免疫相关性全血细胞减少症患者滤泡辅助性T细胞数量及功能研究
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摘要
目的：研究免疫相关性全血细胞减少症(immuno-related pancytopenia, IRP)患者骨髓滤泡辅助性T细胞(T follicular helper cells, Tfh细胞)数量及功能,探讨Tfh细胞在IRP发病中的作用。
方法：研究对象为90例IRP患者,其中初治患者(初诊组)43例、经激素免疫抑制及促造血治疗后血象恢复正常患者(恢复组)47例及正常对照25名。采用流式细胞术(FCM)检测IRP患者骨髓Tfh细胞数量(CD4+CXCR5+/CD4+)、Tfh细胞激活状态(CD4+CXCR5+CD40L+/CD4+CXCR5+, CD4+CXCR5+ICOS+/CD4+CXCR5+)、Tfh细胞胞浆内细胞因子白细胞介素(interleukin, IL-21水平(CD4+CXCR5+IL-21+/CD4+CXCR5+); RT-PCR技术检测其骨髓单个核细胞(BMMNC)转录因子Bcl-6 mRNA相对表达水平。分析CD4+CXCR5+/CD4+细胞比例、CD4+CXCR5+CD40L+/CD4+CXCR5+比例、CD4+CXCR5+ICOS+/CD4+CXCR5+比例、CD4+CXCR5+IL-21+/CD4+CXCR5+比例及Bcl-6 mRNA表达与CD3+CD4+/CD3+CD8+比值、Th1/Th2比例、CD19+/BMMNC比例、骨髓CD5+B淋巴细胞占总B淋巴细胞比例(CD5+CD19+/CD19+)、BMMNC抗体数量、血清免疫球蛋白、补体的相关性。
结果：
1.IRP初诊组骨髓CD4+CXCR5+/CD4+细胞比例[(28.79±19.70)%]明显高于恢复组[(21.15±12.81)%]和正常对照组[(13.42±6.72)%],恢复组高于正常对照组(P值均<0.05)；IRP初诊组骨髓CD4+CXCR5+ICOS+/CD4+CXCR5+比例[(5.05±±4.71)%]明显高于恢复组[(2.96±±2.89)%]和正常对照组[(2.99±2.23)%] (P值均<0.05),恢复组和正常对照组比较无显著性差异；IRP初诊组骨髓CD4+CXCR5+CD40L+/CD4+CXCR5+比例[(5.87±4.14)%]和恢复组[(6.52±5.47)%]明显高于正常对照组[(2.93±2.92)%](P值均<0.05)；IRP初诊组骨髓CD4+CXCR5+IL-21+/CD4+CXCR5+比例[(8.20±7.41)%]和恢复组[(6.30±6.03)%]明显高于正常对照组[(3.43±3.40)%],(P值均<0.05)；初诊组、恢复组、正常对照组三组Bcl-6 mRNA的表达水平[(0.625±0.248)、(0.485±0.253)和(0.306±0.210)],初诊组明显高于恢复组和正常对照组,恢复组高于正常对照组(P值均<0.05)。
2.IRP组骨髓CD4+CXCR5+/CD4+细胞比例与BMMNC Bcl-6 mRNA表达水平呈正相关(r=0.474, P<0.05),与骨髓CD19+/BMMNC细胞比例呈正相关(r=0.252,P<0.05),与骨髓CD3+CD8-IL-4+/CD3+CD8-比例呈正相关(r=0.475,P<0.05),与BMMNC CD34+细胞IgG阳性率呈正相关(r=0.314, P<0.05),与血清IgG水平呈正相关(r=0.376、P<0.05),与Th1/Th2比例呈负相关(r=-0.276,P<0.05),与血清C3水平均呈负相关(r=-0.379, P<0.05)。
3.IRP组骨髓CD4+CXCR5+CD40L+/CD4+CXCR5+比例与CD4+CXCR5+ICOS+/CD4+CXCR5+比例呈正相关(r=0.264, P<0.05)。IRP组骨髓CD4+CXCR5+IL-21+/CD4+CXCR5+比例与CD4+CXCR5+CD40L+/CD4+CXCR5+比例、CD4+CXCR5+ICOS+/CD4+CXCR5+比例、BMMNC Bcl-6 mRNA表达水平均呈正相关(r=0.334、r=0.263、r=0.332, P均<0.05),与血清C3水平呈负相关(r=-0.301, P<0.05)。
结论：Tfh细胞在IRP患者中数量增加,功能亢进,且数量与功能状态的变化具有一致性,随着治疗有效,逐渐趋于正常。Tfh细胞在IRP免疫发病机制中可能发挥重要作用,Tfh细胞及其效应分子有可能成为该疾病潜在的治疗靶点。
Objective:To study the quantity and function of bone marrow (BM) T follicular helper (Tfh) cells of the patients with immuno-related pancytopenia (IRP) and explore the role of Tfh cells in the pathogenesis of this disease.
Methods:Forty-three untreated IRP patients,47 recovered IRP patients and 25 healthy donors were enrolled in this study. The ratio of CD4+CXCR5+/CD4+cells, CD4+CXCR5+ICOS+/CD4+CXCR5+cells,CD4+CXCR5+CD40L+/CD4+CXCR5+cells, intracytoplasm CD4+CXCR5+IL-21+/CD4+CXCR5+cells in BM were examined by flow cytometry (FCM). The expression of Bcl-6 mRNA in bone marrow mononuclear (BMMNC) was measured by semiquantitive RT-PCR. The correlations between the ratio of CD4+CXCR5+/CD4+cells, CD4+CXCR5+CD40L+/CD4+CXCR5+cells, CD4+CXCR5+ICOS+/CD4+CXCR5+cells, CD4+CXCR5+IL-21+/CD4+CXCR5+cells, the expression of Bcl-6 mRNA and the ratio of CD3+CD4+/CD3+CD8+, Th1/Th2, CD19+/BMMNC, the quantity BMMNC-antibody, serum immune globulin, serum complement were analyzed.
Results:
1. The ratio of CD4+CXCR5+/CD4+cells of untreated IRP patients [(28.79±19.70)%] was significiantly higher than that of recovered IRP patients [(21.15±12.81)%] and normal controls [(13.42±6.72)%], the ratio of CD4+CXCR5+/CD4+cells of the recovered IRP patients was significiantly higher than that of normal controls (P＜0.05). The ratio of CD4+CXCR5+ICOS+/CD4+CXCR5+cells of untreated IRP patients [(5.05±4.71)%] was significiantly higher than that of recovered IRP patients [(2.96±2.89)%] and normal controls [(2.99±2.23)%] (P<0.05), there was no significiant difference between that of recovered IRP patients and normal controls. The ratio of CD4+CXCR5+CD40L+/CD4+CXCR5+cells of untreated IRP patients [(5.87±4.14)%] and recovered IRP patients [(6.52±5.47)%] were significiantly higher than that of normal controls [(2.93±2.92)%] (P＜0.05). The ratio of intracytoplasm CD4+CXCR5+IL-21+/CD4+CXCR5+cells of untreated IRP patients [(8.20±7.41)%] and recovered IRP patients [(6.30±6.03)%] were significiantly higher than that of normal controls [(3.43±3.40)%] (P＜0.05). The relative expressions of Bcl-6 mRNA in BMMNC were [(0.625±0.248), (0.485±0.253), (0.306±0.210)] in three groups, respectively. That in untreated IRP patients was significiantly higher than that in recovered IRP patients and normal controls. That in the recovered IRP patients was significiantly higher than that in normal controls (P<0.05).
2. In IRP group, there were significantly positive correlations between the ratio of CD4+CXCR5+/CD4+cells and the expression of Bcl-6 mRNA, the ratio of CD19+/BMMNC, the ratio of CD3+CD8-IL-4+/CD3+CD8-, the ratio of CD34+IgG+/BMMNC, the level of serum IgG (r=0.474,0.252,0.475,0.314,0.376, respectively, P<0.05), there were significantly negative correlations between the ratio of CD4+CXCR5+/CD4+cells and the ratio of Thl/Th2, the level of serum C3(r=-0.276,-0.379, respectively, P＜0.05).
3. There was significantly positive correlation between the ratio of CD4+CXCR5+CD40L+/CD4+CXCR5+and CD4+CXCR5+ICOS+/CD4+CXCR5+ (r=0.264, P＜0.05). There were significantly positive correlations between the ratio of CD4+CXCR5+IL-21+/CD4+CXCR5+and CD4+CXCR5+CD40L+/CD4+CXCR5+, CD4+CXCR5+ICOS+/CD4+CXCR5+, the expression of Bcl-6 mRNA(r=0.334,0.263, 0.332, respectively, P＜0.05), there was significantly negative correlation between the ratio of CD4+CXCR5+IL-21+/CD4+CXCR5+and the level of serum C3(r=-0.301, P＜0.05).
Conclusions:There exists increased quantity and hyperfunction of Tfh cells in the IRP patients, they may play important role in the pathogencsis of IRP. Tfh cells and their effector molecules may be regarded as potential new therapeutic targets of IRP.
方法：研究对象为90例IRP患者,其中初治患者(初诊组)43例、经激素免疫抑制及促造血治疗后血象恢复正常患者(恢复组)47例及正常对照25名。采用流式细胞术(FCM)检测IRP患者骨髓Tfh细胞数量(CD4+CXCR5+/CD4+)、Tfh细胞激活状态(CD4+CXCR5+CD40L+/CD4+CXCR5+, CD4+CXCR5+ICOS+/CD4+CXCR5+)、Tfh细胞胞浆内细胞因子白细胞介素(interleukin, IL-21水平(CD4+CXCR5+IL-21+/CD4+CXCR5+); RT-PCR技术检测其骨髓单个核细胞(BMMNC)转录因子Bcl-6 mRNA相对表达水平。分析CD4+CXCR5+/CD4+细胞比例、CD4+CXCR5+CD40L+/CD4+CXCR5+比例、CD4+CXCR5+ICOS+/CD4+CXCR5+比例、CD4+CXCR5+IL-21+/CD4+CXCR5+比例及Bcl-6 mRNA表达与CD3+CD4+/CD3+CD8+比值、Th1/Th2比例、CD19+/BMMNC比例、骨髓CD5+B淋巴细胞占总B淋巴细胞比例(CD5+CD19+/CD19+)、BMMNC抗体数量、血清免疫球蛋白、补体的相关性。
结果：
1.IRP初诊组骨髓CD4+CXCR5+/CD4+细胞比例[(28.79±19.70)%]明显高于恢复组[(21.15±12.81)%]和正常对照组[(13.42±6.72)%],恢复组高于正常对照组(P值均<0.05)；IRP初诊组骨髓CD4+CXCR5+ICOS+/CD4+CXCR5+比例[(5.05±±4.71)%]明显高于恢复组[(2.96±±2.89)%]和正常对照组[(2.99±2.23)%] (P值均<0.05),恢复组和正常对照组比较无显著性差异；IRP初诊组骨髓CD4+CXCR5+CD40L+/CD4+CXCR5+比例[(5.87±4.14)%]和恢复组[(6.52±5.47)%]明显高于正常对照组[(2.93±2.92)%](P值均<0.05)；IRP初诊组骨髓CD4+CXCR5+IL-21+/CD4+CXCR5+比例[(8.20±7.41)%]和恢复组[(6.30±6.03)%]明显高于正常对照组[(3.43±3.40)%],(P值均<0.05)；初诊组、恢复组、正常对照组三组Bcl-6 mRNA的表达水平[(0.625±0.248)、(0.485±0.253)和(0.306±0.210)],初诊组明显高于恢复组和正常对照组,恢复组高于正常对照组(P值均<0.05)。
2.IRP组骨髓CD4+CXCR5+/CD4+细胞比例与BMMNC Bcl-6 mRNA表达水平呈正相关(r=0.474, P<0.05),与骨髓CD19+/BMMNC细胞比例呈正相关(r=0.252,P<0.05),与骨髓CD3+CD8-IL-4+/CD3+CD8-比例呈正相关(r=0.475,P<0.05),与BMMNC CD34+细胞IgG阳性率呈正相关(r=0.314, P<0.05),与血清IgG水平呈正相关(r=0.376、P<0.05),与Th1/Th2比例呈负相关(r=-0.276,P<0.05),与血清C3水平均呈负相关(r=-0.379, P<0.05)。
3.IRP组骨髓CD4+CXCR5+CD40L+/CD4+CXCR5+比例与CD4+CXCR5+ICOS+/CD4+CXCR5+比例呈正相关(r=0.264, P<0.05)。IRP组骨髓CD4+CXCR5+IL-21+/CD4+CXCR5+比例与CD4+CXCR5+CD40L+/CD4+CXCR5+比例、CD4+CXCR5+ICOS+/CD4+CXCR5+比例、BMMNC Bcl-6 mRNA表达水平均呈正相关(r=0.334、r=0.263、r=0.332, P均<0.05),与血清C3水平呈负相关(r=-0.301, P<0.05)。
结论：Tfh细胞在IRP患者中数量增加,功能亢进,且数量与功能状态的变化具有一致性,随着治疗有效,逐渐趋于正常。Tfh细胞在IRP免疫发病机制中可能发挥重要作用,Tfh细胞及其效应分子有可能成为该疾病潜在的治疗靶点。
Objective:To study the quantity and function of bone marrow (BM) T follicular helper (Tfh) cells of the patients with immuno-related pancytopenia (IRP) and explore the role of Tfh cells in the pathogenesis of this disease.
Methods:Forty-three untreated IRP patients,47 recovered IRP patients and 25 healthy donors were enrolled in this study. The ratio of CD4+CXCR5+/CD4+cells, CD4+CXCR5+ICOS+/CD4+CXCR5+cells,CD4+CXCR5+CD40L+/CD4+CXCR5+cells, intracytoplasm CD4+CXCR5+IL-21+/CD4+CXCR5+cells in BM were examined by flow cytometry (FCM). The expression of Bcl-6 mRNA in bone marrow mononuclear (BMMNC) was measured by semiquantitive RT-PCR. The correlations between the ratio of CD4+CXCR5+/CD4+cells, CD4+CXCR5+CD40L+/CD4+CXCR5+cells, CD4+CXCR5+ICOS+/CD4+CXCR5+cells, CD4+CXCR5+IL-21+/CD4+CXCR5+cells, the expression of Bcl-6 mRNA and the ratio of CD3+CD4+/CD3+CD8+, Th1/Th2, CD19+/BMMNC, the quantity BMMNC-antibody, serum immune globulin, serum complement were analyzed.
Results:
1. The ratio of CD4+CXCR5+/CD4+cells of untreated IRP patients [(28.79±19.70)%] was significiantly higher than that of recovered IRP patients [(21.15±12.81)%] and normal controls [(13.42±6.72)%], the ratio of CD4+CXCR5+/CD4+cells of the recovered IRP patients was significiantly higher than that of normal controls (P＜0.05). The ratio of CD4+CXCR5+ICOS+/CD4+CXCR5+cells of untreated IRP patients [(5.05±4.71)%] was significiantly higher than that of recovered IRP patients [(2.96±2.89)%] and normal controls [(2.99±2.23)%] (P<0.05), there was no significiant difference between that of recovered IRP patients and normal controls. The ratio of CD4+CXCR5+CD40L+/CD4+CXCR5+cells of untreated IRP patients [(5.87±4.14)%] and recovered IRP patients [(6.52±5.47)%] were significiantly higher than that of normal controls [(2.93±2.92)%] (P＜0.05). The ratio of intracytoplasm CD4+CXCR5+IL-21+/CD4+CXCR5+cells of untreated IRP patients [(8.20±7.41)%] and recovered IRP patients [(6.30±6.03)%] were significiantly higher than that of normal controls [(3.43±3.40)%] (P＜0.05). The relative expressions of Bcl-6 mRNA in BMMNC were [(0.625±0.248), (0.485±0.253), (0.306±0.210)] in three groups, respectively. That in untreated IRP patients was significiantly higher than that in recovered IRP patients and normal controls. That in the recovered IRP patients was significiantly higher than that in normal controls (P<0.05).
2. In IRP group, there were significantly positive correlations between the ratio of CD4+CXCR5+/CD4+cells and the expression of Bcl-6 mRNA, the ratio of CD19+/BMMNC, the ratio of CD3+CD8-IL-4+/CD3+CD8-, the ratio of CD34+IgG+/BMMNC, the level of serum IgG (r=0.474,0.252,0.475,0.314,0.376, respectively, P<0.05), there were significantly negative correlations between the ratio of CD4+CXCR5+/CD4+cells and the ratio of Thl/Th2, the level of serum C3(r=-0.276,-0.379, respectively, P＜0.05).
3. There was significantly positive correlation between the ratio of CD4+CXCR5+CD40L+/CD4+CXCR5+and CD4+CXCR5+ICOS+/CD4+CXCR5+ (r=0.264, P＜0.05). There were significantly positive correlations between the ratio of CD4+CXCR5+IL-21+/CD4+CXCR5+and CD4+CXCR5+CD40L+/CD4+CXCR5+, CD4+CXCR5+ICOS+/CD4+CXCR5+, the expression of Bcl-6 mRNA(r=0.334,0.263, 0.332, respectively, P＜0.05), there was significantly negative correlation between the ratio of CD4+CXCR5+IL-21+/CD4+CXCR5+and the level of serum C3(r=-0.301, P＜0.05).
Conclusions:There exists increased quantity and hyperfunction of Tfh cells in the IRP patients, they may play important role in the pathogencsis of IRP. Tfh cells and their effector molecules may be regarded as potential new therapeutic targets of IRP.
引文
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[34]Tackenberg B, Kruth J, Bartholomaeus JE, et al. Clonal expansions of CD4+B helper T cells in autoimmune myasthenia gravis[J]. Eur. J. Immunol,2007,37: 849-863.
[35]Simpson N, Gatenby PA, Wilson A, et al. Expansion of Circulating T Cells Resembling Follicular Helper T Cells Is a Fixed Phenotype That Identifies a Subset of Severe Systemic Lupus Erythematosus[J]. Arthritis Rheum.2010 Jan; 62(1):234-44.
[36]Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion[J]. Immunity.2011 Jan 28; 34(1):108-21.
[37]Yu D, Vinuesa CG. Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity[J]. Cell Mol Immunol.2010 May;7(3):198-203.
[38]Crotty S. Follicular Helper CD4 T Cells (T(FH)) [J]. Annu Rev Immunol.2011 Apr 23; 29:621-63.
[39]Zaidan M, Cervera-Pierot P, de Seigneux S, et al. Evidence of follicular T-cell implication in a case of IgG4-related systemic disease with interstitial nephritis[J]. Nephrol Dial Transplant.2011 Mar 15. [Epub ahead of print]
[1]King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol,2008,26:741-766.
[2]Vinuesa CG, Tangye SG, Moser B, et al. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol,2005,5:853-865.
[3]Bossaller L, Burger J, Draeger R, et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol,2006,177: 4927-932.
[4]Bauquet AT, Jin H, Paterson AM, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol,2009,10:167-175.
[5]Leonard WJ, Zeng R, Spolski R. Interleukin 21:a cytokine/cytokine receptor system that has come of age. J Leukoc Biol,2008,84:348-356.
[6]Bryant VL, Ma CS, Avery DT, et al. Cytokine-mediated regulation of human B-cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J. Immunol,2007,179:8180-8190.
[7]Vinuesa CG, Cook MC, Angelucci C, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature,2005, 435:452-458.
[8]Yu D, Tan AH-M, Hu X, et al. Roquin represses autoimmunity by limiting inducible T cell costimulator messenger mRNA. Nature,2007,450:299-303.
[9]Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med,2009,206:561-576.
[10]Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol,2009,10:385-393.
[11]Kendall PL, Yu G, Woodward EJ, et al. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol, 2007,178:5643-5651.
[12]Howard OM, Dong HF, Su SB, et al. Autoantigens signal through chemokine receptors:uveitis antigens induce CXCR3-and CXCR5-expressing lymphocytes and immature dendritic cells to migrate. Blood,2005,105:4207-4214.
[13]Tackenberg B, Kruth J, Bartholomaeus JE, et al. Clonal expansions of CD4+B helper T cells in autoimmune myasthenia gravis. Eur. J. Immunol,2007,37:849-863.
[14]Manzo A, Vitolo B, Humby F, et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum,2008,58:3377-3387.
[15]Boles KS, Vermi W, Facchetti F, et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur. J. Immunol,2009,39: 695-703.
[16]Takahashi N, Matsumoto K, Saito H, et al. Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J Immunol,2009,182:5515-5527.
[17]Hu YL, Metz DP, Chung J, et al. B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells. J Immunol,2009,182:1421-1428.
[18]Odegard JM, Marks BR, DiPlacido LD, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med, 2008,205:2873-2886.
[19]Li HS, Ligons DL, Rose NR. Genetic complexity of autoimmune myocarditis. Autoimmun Rev,2008,7:168-173.
[20]Ansari MJ, Fiorina P, Dada S, et al. Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clin Immunol,2008,126:140-147.
[21]Ettinger R, Kuchen S, Lipsky PE. Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis,2008,67 Suppl 3:ⅲ83-86.
[22]Vogelzang A, King C. The modulatory capacity of interleukin-21 in the pathogenesis of autoimmune disease. Front Biosci,2008,13:5304-5315.
[23]Jang E, Cho SH, Park H, et al. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol,2009,182: 4649-4656.
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[21]King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses[J]. Annu Rev Immunol,2008,26:741-766.
[22]Vinuesa CG, Tangye SG, Moser B, et al. Follicular B helper T cells in antibody responses and autoimmunity[J]. Nat. Rev. Immunol,2005,5:853-865.
[23]Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire[J]. Nat Immunol,2009,10:385-393.
[24]Howard OM, Dong HF, Su SB, et al. Autoantigens signal through chemokine receptors:uveitis antigens induce CXCR3-and CXCR5-expressing lymphocytes and immature dendritic cells to migrate[J]. Blood,2005,105:4207-4214.
[25]Manzo A, Vitolo B, Humby F, et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint[J]. Arthritis Rheum,2008,58:3377-3387.
[26]Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity[J]. J Exp Med,2009,206:561-576.
[27]Hu YL, Metz DP, Chung J, et al. B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells[J]. J Immunol,2009,182: 1421-1428.
[28]Odegard JM, Marks BR, DiPlacido LD, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity[J]. J Exp Med,2008,205:2873-2886.
[29]Li HS, Ligons DL, Rose NR. Genetic complexity of autoimmune myocarditis[J]. Autoimmun Rev,2008,7:168-173.
[30]Ansari MJ, Fiorina P, Dada S, et al. Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice[J]. Clin Immunol,2008,126:140-147.
[31]Vogelzang A, King C. The modulatory capacity of interleukin-21 in the pathogenesis of autoimmune disease[J]. Front Biosci,2008,13:5304-5315.
[32]Jang E, Cho SH, Park H, et al. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25-T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice[J]. J Immunol,2009,182: 4649-4656.
[33]Aoki N, Kido M, Iwamoto S, et al. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice[J]. Gastroenterology. 2011 Jan 13. [Epub ahead of print]
[34]Tackenberg B, Kruth J, Bartholomaeus JE, et al. Clonal expansions of CD4+B helper T cells in autoimmune myasthenia gravis[J]. Eur. J. Immunol,2007,37: 849-863.
[35]Simpson N, Gatenby PA, Wilson A, et al. Expansion of Circulating T Cells Resembling Follicular Helper T Cells Is a Fixed Phenotype That Identifies a Subset of Severe Systemic Lupus Erythematosus[J]. Arthritis Rheum.2010 Jan; 62(1):234-44.
[36]Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion[J]. Immunity.2011 Jan 28; 34(1):108-21.
[37]Yu D, Vinuesa CG. Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity[J]. Cell Mol Immunol.2010 May;7(3):198-203.
[38]Crotty S. Follicular Helper CD4 T Cells (T(FH)) [J]. Annu Rev Immunol.2011 Apr 23; 29:621-63.
[39]Zaidan M, Cervera-Pierot P, de Seigneux S, et al. Evidence of follicular T-cell implication in a case of IgG4-related systemic disease with interstitial nephritis[J]. Nephrol Dial Transplant.2011 Mar 15. [Epub ahead of print]
[1]King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol,2008,26:741-766.
[2]Vinuesa CG, Tangye SG, Moser B, et al. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol,2005,5:853-865.
[3]Bossaller L, Burger J, Draeger R, et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol,2006,177: 4927-932.
[4]Bauquet AT, Jin H, Paterson AM, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol,2009,10:167-175.
[5]Leonard WJ, Zeng R, Spolski R. Interleukin 21:a cytokine/cytokine receptor system that has come of age. J Leukoc Biol,2008,84:348-356.
[6]Bryant VL, Ma CS, Avery DT, et al. Cytokine-mediated regulation of human B-cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J. Immunol,2007,179:8180-8190.
[7]Vinuesa CG, Cook MC, Angelucci C, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature,2005, 435:452-458.
[8]Yu D, Tan AH-M, Hu X, et al. Roquin represses autoimmunity by limiting inducible T cell costimulator messenger mRNA. Nature,2007,450:299-303.
[9]Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med,2009,206:561-576.
[10]Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol,2009,10:385-393.
[11]Kendall PL, Yu G, Woodward EJ, et al. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol, 2007,178:5643-5651.
[12]Howard OM, Dong HF, Su SB, et al. Autoantigens signal through chemokine receptors:uveitis antigens induce CXCR3-and CXCR5-expressing lymphocytes and immature dendritic cells to migrate. Blood,2005,105:4207-4214.
[13]Tackenberg B, Kruth J, Bartholomaeus JE, et al. Clonal expansions of CD4+B helper T cells in autoimmune myasthenia gravis. Eur. J. Immunol,2007,37:849-863.
[14]Manzo A, Vitolo B, Humby F, et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum,2008,58:3377-3387.
[15]Boles KS, Vermi W, Facchetti F, et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur. J. Immunol,2009,39: 695-703.
[16]Takahashi N, Matsumoto K, Saito H, et al. Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J Immunol,2009,182:5515-5527.
[17]Hu YL, Metz DP, Chung J, et al. B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells. J Immunol,2009,182:1421-1428.
[18]Odegard JM, Marks BR, DiPlacido LD, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med, 2008,205:2873-2886.
[19]Li HS, Ligons DL, Rose NR. Genetic complexity of autoimmune myocarditis. Autoimmun Rev,2008,7:168-173.
[20]Ansari MJ, Fiorina P, Dada S, et al. Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clin Immunol,2008,126:140-147.
[21]Ettinger R, Kuchen S, Lipsky PE. Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis,2008,67 Suppl 3:ⅲ83-86.
[22]Vogelzang A, King C. The modulatory capacity of interleukin-21 in the pathogenesis of autoimmune disease. Front Biosci,2008,13:5304-5315.
[23]Jang E, Cho SH, Park H, et al. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol,2009,182: 4649-4656.