干燥综合征患者外周血Th17、Treg及B细胞研究
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摘要
背景：干燥综合征是以口干、眼干为主要临床表现的自身免疫性疾病,病理上以腺体尤其是外分泌腺炎症细胞浸润及次级生发中心形成为主要特点。目前关于该病的发病机制尚不清楚,对该病无针对性有效治疗手段。Th17细胞和Treg细胞是近年来发现的辅助性T细胞的新亚群,对免疫性疾病的发生有关键调节作用。目前关于Th17、Treg在该病中的研究较少。另外B细胞在该病的发病过程中起关键作用,而B细胞的激活需要B细胞激活因子(BAFF)的作用,BAFF与该疾病的发生发展的具体关系目前尚不清楚。
目的：评价干燥综合征患者Th17、Treg、记忆性B细胞的外周表达及其与临床相关性,评价BAFF的外周表达及其与临床的相关性。
方法：干燥综合征国际合作联盟(SICCA)与北京协和医院合作确诊的原发性干燥综合征(pSS)患者41例,患者家属7例及正常健康献血者27例为样本,采集外周血用流式细胞仪分析Th17、Treg、记忆性B细胞,ELISA法检测血浆中的B细胞激活因子(BAFF)浓度,并且结合患者临床资料进行分析。
结果：患者Th17细胞数目较正常人显著升高(5.02±1.95%vs3.8%±1.0%,p=0.004)：记忆性B细胞数目较正常人显著升高(11.1%±5.1%vs9.24%±6.99%,p=0.0002)：BAFF浓度较正常人有显著性升高(1.18±0.72ng/ml vs0.43±0.19ng/ml p=0.0005)：Treg数目较正常人无明显差异(3.14±1.63%vs2.8%±1.2%,p=0.098)。患者及家属检测结果显示Th17数目无显著性差异(5.26%±1.35%vs5.2%±2.1%,p=0.94)；Treg数目无显著性差异(3.17±1.62%vs3.08%±1.08%p=0.90)；记忆性B细胞数目无显著性差异(16.26%±8.3%vs8.75%±3.82%,p=0.088)；患者BAFF水平较其家属有显著性升高(1.29±0.46ng/ml vs0.56±0.11ng/ml p=0.015)。同时结合临床资料分析得出Thl7与IgG具有正相关关系(r=0.457,p=0.005),但对评估疾病严重程度的临床症状、体征及血清学IgM.IgA、补体C3、补体C4、口腔科、眼科检查并无相关关系(p>0.05)。Treg与唇腺病理Focus评分成正相关关系(r=0.480,p=0.005)。CD27+B细胞与5min未刺激唾液量成正相关(r=0.345,p=0.021),与眼科角结膜评分成负相关关系(r=-0.321p=0.041), BAFF与临床症状、体征及血清学IgM、IgA、IgG、补体C3、补体C4、口腔科、眼科检查并无相关关系(p>0.05)。
结论：1Th17在患者及一级亲属中较正常人高表达,与IgG正相关,说明Th17可能与干燥综合征发病有关。2Treg表达较正常人无差异,说明Treg与疾病的关系目前尚不清楚。3记忆B细胞在患者及一级亲属高表达,与临床指标负相关,说明记忆B细胞在疾病发生发展过程中有重要作用。4患者BAFF水平明显高于正常人及一级亲属,与临床指标不相关,说明BAFF可能参与疾病的发生,但与疾病的严重程度不平行。
Background. Primary Sjogren's syndrome is an autoimmune disease with both organ-specific and systemic manifestations. pSS affects the salivary and lacrimal glands preferentially but may frequently also involve other exocrine glands. It is characterized by specific pathological features:the formation of ectopic lymphoid tissue. The mechanism of pSS is unclear and there is not any specific therapies either.Thl7and Treg are newly defined subgroups of helper T cell and are considered critical to the development of autoimmune diseases. B cell plays important role in the occurrence of pSS. However there is still fewer researches on the expression of Th17, Treg and memory B cell. B-lymphocyte activating factor (BAFF) is a key survival factor for B-cells and ensures their existence through reducing apoptotic clearance.
Objective. To investigate the expression of CD4+IL-17+Th17cell, CD4+CD25+regulatory T cells (Tregs) and memory B cell, in the peripheral blood of patients with primary Sjogren's syndrome (pSS) and healthy people. Then to examine BAFF level in pSS and in healthy controls. To analyze the correlations of the cells with clinical symptoms and lab tests.
Methods. Samples of peripheral venous blood were collected from41newly diagnosed pSS patients from SICCA and PUMCH, all females and27healthy controls and7family members of the patients. The levels of CD4+IL-17+Th17cell, CD4+CD25+regulatory T cells (Tregs) and memory B cell in the peripheral blood were measured by flow-cytometric assay. The level of BAFF in serum is tested with ELISA. The clinical indexes including IgG, IgA, IgM, C3, C4, Focus score,5min salivary rate, ocular score, schirmer test were collected to analyze the correlations.
Results. The level of CD4+IL-17+Th17in the blood of pSS patients was5.02%±1.95%, significantly higher than that of the healthy controls3.8%±1.0%(p=0.004). The level of CD4+CD25+Tregs in the blood of pSS patients was3.14%±1.63%, higher than that of the healthy controls2.8%±1.2%, but without statistical difference(p=0.098). The level of memory B cell in the blood of pSS patients was11.1%±5.1%, significantly higher than that of the healthy controls9.24%±6.99%(p=0.0002). There were no statistical differences between Th17, Treg, memory B cell in patients and in family members.(p>0.05). BAFF in pSS was1.18±0.72ng/ml, significantly higher than that of the healthy controls0.43±0.19ng/ml (p=0.0005) and also significantly higher than that of the family members0.56±0.11ng/ml (p=0.015). Th17level were significantly positively correlated with IgG(r=0.457,p=0.005). Treg level were significantly positively correlated with Focus score (r=0.480,p=0.005).CD27+B cell were significantly positively correlated with5min salivary rate (r=0.345,p=0.005) and significantly negatively correlated with ocular score (r=-0.321,p=0.041). BAFF was not correlated with IgG, IgA, IgM, C3, C4, Focus score,5min salivary rate, ocular score, schirmer test.(p>0.05)
Conclusion. Th17is overexpressed in pSS patients and relationships than in healthy people. It is significantly positively correlated with IgG. Th17may involve in pSS mechanism. There is no statistic difference between pSS and controls. Its role in pSS is less obvious. Similarly the memory B cell is overexpression in pSS patients and relationships than in healthy people. It is negatively correlated with clinical indexes. It plays important roles in the developing of the disease. BAFF level is statistically elevated in pSS compared with relationships and controls. It is proved to be not associated with clinical disease activity in pSS. It is not parallel with exocrine dysfunction. These finding suggest that BAFF may contribute to pSS by other mechanisms.
目的：评价干燥综合征患者Th17、Treg、记忆性B细胞的外周表达及其与临床相关性,评价BAFF的外周表达及其与临床的相关性。
方法：干燥综合征国际合作联盟(SICCA)与北京协和医院合作确诊的原发性干燥综合征(pSS)患者41例,患者家属7例及正常健康献血者27例为样本,采集外周血用流式细胞仪分析Th17、Treg、记忆性B细胞,ELISA法检测血浆中的B细胞激活因子(BAFF)浓度,并且结合患者临床资料进行分析。
结果：患者Th17细胞数目较正常人显著升高(5.02±1.95%vs3.8%±1.0%,p=0.004)：记忆性B细胞数目较正常人显著升高(11.1%±5.1%vs9.24%±6.99%,p=0.0002)：BAFF浓度较正常人有显著性升高(1.18±0.72ng/ml vs0.43±0.19ng/ml p=0.0005)：Treg数目较正常人无明显差异(3.14±1.63%vs2.8%±1.2%,p=0.098)。患者及家属检测结果显示Th17数目无显著性差异(5.26%±1.35%vs5.2%±2.1%,p=0.94)；Treg数目无显著性差异(3.17±1.62%vs3.08%±1.08%p=0.90)；记忆性B细胞数目无显著性差异(16.26%±8.3%vs8.75%±3.82%,p=0.088)；患者BAFF水平较其家属有显著性升高(1.29±0.46ng/ml vs0.56±0.11ng/ml p=0.015)。同时结合临床资料分析得出Thl7与IgG具有正相关关系(r=0.457,p=0.005),但对评估疾病严重程度的临床症状、体征及血清学IgM.IgA、补体C3、补体C4、口腔科、眼科检查并无相关关系(p>0.05)。Treg与唇腺病理Focus评分成正相关关系(r=0.480,p=0.005)。CD27+B细胞与5min未刺激唾液量成正相关(r=0.345,p=0.021),与眼科角结膜评分成负相关关系(r=-0.321p=0.041), BAFF与临床症状、体征及血清学IgM、IgA、IgG、补体C3、补体C4、口腔科、眼科检查并无相关关系(p>0.05)。
结论：1Th17在患者及一级亲属中较正常人高表达,与IgG正相关,说明Th17可能与干燥综合征发病有关。2Treg表达较正常人无差异,说明Treg与疾病的关系目前尚不清楚。3记忆B细胞在患者及一级亲属高表达,与临床指标负相关,说明记忆B细胞在疾病发生发展过程中有重要作用。4患者BAFF水平明显高于正常人及一级亲属,与临床指标不相关,说明BAFF可能参与疾病的发生,但与疾病的严重程度不平行。
Background. Primary Sjogren's syndrome is an autoimmune disease with both organ-specific and systemic manifestations. pSS affects the salivary and lacrimal glands preferentially but may frequently also involve other exocrine glands. It is characterized by specific pathological features:the formation of ectopic lymphoid tissue. The mechanism of pSS is unclear and there is not any specific therapies either.Thl7and Treg are newly defined subgroups of helper T cell and are considered critical to the development of autoimmune diseases. B cell plays important role in the occurrence of pSS. However there is still fewer researches on the expression of Th17, Treg and memory B cell. B-lymphocyte activating factor (BAFF) is a key survival factor for B-cells and ensures their existence through reducing apoptotic clearance.
Objective. To investigate the expression of CD4+IL-17+Th17cell, CD4+CD25+regulatory T cells (Tregs) and memory B cell, in the peripheral blood of patients with primary Sjogren's syndrome (pSS) and healthy people. Then to examine BAFF level in pSS and in healthy controls. To analyze the correlations of the cells with clinical symptoms and lab tests.
Methods. Samples of peripheral venous blood were collected from41newly diagnosed pSS patients from SICCA and PUMCH, all females and27healthy controls and7family members of the patients. The levels of CD4+IL-17+Th17cell, CD4+CD25+regulatory T cells (Tregs) and memory B cell in the peripheral blood were measured by flow-cytometric assay. The level of BAFF in serum is tested with ELISA. The clinical indexes including IgG, IgA, IgM, C3, C4, Focus score,5min salivary rate, ocular score, schirmer test were collected to analyze the correlations.
Results. The level of CD4+IL-17+Th17in the blood of pSS patients was5.02%±1.95%, significantly higher than that of the healthy controls3.8%±1.0%(p=0.004). The level of CD4+CD25+Tregs in the blood of pSS patients was3.14%±1.63%, higher than that of the healthy controls2.8%±1.2%, but without statistical difference(p=0.098). The level of memory B cell in the blood of pSS patients was11.1%±5.1%, significantly higher than that of the healthy controls9.24%±6.99%(p=0.0002). There were no statistical differences between Th17, Treg, memory B cell in patients and in family members.(p>0.05). BAFF in pSS was1.18±0.72ng/ml, significantly higher than that of the healthy controls0.43±0.19ng/ml (p=0.0005) and also significantly higher than that of the family members0.56±0.11ng/ml (p=0.015). Th17level were significantly positively correlated with IgG(r=0.457,p=0.005). Treg level were significantly positively correlated with Focus score (r=0.480,p=0.005).CD27+B cell were significantly positively correlated with5min salivary rate (r=0.345,p=0.005) and significantly negatively correlated with ocular score (r=-0.321,p=0.041). BAFF was not correlated with IgG, IgA, IgM, C3, C4, Focus score,5min salivary rate, ocular score, schirmer test.(p>0.05)
Conclusion. Th17is overexpressed in pSS patients and relationships than in healthy people. It is significantly positively correlated with IgG. Th17may involve in pSS mechanism. There is no statistic difference between pSS and controls. Its role in pSS is less obvious. Similarly the memory B cell is overexpression in pSS patients and relationships than in healthy people. It is negatively correlated with clinical indexes. It plays important roles in the developing of the disease. BAFF level is statistically elevated in pSS compared with relationships and controls. It is proved to be not associated with clinical disease activity in pSS. It is not parallel with exocrine dysfunction. These finding suggest that BAFF may contribute to pSS by other mechanisms.
引文
1 Carsten B. Schmidt-Weber, PhD, Mu" beccel Akdis, MD, PhD, and Cezmi A. Akdis, MD Davos, Switzerland. TH17 cells in the big picture of immunology J Allergy Clin Immunol 2007; 120:247-54.
2 B. Afzali, G. Lombardi, R. I. Lechler and G. M. Lord Department of Nephrology and Transplantation, King's College London, Guy's and St Thomas'Hospital, UK.The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease
3 Cuong Q. Nguyen, Min H. Hu, Yi Li, Carol Stewart, and Ammon B. Peck Salivary Gland Tissue Expression of Interleukin-23 and Interleukin-17 in Sjo"gren's Syndrome Findings in Humans and Mice ARTHRITIS & RHEUMATISM Vol.58, No.3, March 2008, pp 734-743 DOI 10.1002/art.23214.2008, American College of Rheumatology
4 Arne Hansen,(?)l Peter E Lipsky,2 and Thomas Dorner11Charite Centers (CC) 12 and 14, Departments of Medicine and Transfusion Medicine, Charite-Universitatsmedizin Berlin, Charite-Platz 01,10098 Berlin, Germany 2Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Bethesda, MD 20892, USA.B cells in Sjogren's syndrome:indications for disturbed selection and differentiation in ectopic lymphoid tissue Arthritis Res Ther. 2007; 9(4): 218. Published online 2007 August 6:10.1186/ar2210.
5蔡丽敏 陈志强B细胞活化因子与干燥综合征国际皮肤性病学杂志2007年3月第33卷第2期
6 Jaime R. Darce, Bonnie K. Arendt, Sook Kyung Chang and Diane F. Jelinek, Department of Immunology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN 55905 Divergent Effects of BAFF on Human Memory B Cell Differentiation into Ig-Secreting Cells The Journal of Immunology,2007,178 (9) P.5612-5622
7 MarieteX, Roux S, Zhang J, et al. The level of BLyS (BAFF)correlates with the titre of autoantibodies in human Sjogren's syndrome. Ann.Rheum.Dis,2003,62(2): 168.171.
8 Jean-David Bouazizl, Koichi Yanabal, Thomas F. Tedder11 Department of Immunology, Duke University Medical Center, Durham, NC, USA. Regulatory B cells as inhibitors of immune responses and inflammation Immunological Reviews 2008 Vol. 224:201-214
1 Carsten B. Schmidt-Weber, PhD, Mu" beccel Akdis, MD, PhD, and Cezmi A. Akdis, MD Davos, Switzerland. TH17 cells in the big picture of immunology J Allergy Clin Immunol 2007; 120:247-54.
2 Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD41 effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6:1123-32.
3 Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133-41.
4 Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T (H) 17 lineage. Nature 2006; 441:231-4.
5 Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. Expression and regulation of IL-22 in the IL-17-producing CD41 T lymphocytes. Cell Res 2006; 16:902-7.
6 Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445:648-51.
7 Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, et al. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp Med 2006; 203:2009-19.
8 Bush KA, Farmer KM, Walker JS, Kirkham BW. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum 2002; 46:802-5.
9 B. Afzali, G. Lombardi, R. I. Lechler and G. M. Lord Department of Nephrology and Transplantation, King's College London, Guy's and St Thomas'Hospital, UK The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease
10 Arne Hansen,'Peter E Lipsky,2 and Thomas Dorner1'Charite Centers (CC) 12 and 14, Departments of Medicine and Transfusion Medicine, Charite-Universitatsmedizin Berlin,Charite-Platz 01,10098 Berlin, Germany Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Bethesda, MD 20892, USA.B cells in Sjogren's syndrome:indications for disturbed selection and differentiation in ectopic lymphoid tissue Arthritis Res Ther. 2007; 9(4):218. Published online 2007 August 6. doi:10.1186/ar2210.
11 Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 1998; 161:409-14.
12 Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts:a possible role as a'fine-tuning cytokine'in inflammation processes. Arthritis Rheum 2001; 44:2176-84.
13 LeGrand A, Fermor B, Fink C et al. Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci. Arthritis Rheum 2001; 44:2078-83.
14 Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000; 9:589-93.
15 Fujino S, Andoh A, Bamba S et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003; 52:65-70.
16 Grazia Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006; 212:28-50.
17 Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001; 182:207-14.
18 Lu L, Werneck MBF, Cantor H. The immunoregulatory effects of Qa-1. Immunol Rev 2006; 212:51-9.
19 Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NSF. CD8+CD28-T suppressor cells and the induction of antigen-specific, antigenpresenting cell-mediated suppression of Th reactivity. Immunol Rev 2001; 182:201-6.
20 Rifa'i M, Kawamoto Y, Nakashima I, Suzuki H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med 2004; 200:1123-34.
21 Hanninen A, Harrison LC. Gamma delta T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol Rev 2000; 173:109-19.
22 Zhang C, Zhang J, Tian ZG. The regulatory effect of natural killer cells:do'NK-reg cells'exist? Cell Mol Immunol 2006; 3:241-54.
23 Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med 2006; 203:1851-8.
24 Ochando JC, Homma C, Yang Y et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006; 7:652-62.
25 Ariel A, Fredman G, Sun YP et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol 2006;7:1209-16.
26 Liu J, Liu Z, Witkowski P et al. Rat CD8+ FOXP3+ T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection. Transpl Immunol 2004; 13:239-47.
27 Suciu-Foca N, Manavalan JS, Scotto L et al. Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells:review. Int Immunopharmacol 2005; 5:7-11.
28 Liu Z, Tugulea S, Cortesini R, Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+. Int Immunol 1998; 10:775-83.
29 Kapp JA, Honjo K, Kapp LM, Xu XY, Cozier A, Bucy RP. TCR transgenic CD8+T cells activated in the presence of TGF{beta} express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection, Int Immunol 2006; 18:1549-62.
30 Zhang ZX, Young K, Zhang L. CD3+CD4-CD8-alphabeta-TCR+T cell as immune regulatory cell. J Mol Med 2001; 79:419-27.
31 Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 2000; 6:782-9.
32 Sakaguchi S, Sakaguchi N,AsanoM, ItohM, TodaM. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151-64.
2 B. Afzali, G. Lombardi, R. I. Lechler and G. M. Lord Department of Nephrology and Transplantation, King's College London, Guy's and St Thomas'Hospital, UK.The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease
3 Cuong Q. Nguyen, Min H. Hu, Yi Li, Carol Stewart, and Ammon B. Peck Salivary Gland Tissue Expression of Interleukin-23 and Interleukin-17 in Sjo"gren's Syndrome Findings in Humans and Mice ARTHRITIS & RHEUMATISM Vol.58, No.3, March 2008, pp 734-743 DOI 10.1002/art.23214.2008, American College of Rheumatology
4 Arne Hansen,(?)l Peter E Lipsky,2 and Thomas Dorner11Charite Centers (CC) 12 and 14, Departments of Medicine and Transfusion Medicine, Charite-Universitatsmedizin Berlin, Charite-Platz 01,10098 Berlin, Germany 2Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Bethesda, MD 20892, USA.B cells in Sjogren's syndrome:indications for disturbed selection and differentiation in ectopic lymphoid tissue Arthritis Res Ther. 2007; 9(4): 218. Published online 2007 August 6:10.1186/ar2210.
5蔡丽敏 陈志强B细胞活化因子与干燥综合征国际皮肤性病学杂志2007年3月第33卷第2期
6 Jaime R. Darce, Bonnie K. Arendt, Sook Kyung Chang and Diane F. Jelinek, Department of Immunology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN 55905 Divergent Effects of BAFF on Human Memory B Cell Differentiation into Ig-Secreting Cells The Journal of Immunology,2007,178 (9) P.5612-5622
7 MarieteX, Roux S, Zhang J, et al. The level of BLyS (BAFF)correlates with the titre of autoantibodies in human Sjogren's syndrome. Ann.Rheum.Dis,2003,62(2): 168.171.
8 Jean-David Bouazizl, Koichi Yanabal, Thomas F. Tedder11 Department of Immunology, Duke University Medical Center, Durham, NC, USA. Regulatory B cells as inhibitors of immune responses and inflammation Immunological Reviews 2008 Vol. 224:201-214
1 Carsten B. Schmidt-Weber, PhD, Mu" beccel Akdis, MD, PhD, and Cezmi A. Akdis, MD Davos, Switzerland. TH17 cells in the big picture of immunology J Allergy Clin Immunol 2007; 120:247-54.
2 Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD41 effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6:1123-32.
3 Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133-41.
4 Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T (H) 17 lineage. Nature 2006; 441:231-4.
5 Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. Expression and regulation of IL-22 in the IL-17-producing CD41 T lymphocytes. Cell Res 2006; 16:902-7.
6 Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445:648-51.
7 Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, et al. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp Med 2006; 203:2009-19.
8 Bush KA, Farmer KM, Walker JS, Kirkham BW. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum 2002; 46:802-5.
9 B. Afzali, G. Lombardi, R. I. Lechler and G. M. Lord Department of Nephrology and Transplantation, King's College London, Guy's and St Thomas'Hospital, UK The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease
10 Arne Hansen,'Peter E Lipsky,2 and Thomas Dorner1'Charite Centers (CC) 12 and 14, Departments of Medicine and Transfusion Medicine, Charite-Universitatsmedizin Berlin,Charite-Platz 01,10098 Berlin, Germany Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Bethesda, MD 20892, USA.B cells in Sjogren's syndrome:indications for disturbed selection and differentiation in ectopic lymphoid tissue Arthritis Res Ther. 2007; 9(4):218. Published online 2007 August 6. doi:10.1186/ar2210.
11 Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 1998; 161:409-14.
12 Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts:a possible role as a'fine-tuning cytokine'in inflammation processes. Arthritis Rheum 2001; 44:2176-84.
13 LeGrand A, Fermor B, Fink C et al. Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci. Arthritis Rheum 2001; 44:2078-83.
14 Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000; 9:589-93.
15 Fujino S, Andoh A, Bamba S et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003; 52:65-70.
16 Grazia Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006; 212:28-50.
17 Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001; 182:207-14.
18 Lu L, Werneck MBF, Cantor H. The immunoregulatory effects of Qa-1. Immunol Rev 2006; 212:51-9.
19 Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NSF. CD8+CD28-T suppressor cells and the induction of antigen-specific, antigenpresenting cell-mediated suppression of Th reactivity. Immunol Rev 2001; 182:201-6.
20 Rifa'i M, Kawamoto Y, Nakashima I, Suzuki H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med 2004; 200:1123-34.
21 Hanninen A, Harrison LC. Gamma delta T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol Rev 2000; 173:109-19.
22 Zhang C, Zhang J, Tian ZG. The regulatory effect of natural killer cells:do'NK-reg cells'exist? Cell Mol Immunol 2006; 3:241-54.
23 Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med 2006; 203:1851-8.
24 Ochando JC, Homma C, Yang Y et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006; 7:652-62.
25 Ariel A, Fredman G, Sun YP et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol 2006;7:1209-16.
26 Liu J, Liu Z, Witkowski P et al. Rat CD8+ FOXP3+ T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection. Transpl Immunol 2004; 13:239-47.
27 Suciu-Foca N, Manavalan JS, Scotto L et al. Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells:review. Int Immunopharmacol 2005; 5:7-11.
28 Liu Z, Tugulea S, Cortesini R, Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+. Int Immunol 1998; 10:775-83.
29 Kapp JA, Honjo K, Kapp LM, Xu XY, Cozier A, Bucy RP. TCR transgenic CD8+T cells activated in the presence of TGF{beta} express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection, Int Immunol 2006; 18:1549-62.
30 Zhang ZX, Young K, Zhang L. CD3+CD4-CD8-alphabeta-TCR+T cell as immune regulatory cell. J Mol Med 2001; 79:419-27.
31 Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 2000; 6:782-9.
32 Sakaguchi S, Sakaguchi N,AsanoM, ItohM, TodaM. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151-64.