, P<0.01),而PD-L1~+单核细胞百分率与SLEDAI评分呈正相关(r=0.884, P<0.01)。⑥SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与24h尿蛋白定量的相关性:PD-1~+ CD4~+ T细胞百分率、PD-1~+ CD8~+ T细胞百分率与24h尿蛋白定量(r=0.475, P<0.01、r=0.358,P<0.05)均呈正相关,PD-L1~+ B细胞百分率与24h尿蛋白定量负相关(r=-0.524, P<0.01),PD-L1~+单核细胞百分率与24h尿蛋白定量正相关(r=0.436, P<0.01)。⑦SLE患者外周血CD4~+、CD8~+ T细胞PD-1和单个核细胞PD-L1表达水平与补体C3水平的相关性:PD-1~+ CD4~+ T细胞百分率、PD-1~+ CD8~+ T细胞百分率与补体C3均呈负相关(r=-0.403, P<0.01、r=-0.439, P<0.01)。PD-L1~+ T细胞百分率、PD-L1~+ B细胞百分率与补体C3均呈正相关(r=0.440, P<0.01、r=0.382,P<0.01);PD-L1~+单核细胞百分率与补体C3呈负相关(r=-0.574, P<0.01)。
结论⑴系统性红斑狼疮疾病状态下,CD4~+、CD8~+ T淋巴细胞表面PD-1表达增高,T淋巴细胞、B淋巴细胞和单核细胞表面PD-L1表达增高。⑵系统性红斑狼疮疾病状态下,PD-1~+ CD4~+、PD-1~+ CD8~+T淋巴细胞百分率、PD-L1~+单核细胞百分率与病情活动情况呈正相关。⑶系统性红斑狼疮疾病状态下,PD-L1~+T淋巴细胞、PD-L1~+B淋巴细胞百分率与病情活动情况呈负相关。
Objective To investigate the expression of PD-1 on T lymphocytes and PD-L1 on peripheral blood mononuclear cells (PBMCs)from the patients with systemic lupus erythematosus(SLE)and analyze the clinical relevance to disease severity.
Methods The expression of PD-1 on the subsets of T cells and PD-L1 on PBMCs were examined from 51 SLE patients ( included 33 active SLE,18 inactive SLE) and 38 healthy controls (HC) by the technique of the immunofluorescence and the flow cytometry.Clinical manifestations and laboratory findings of SLE were also collected.Patients were divided into two groups according to their SLE disease activity index(SLEDAI).SLEDAI score≥10 was defined as activity group and <10 as inactivity group .The percentage of PD-1 and PD-L1 was compared with inactive or active SLE patients and HC, and analyze its significance.
Results①The percentage of CD4~+ PD-1~+ T cells and CD8~+ PD-1~+ T cells : Proportions of CD4~+ PD-1~+ T cells were significantly increased in active SLE patients (14.39±3.76)% as compared with inactive SLE patients (5.35±2.09)% and HC (4.89±2.56)%(P<0.05). No significant difference was observed between inactive SLE patients and HC. Proportions of CD8~+ PD-1~+ T cells were significantly increased in active(47.98±14.30)% and inactive SLE patients (24.85±6.41)% as compared with HC (16.92±4.53)%(P<0.05). Proportions of CD8~+ PD-1~+ T cells in active SLE patients were higher than that in inactive patients(P<0.05).②The percentages of PD-L1~+ cells in PBMCs in patients with SLE: Proportions of CD19+ PD-L1~+ B cells were significantly increased in inactive SLE patients (11.70±0.68)% as compared with that in active SLE patients(0.65±0.62)% and HC(0.43±0.24)% (P<0.05). No significant difference was observed between active SLE patients and HC. Proportions of CD14+ PD-L1~+ monocytes were significantly increased in active SLE patients (39.48±7.01)% as compared with inactive SLE patients (20.26±5.46)% and HC (10.21±4.50)%(P<0.05). Proportions of CD14+ PD-L1~+ monocytes in inactive SLE patients were higher than that in HC(P<0.05).③The percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+T cells and PD-L1 cells in PBMCs in SLE patients with or without nephritis: Proportions of CD4~+PD-1~+ T cells (13.40±5.05)% and CD8~+ PD-1~+ T cells (46.46±15.70)% in SLE patients with nephritis were respectively higher than those in patients without nephritis [(30.31±12.44)%, P=0.001; (30.31±12.44)%, P=0.000]. Proportions of PD-L1~+ T cells(18.95±9.00)% and of PD-L1~+B cells (1.46±0.83)% were significantly increased in SLE patients with nephritis as compared those without nephritis [(9.90±8.38)%, P=0.002; (0.71±0.66)%, P=0.000, respectively]. Proportions of PD-L1 on monocytes (26.41±10.42)% in SLE patients without nephritis were lower than those in SLE patients with nephritis [ (37.10±9.82)%, P=0.001].④The percentages of CD4~+ PD-1~+T cells or CD8~+ PD-1~+T cells and PD-L1~+ cells in peripheral blood mononuclear cells in SLE patients with or without anti-dsDNA: Proportions of CD4~+ PD-1~+ (13.22±4.84) % and CD8~+ PD-1~+(45.97±15.27)% T cells in SLE patients with positive anti-dsDNA were respectively higher than those in SLE patients with negative anti-dsDNA[(8.54±5.11)%,P=0.002;(31.71±14.47)%,P=0.001 respectively].Proportions of PD-L1~+ B cells (17.55±9.34)% and PD-L1~+(1.36±0.89)% T cells in SLE patients without anti-dsDNA were respectively higher than those in SLE patients with anti-dsDNA[(10.65±8.95)%,P=0.016;(0.76±0.66)%,P=0.037, respectively]. Proportions of PD-L1~+ cells in monocytes (25.04±10.63)% in SLE patients without anti-dsDNA were lower than those in SLE patients with anti-dsDNA [(38.51±7.89)%, P=0.000.].⑤The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and SLEDAI: A positive correlation was observed for proportios of CD4~+ PD-1~+ and CD8~+ PD-1~+ T cells with the SLEDAI score(r=0.830, P<0.01; r=0.804, P<0.01,respectively). Proportios of PD-L1~+ B cells and PD-L1~+ T cells were inversely correlated with SLEDAI score(r=﹣0.813, P<0.01; r=﹣0.643, P<0.01, respectively). Proportios of PD-L1~+ cells in monocytes were positively correlated with SLEDAI score(r=0.884, P<0.01).⑥The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and amounts of proteinuria: A positive correlation was observed for proportios of CD4~+PD-1~+ or CD8~+ PD-1~+ T cells and PD-L1~+ cells in monocytes with the amounts of proteinuria(r=0.475, P<0.01; r=0.358, P<0.05; r=0.436, P<0.01, respectively). Proportios of PD-L1~+ B cells were inversely correlated with amounts of proteinuria(r=-0.524, P<0.01).⑦The relationships between percentages of CD4~+ PD-1~+ T cells or CD8~+ PD-1~+ T cells and PD-L1~+ cells in PBMCs in SLE patients and complement 3(C3) levels: A negative correlation was observed for proportios of CD4~+ PD-1~+ or CD8~+ PD-1~+ T cells and PD-L1~+ cells in monocytes with the level of C3(r=-0.403, P<0.01; r=-0.439, P<0.01; r=-0.574, P<0.01, respectively). Proportions of PD-L1~+ T cells and PD-L1~+ B cells were positively correlated with C3 (r=0.440, P<0.01; r=0.382, P<0.01)
Conclusions⑴Systemic lupus erythematosus disease state, the expression of PD-1 on the surface of the CD4 +, CD8 + T lymphocytes were increased, the expression of PD-L1 on the surface of T lymphocytes, B lymphocytes and monocytes are increased.⑵Systemic lupus erythematosus disease state, PD-1~+ CD4~+, PD-1~+ CD8~+ T lymphocyte percentage, and PD-L1~+ monocyte percentage were positively correlated with disease activity.⑶Systemic lupus erythematosus disease state, PD-L1~+T lymphocytes, PD-L1~+ B lymphocyte percentage were negatively correlated with disease activity .
引文
[1]陈顺乐.系统性红斑狼疮诊治之我见.上海医学, 2000,23(5):257-259.
[2]鲍春德,陈晓翔.系统性红斑狼疮的治疗进展.现代实用医学, 2008,20(11):837-838.
[3] Ni JD, Yao X, Pan HF, et al. Clinical and serological correlates of anti-Sm autoantibodies in Chinese patients with systemic lupus erythematosus: 1,584 cases. Rheumatol Int, 2009,29(11):1323-6.
[4] Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol, 2006,6(11):823-35.
[5] Katsiari CG, Liossis SN, Sfikakis PP. The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal. Semin Arthritis Rheum, 2010,39(6):491-503.
[6] Blanco P, Palucka AK, Gill M, et al. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science (80- ), 2001,294(5546):1540-3.
[7] Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity, 2008,28(1):18-28.
[8] Wang S, Chen L. Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses. Microbes Infect, 2004,6(8):759-66.
[9] Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 2000,192(7):1027-34.
[10] Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 1996,8(5):765-72.
[11] Ravetch JV, Lanier LL. Immune inhibitory receptors. Science (80- ), 2000,290(5489):84-9.
[12] Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (80- ), 2001,291(5502):319-22.
[13] Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999,11(2):141-51.
[14] Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med, 2003,198(1):63-9.
[15] Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (80- ), 2001,291(5502):319-22.
[16] Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999,5(12):1365-9.
[17] Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol, 2007,8(3):239-45.
[18] Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med, 2001,193(7):839-46.
[19] Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001,2(3):261-8.
[20] Rodig N, Ryan T, Allen JA, et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol, 2003,33(11):3117-26.
[21] Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol, 2004,4(5):336-47.
[22] Grakoui A, John WE, Hanson HL, et al. Turning on the off switch: regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway. J Hepatol, 2006,45(4):468-72.
[23] Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001,2(3):261-8.
[24] Gifford AH, Klippenstein JR, Moore MM. Serum stimulates growth of and proteinase secretion by Aspergillus fumigatus. Infect Immun, 2002,70(1):19-26.
[25] Hoffman IE, Peene I, Meheus L, et al. Specific antinuclear antibodies are associated with clinical features in systemic lupus erythematosus. Ann Rheum Dis, 2004,63(9):1155-8.
[26] June CH, Bluestone JA, Nadler LM, et al. The B7 and CD28 receptor families. Immunol Today, 1994,15(7):321-31.
[27] Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol,2003,33(10):2706-16.
[28] Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med, 2000,191(5):891-8.
[29] Keir ME, Latchman YE, Freeman GJ, et al. Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol, 2005,175(11):7372-9.
[30] Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev, 2010,236:219-42.
[31] Kasagi S, Kawano S, Okazaki T, et al. Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice. J Immunol, 2010,184(5):2337-47.
[32] Liu MF, Weng CT, Weng MY. Variable increased expression of program death-1 and program death-1 ligands on peripheral mononuclear cells is not impaired in patients with systemic lupus erythematosus. J Biomed Biotechnol, 2009,2009:406136.
[33] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med, 2006,12(10):1198-202.
[34] Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature, 2006,443(7109):350-4.
[35] Karim R, Jordanova ES, Piersma SJ, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res, 2009,15(20):6341-7.
[36]赵宏丽,孙晓慧,赵俊芳,等.流式细胞仪对系统性红斑狼疮患者CD8+T淋巴细胞亚群的检测.中国中西医结合皮肤性病学杂志, 2005,4(1):7-9.
[37] Cai G, Karni A, Oliveira EM, et al. PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells. Cell Immunol, 2004,230(2):89-98.
[38] Groux H, Cottrez F. The complex role of interleukin-10 in autoimmunity. J Autoimmun, 2003,20(4):281-5.
1. Parry, RV.Chemnitz JM.Frauwirth KA .et al.CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mecha- nisms. Mol. Cell. Biol. 2005,NOV;25(21):9543-9553.
2. LatchmanY,WoodCR,ChernovaT etal.:PD-L2 is a second ligand for PD-1 and inhibits T cell activation.NatImmunol 2(3):261-268,2001.
3. Nishimura H,Nose M,Hiai H,Minato N,Honjo T.Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999 Aug;11(2):141-51.
4. Ansari MJ, Salama AD,Chitnis T et a.:The programmed death-1 (PD-1)pathway regulates autoimmune diabetes in nonobese diabetic (NOD)mice. J Exp Med. 2003 Jul 7; 198(1):63-9.
5. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001 Jan 12; 291(5502):319-22.
6. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death- 1 and its ligands in regulating autoimmunity and infection.Nat Immunol. 2007 Mar;8(3):239-45.
7. Okazaki, T. & Honjo, T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006 Apr;27(4):195-201.
8. Nakae S, Suto H, Iikura M. et al. Mast cells enhance T cell activation: importance of mast cell costimula-tory molecules and secreted TNF. J. Immunol. 2006;176(4), 2238-2248 .
9. Augello A, Tasso R, Negrini SM. et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway.Eur J Immunol. 2005 May; 35(5):1482-90.
10. Loke P, Allison JP.PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.Proc Natl Acad Sci U S A. 2003 Apr 29; 100(9):5336-41.
11. Mühlbauer M, Fleck M, Schütz C et al.PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis.J Hepatol. 2006 Oct;45(4):520-8
12. Selenko-Gebauer N, Majdic O, Szekeres A, H?fler G et al.B7-H1 (programmed death-1 ligand) on dendritic cells is involved in theinduction and maintenance of T cell anergy.J Immunol. 2003 Apr 1;170(7):3637-44.
13. Liang SC, Latchman YE, Buhlmann JE. et al.Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses.Eur J Immunol. 2003 Oct; 33(10):2706-16.
14. Nishimura H, Honjo T, Minato N.Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice.J Exp Med. 2000 Mar 6;191(5):891-8.
15. Keir ME, Latchman YE, Freeman GJ et al.Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.J Immunol. 2005 Dec 1;175(11):7372-9.
16. Blank C, Brown I, Marks R et al.Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells.J Immunol. 2003 Nov 1;171(9):4574-81.
17. Brown JA, Dorfman DM, Ma FR et al.Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.J Immunol. 2003 Feb 1;170(3):1257-66.
18. Sabapatha A, Gercel-Taylor C, Taylor DD. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol. 2006 Nov-Dec;56(5-6):345-55.
19. Holets LM, Hunt JS, Petroff MG.Trophoblast CD274 (B7-H1) is differentially expressed across gestation: influence of oxygen concentration.Biol Reprod. 2006 Feb;74(2):352-8.
20. Hori J, Wang M, Miyashita M.B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts.J Immunol. 2006 Nov 1;177(9):5928-35.
21. Wang J, Yoshida T, Nakaki F, et al.Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes.Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11823-8
22. Yadav D, Hill N, Yagita H et al. Altered availability of PD-1/PD ligands is associated with the failure to control autoimmunity in NOD mice.Cell Immunol. 2009;258(2):161-71. Epub 2009 May 6.
23. Probst HC, McCoy K, Okazaki T et al.Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4.Nat Immunol. 2005 Mar;6(3):280-6
24. Kuipers H, Muskens F, Willart M etal .Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation.Eur J Immunol. 2006 Sep;36(9):2472-82.
25. Van Keulen VP, Ciric B, Radhakrishnan S et al.Immunomodulation using the recombinant monoclonal human B7-DC cross-linking antibody rHIgM12.Clin Exp Immunol. 2006 Feb;143(2):314-21.
26. Lindqvist AK, Steinsson K, Johanneson B et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q.J Autoimmun. 2000 Mar;14(2):169-78.
27. Prokunina L, Castillejo-López C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.Nat Genet. 2002 Dec;32(4):666-9.
28. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects.Arthritis Rheum. 2004 Aug;50(8):2590-7.
29. Lee YH, Woo JH, Choi SJ et al. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis.Lupus. 2009 Jan;18(1):9-15.
30. Wang SC, Chen YJ, Ou TT et al.Programmed death-1 gene polymorphisms in patients with systemic lupus erythematosus in Taiwan.J Clin Immunol. 2006 Nov;26(6):506-11.
31. Lin SC, Yen JH, Tsai JJ et al.Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus.Arthritis Rheum. 2004 Mar;50(3):770-5.
32. Bertsias GK, Nakou M, Choulaki C,et al.Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus.Arthritis Rheum. 2009 Jan;60(1):207-18
33. Kristjansdottir H, Steinsson K, Gunnarsson I et al. Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus.Arthritis Rheum. 2010 Jun;62(6):1702-11
34. Liu MF, Weng CT, Weng MY.Variable increased expression of program death-1 and program death-1 ligands on peripheral mononuclear cells is not impaired in patients with systemic lupus erythematosus.J Biomed Biotechnol. 2009;2009:406136.
35. Kasagi S, Kawano S, Okazaki T eat al.Anti-programmed cell death 1 antibody reduces PD-1+CD4+ T cells and relieves the lupus-like nephritis of NZB/WF1 mice.J Immunol. 2010 Mar 1;184(5):2337-47.
[2]鲍春德,陈晓翔.系统性红斑狼疮的治疗进展.现代实用医学, 2008,20(11):837-838.
[3] Ni JD, Yao X, Pan HF, et al. Clinical and serological correlates of anti-Sm autoantibodies in Chinese patients with systemic lupus erythematosus: 1,584 cases. Rheumatol Int, 2009,29(11):1323-6.
[4] Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol, 2006,6(11):823-35.
[5] Katsiari CG, Liossis SN, Sfikakis PP. The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal. Semin Arthritis Rheum, 2010,39(6):491-503.
[6] Blanco P, Palucka AK, Gill M, et al. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science (80- ), 2001,294(5546):1540-3.
[7] Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity, 2008,28(1):18-28.
[8] Wang S, Chen L. Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses. Microbes Infect, 2004,6(8):759-66.
[9] Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 2000,192(7):1027-34.
[10] Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 1996,8(5):765-72.
[11] Ravetch JV, Lanier LL. Immune inhibitory receptors. Science (80- ), 2000,290(5489):84-9.
[12] Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (80- ), 2001,291(5502):319-22.
[13] Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999,11(2):141-51.
[14] Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med, 2003,198(1):63-9.
[15] Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (80- ), 2001,291(5502):319-22.
[16] Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999,5(12):1365-9.
[17] Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol, 2007,8(3):239-45.
[18] Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med, 2001,193(7):839-46.
[19] Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001,2(3):261-8.
[20] Rodig N, Ryan T, Allen JA, et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol, 2003,33(11):3117-26.
[21] Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol, 2004,4(5):336-47.
[22] Grakoui A, John WE, Hanson HL, et al. Turning on the off switch: regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway. J Hepatol, 2006,45(4):468-72.
[23] Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001,2(3):261-8.
[24] Gifford AH, Klippenstein JR, Moore MM. Serum stimulates growth of and proteinase secretion by Aspergillus fumigatus. Infect Immun, 2002,70(1):19-26.
[25] Hoffman IE, Peene I, Meheus L, et al. Specific antinuclear antibodies are associated with clinical features in systemic lupus erythematosus. Ann Rheum Dis, 2004,63(9):1155-8.
[26] June CH, Bluestone JA, Nadler LM, et al. The B7 and CD28 receptor families. Immunol Today, 1994,15(7):321-31.
[27] Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol,2003,33(10):2706-16.
[28] Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med, 2000,191(5):891-8.
[29] Keir ME, Latchman YE, Freeman GJ, et al. Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol, 2005,175(11):7372-9.
[30] Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev, 2010,236:219-42.
[31] Kasagi S, Kawano S, Okazaki T, et al. Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice. J Immunol, 2010,184(5):2337-47.
[32] Liu MF, Weng CT, Weng MY. Variable increased expression of program death-1 and program death-1 ligands on peripheral mononuclear cells is not impaired in patients with systemic lupus erythematosus. J Biomed Biotechnol, 2009,2009:406136.
[33] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med, 2006,12(10):1198-202.
[34] Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature, 2006,443(7109):350-4.
[35] Karim R, Jordanova ES, Piersma SJ, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res, 2009,15(20):6341-7.
[36]赵宏丽,孙晓慧,赵俊芳,等.流式细胞仪对系统性红斑狼疮患者CD8+T淋巴细胞亚群的检测.中国中西医结合皮肤性病学杂志, 2005,4(1):7-9.
[37] Cai G, Karni A, Oliveira EM, et al. PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells. Cell Immunol, 2004,230(2):89-98.
[38] Groux H, Cottrez F. The complex role of interleukin-10 in autoimmunity. J Autoimmun, 2003,20(4):281-5.
1. Parry, RV.Chemnitz JM.Frauwirth KA .et al.CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mecha- nisms. Mol. Cell. Biol. 2005,NOV;25(21):9543-9553.
2. LatchmanY,WoodCR,ChernovaT etal.:PD-L2 is a second ligand for PD-1 and inhibits T cell activation.NatImmunol 2(3):261-268,2001.
3. Nishimura H,Nose M,Hiai H,Minato N,Honjo T.Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999 Aug;11(2):141-51.
4. Ansari MJ, Salama AD,Chitnis T et a.:The programmed death-1 (PD-1)pathway regulates autoimmune diabetes in nonobese diabetic (NOD)mice. J Exp Med. 2003 Jul 7; 198(1):63-9.
5. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001 Jan 12; 291(5502):319-22.
6. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death- 1 and its ligands in regulating autoimmunity and infection.Nat Immunol. 2007 Mar;8(3):239-45.
7. Okazaki, T. & Honjo, T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006 Apr;27(4):195-201.
8. Nakae S, Suto H, Iikura M. et al. Mast cells enhance T cell activation: importance of mast cell costimula-tory molecules and secreted TNF. J. Immunol. 2006;176(4), 2238-2248 .
9. Augello A, Tasso R, Negrini SM. et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway.Eur J Immunol. 2005 May; 35(5):1482-90.
10. Loke P, Allison JP.PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.Proc Natl Acad Sci U S A. 2003 Apr 29; 100(9):5336-41.
11. Mühlbauer M, Fleck M, Schütz C et al.PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis.J Hepatol. 2006 Oct;45(4):520-8
12. Selenko-Gebauer N, Majdic O, Szekeres A, H?fler G et al.B7-H1 (programmed death-1 ligand) on dendritic cells is involved in theinduction and maintenance of T cell anergy.J Immunol. 2003 Apr 1;170(7):3637-44.
13. Liang SC, Latchman YE, Buhlmann JE. et al.Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses.Eur J Immunol. 2003 Oct; 33(10):2706-16.
14. Nishimura H, Honjo T, Minato N.Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice.J Exp Med. 2000 Mar 6;191(5):891-8.
15. Keir ME, Latchman YE, Freeman GJ et al.Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.J Immunol. 2005 Dec 1;175(11):7372-9.
16. Blank C, Brown I, Marks R et al.Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells.J Immunol. 2003 Nov 1;171(9):4574-81.
17. Brown JA, Dorfman DM, Ma FR et al.Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.J Immunol. 2003 Feb 1;170(3):1257-66.
18. Sabapatha A, Gercel-Taylor C, Taylor DD. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol. 2006 Nov-Dec;56(5-6):345-55.
19. Holets LM, Hunt JS, Petroff MG.Trophoblast CD274 (B7-H1) is differentially expressed across gestation: influence of oxygen concentration.Biol Reprod. 2006 Feb;74(2):352-8.
20. Hori J, Wang M, Miyashita M.B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts.J Immunol. 2006 Nov 1;177(9):5928-35.
21. Wang J, Yoshida T, Nakaki F, et al.Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes.Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11823-8
22. Yadav D, Hill N, Yagita H et al. Altered availability of PD-1/PD ligands is associated with the failure to control autoimmunity in NOD mice.Cell Immunol. 2009;258(2):161-71. Epub 2009 May 6.
23. Probst HC, McCoy K, Okazaki T et al.Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4.Nat Immunol. 2005 Mar;6(3):280-6
24. Kuipers H, Muskens F, Willart M etal .Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation.Eur J Immunol. 2006 Sep;36(9):2472-82.
25. Van Keulen VP, Ciric B, Radhakrishnan S et al.Immunomodulation using the recombinant monoclonal human B7-DC cross-linking antibody rHIgM12.Clin Exp Immunol. 2006 Feb;143(2):314-21.
26. Lindqvist AK, Steinsson K, Johanneson B et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q.J Autoimmun. 2000 Mar;14(2):169-78.
27. Prokunina L, Castillejo-López C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.Nat Genet. 2002 Dec;32(4):666-9.
28. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects.Arthritis Rheum. 2004 Aug;50(8):2590-7.
29. Lee YH, Woo JH, Choi SJ et al. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis.Lupus. 2009 Jan;18(1):9-15.
30. Wang SC, Chen YJ, Ou TT et al.Programmed death-1 gene polymorphisms in patients with systemic lupus erythematosus in Taiwan.J Clin Immunol. 2006 Nov;26(6):506-11.
31. Lin SC, Yen JH, Tsai JJ et al.Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus.Arthritis Rheum. 2004 Mar;50(3):770-5.
32. Bertsias GK, Nakou M, Choulaki C,et al.Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus.Arthritis Rheum. 2009 Jan;60(1):207-18
33. Kristjansdottir H, Steinsson K, Gunnarsson I et al. Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus.Arthritis Rheum. 2010 Jun;62(6):1702-11
34. Liu MF, Weng CT, Weng MY.Variable increased expression of program death-1 and program death-1 ligands on peripheral mononuclear cells is not impaired in patients with systemic lupus erythematosus.J Biomed Biotechnol. 2009;2009:406136.
35. Kasagi S, Kawano S, Okazaki T eat al.Anti-programmed cell death 1 antibody reduces PD-1+CD4+ T cells and relieves the lupus-like nephritis of NZB/WF1 mice.J Immunol. 2010 Mar 1;184(5):2337-47.