系统性硬化症患者外周血中Th17细胞、CD4+CD25+Treg细胞及B细胞的研究
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摘要
背景
系统性硬化症(systemic sclerosis, SSc)是一种病因不明的慢性自身免疫性疾病,以进行性的皮肤和内脏纤维化、微血管系统改变和多种细胞、体液免疫异常为特征,最终导致组织和器官的萎缩,预后不良。T细胞和B细胞在SSc的发病中起着重要的作用,T细胞通过分泌细胞因子及与成纤维细胞直接接触促进炎症反应和纤维化发生,B细胞主要通过产生各种自身抗体介导病变发生。辅助T细胞17(T-helper17,Th17)和CD4+CD25+调节性T细胞(regulatory T cell, Treg)是两种特殊的T淋巴细胞,分别对炎症反应起正向和负向调控作用；CD27、CD38分子分别主要表达在记忆B细胞、浆细胞的表面；CD268分子是B细胞激活因子(B cell activating factor, BAFF)的主要受体。近年来,Th17、CD4+CD25+Treg、CD27、CD38、CD268在自身免疫性疾病中的作用是人们研究的热点,而它们与SSc的相关报道则不多。欧洲抗风湿病联盟硬皮病试验研究组(EULAR Scleroderma Trial and Research group, EUSTAR)是全球性的硬皮病研究组织,北京协和医院是其成员之一。本实验将选取EUSTAR项目入组患者作为研究对象。
目的
测定系统性硬化症病人外周血单个核细胞(peripheral blood mononuclear cells, PBMC)中Th17细胞、CD4+CD25+Treg细胞及表达CD27、CD38、CD268分子的B细胞所占比例,并分析其与病人临床数据的相关性。
方法
采用流式细胞仪对系统性硬化症患者及健康人PBMC中的Th17细胞(CD4+IL-17+)、Treg细胞(CD4+CD25+Foxp3+)、CD27+、CD38+、CD268+B细胞进行计数。比较患者与健康人结果的差异,并分析患者中细胞计数与患者临床数据的相关性。
结果
1.系统性硬化症患者外周血中Th17细胞比例较正常人显著升高,其升高程度与患者病程呈正相关；
2.系统性硬化症患者外周血中CD4+CD25+Treg细胞比例较正常人显著升高；
3.系统性硬化症患者外周血中B细胞比例较正常人显著降低,其降低程度与抗U1RNP抗体阳性率呈负相关；
4.系统性硬化症患者外周血中CD268+B细胞比例较正常人无明显差别；
5.系统性硬化症患者外周血中CD38+B细胞比例较正常人无明显差别。
结论
系统性硬化症中存在着明显的T细胞和B细胞异常：
1.外周血Th17细胞增生,分泌IL-17,参与炎症和纤维化病变；
2.外周血CD4+CD25+Treg细胞增生,参与纤维化的过程；
3.外周血中幼稚B细胞增生,记忆B细胞减少；
4. BAFF—BAFF-R系统的激活并不依赖于BAFF-R阳性B细胞数量的扩增。
Background
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown origin. It is characterized by progressive fibrosis of the skin and visceral organs, microvascular alterations and a variety of cellular or humoral immune abnormalities. These changes finally lead to atrophy of the tissues and the organs, so SSc has a poor prognosis. T cells and B cells play important roles in the pathogenesis of this disease. T cells promote inflammations and fibrosis by secreting the cytokines or contact with the fibroblasts. B cells generate a series of autoantibodies to induce the alterations. T-helper17(Th17) cells and CD4+CD25+regulatory T cells (Treg) are two kinds of special T lymphocytes. They respectively enhance and control inflammatory responses. CD27molecules and CD38molecules were respectively expressed on the surface of memory B cells and plasma cells. CD268molecules are the dominant receptors of B cell activating factor (BAFF). The effects of Th17, Treg, CD27, CD38and CD268in autoimmune diseases are becoming the foci of the researchers. But there are few reports in SSc. EULAR Scleroderma Trial and Research group (EUSTAR) is a global research organization on scleroderma. Peking Union Medical College Hospital is one of its members. In our study, objects are chosen from EUSTAR patients.
Objective
To measure the ratios of Th17, CD4+CD25+Treg cells and cells expressing CD27, CD38or CD268molecules in the peripheral blood mononuclear cells (PBMC) of the SSc patients. To analyze the relativities of the cell ratios and the clinical data of the patients.
Methods
Th17cells (CD4+IL-17+), Treg cells (CD4+CD25+Foxp3+), CD27+, CD38+or CD268+B cells in the PBMC of SSc patients and healthy controls were counted by flow cytometry. The different results of the patients and the healthy controls and the relativities of the cell counts and the clinical data in the patients were analyzed.
Results
1. The ratio of Th17cells in SSc patients is significantly higher than the ratio in healthy controls. The level of Th17cells correlates with the duration of the disease.
2. The ratio of CD4+CD25+Treg cells in SSc patients is significantly higher than the ratio in healthy controls.
3. The ratio of CD27+B cells in SSc patients is significantly lower than the ratio in healthy controls. The level of CD27+B cells negatively correlates with the anti-U1RNP antibody.
4. The ratio of BAFF-R+cells in SSc patients did not show significant difference with the ratio in healthy controls.
5. The ratio of CD38+cells in SSc patients did not show significant difference with the ratio in healthy controls.
Conclusions
There are remarkable T cell and B cell abnormalities in systemic sclerosis.
1. Proliferation of Th17cells in the periphery:Th17cells participate in inflammatory and fibrotic processes by secreting IL-17
2. Proliferation of CD4+CD25+Treg cells in the periphery:Treg cells participate in fibrotic process
3. Proliferation of naive B cells; Reduction of memory B cells
4. Activation of BAFF--BAFF-R system does not rely on the proliferation of BAFF-R positive B cells.
系统性硬化症(systemic sclerosis, SSc)是一种病因不明的慢性自身免疫性疾病,以进行性的皮肤和内脏纤维化、微血管系统改变和多种细胞、体液免疫异常为特征,最终导致组织和器官的萎缩,预后不良。T细胞和B细胞在SSc的发病中起着重要的作用,T细胞通过分泌细胞因子及与成纤维细胞直接接触促进炎症反应和纤维化发生,B细胞主要通过产生各种自身抗体介导病变发生。辅助T细胞17(T-helper17,Th17)和CD4+CD25+调节性T细胞(regulatory T cell, Treg)是两种特殊的T淋巴细胞,分别对炎症反应起正向和负向调控作用；CD27、CD38分子分别主要表达在记忆B细胞、浆细胞的表面；CD268分子是B细胞激活因子(B cell activating factor, BAFF)的主要受体。近年来,Th17、CD4+CD25+Treg、CD27、CD38、CD268在自身免疫性疾病中的作用是人们研究的热点,而它们与SSc的相关报道则不多。欧洲抗风湿病联盟硬皮病试验研究组(EULAR Scleroderma Trial and Research group, EUSTAR)是全球性的硬皮病研究组织,北京协和医院是其成员之一。本实验将选取EUSTAR项目入组患者作为研究对象。
目的
测定系统性硬化症病人外周血单个核细胞(peripheral blood mononuclear cells, PBMC)中Th17细胞、CD4+CD25+Treg细胞及表达CD27、CD38、CD268分子的B细胞所占比例,并分析其与病人临床数据的相关性。
方法
采用流式细胞仪对系统性硬化症患者及健康人PBMC中的Th17细胞(CD4+IL-17+)、Treg细胞(CD4+CD25+Foxp3+)、CD27+、CD38+、CD268+B细胞进行计数。比较患者与健康人结果的差异,并分析患者中细胞计数与患者临床数据的相关性。
结果
1.系统性硬化症患者外周血中Th17细胞比例较正常人显著升高,其升高程度与患者病程呈正相关；
2.系统性硬化症患者外周血中CD4+CD25+Treg细胞比例较正常人显著升高；
3.系统性硬化症患者外周血中B细胞比例较正常人显著降低,其降低程度与抗U1RNP抗体阳性率呈负相关；
4.系统性硬化症患者外周血中CD268+B细胞比例较正常人无明显差别；
5.系统性硬化症患者外周血中CD38+B细胞比例较正常人无明显差别。
结论
系统性硬化症中存在着明显的T细胞和B细胞异常：
1.外周血Th17细胞增生,分泌IL-17,参与炎症和纤维化病变；
2.外周血CD4+CD25+Treg细胞增生,参与纤维化的过程；
3.外周血中幼稚B细胞增生,记忆B细胞减少；
4. BAFF—BAFF-R系统的激活并不依赖于BAFF-R阳性B细胞数量的扩增。
Background
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown origin. It is characterized by progressive fibrosis of the skin and visceral organs, microvascular alterations and a variety of cellular or humoral immune abnormalities. These changes finally lead to atrophy of the tissues and the organs, so SSc has a poor prognosis. T cells and B cells play important roles in the pathogenesis of this disease. T cells promote inflammations and fibrosis by secreting the cytokines or contact with the fibroblasts. B cells generate a series of autoantibodies to induce the alterations. T-helper17(Th17) cells and CD4+CD25+regulatory T cells (Treg) are two kinds of special T lymphocytes. They respectively enhance and control inflammatory responses. CD27molecules and CD38molecules were respectively expressed on the surface of memory B cells and plasma cells. CD268molecules are the dominant receptors of B cell activating factor (BAFF). The effects of Th17, Treg, CD27, CD38and CD268in autoimmune diseases are becoming the foci of the researchers. But there are few reports in SSc. EULAR Scleroderma Trial and Research group (EUSTAR) is a global research organization on scleroderma. Peking Union Medical College Hospital is one of its members. In our study, objects are chosen from EUSTAR patients.
Objective
To measure the ratios of Th17, CD4+CD25+Treg cells and cells expressing CD27, CD38or CD268molecules in the peripheral blood mononuclear cells (PBMC) of the SSc patients. To analyze the relativities of the cell ratios and the clinical data of the patients.
Methods
Th17cells (CD4+IL-17+), Treg cells (CD4+CD25+Foxp3+), CD27+, CD38+or CD268+B cells in the PBMC of SSc patients and healthy controls were counted by flow cytometry. The different results of the patients and the healthy controls and the relativities of the cell counts and the clinical data in the patients were analyzed.
Results
1. The ratio of Th17cells in SSc patients is significantly higher than the ratio in healthy controls. The level of Th17cells correlates with the duration of the disease.
2. The ratio of CD4+CD25+Treg cells in SSc patients is significantly higher than the ratio in healthy controls.
3. The ratio of CD27+B cells in SSc patients is significantly lower than the ratio in healthy controls. The level of CD27+B cells negatively correlates with the anti-U1RNP antibody.
4. The ratio of BAFF-R+cells in SSc patients did not show significant difference with the ratio in healthy controls.
5. The ratio of CD38+cells in SSc patients did not show significant difference with the ratio in healthy controls.
Conclusions
There are remarkable T cell and B cell abnormalities in systemic sclerosis.
1. Proliferation of Th17cells in the periphery:Th17cells participate in inflammatory and fibrotic processes by secreting IL-17
2. Proliferation of CD4+CD25+Treg cells in the periphery:Treg cells participate in fibrotic process
3. Proliferation of naive B cells; Reduction of memory B cells
4. Activation of BAFF--BAFF-R system does not rely on the proliferation of BAFF-R positive B cells.
引文
1 Hayes MD, Lacey JV, Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D. Prevalence, incidence, survival and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:2246-2255.
I Armando Gabrielli, M.D., Enrico V. Avvedimento, M.D., and Thomas Krieg, M.D. Mechanisms of Disease:Scleroderma. N Engl J Med 2009;360:1989-2003.
3 唐福林主编.风湿免疫科医师效率手册.北京：中国协和医科大学出版社,2001.3：107-112.
4 Denton CP et al. (2006) Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol 2:134-144.
5 Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166:255-63.
0 Perlish JS, Lemlich G, Fleischmajer R. Identification of collagen fibrils in scleroderma skin. J Invest Dermatol 1988;90:48-54.
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12 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
13 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
14 Miossec P. Interleukin-17 in rheumatoid arthritis:if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum 2003; 48:594-601.
15 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.
16 Kurasawa K et al. Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
17 Fossiez F et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
18 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
19 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
20 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.
21 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
22 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cells development by the transcription factor Foxp3. Science,2003,299:1057-1061.
" Roncador G et al. Analysis of FOXP3 protein expression in human CD4+CD25+regulatory T cells at the single-cell level. Eur J Immunol.2005 Jun;35(6):1681-91.
24 Agematsu K, Hokibara S, Nagumo H, Komiyama A. CD27:a memory B-cell marker. Immunol Today.2000 May;21(5):204-6.
25 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000;165:5970-9.
26 Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
27 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
28 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004;50:1918-27.
29 刘翠杰等.系统性红斑狼疮病人外周血淋巴细胞CD38的表达.中国麻风皮肤病杂志.2001年9月第17卷第3期.162-163.
30 Ng LG, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol.2004 Jul 15;173(2):807-17.
31 Rauch M, et al. Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells. PLoS ONE.2009;4(5):e5456. Epub 2009 May 6.
32 Carter RH, et al. Expression and Occupancy of BAFF-R on B Cells in Systemic Lupus Erythematosus. Arthritis Rheum.2005,52:3943-3954.
33 Matsushita T, et al. Elevated Serum BAFF Levels in Patients With Systemic Sclerosis:Enhanced BAFF Signaling in Systemic Sclerosis B Lymphocytes. Arthritis Rheum.2006,54:192-201.
34 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
35 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
36 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
37 Kotake S, Udagawa N, Takahashi N et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999; 103:1345-52.
38 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.
39 Kurasawa K et al. Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
40 Fossiez F et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
41 Fehervari Z, Sakaguchi S. CD4(+) Tregs and immune control. J Clin Invest 2004; 114(9):1209-1217.
42 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
43 Piccirillo CA, Thornton AM. Cornerstone of peripheral tolerance:naturally occurring CD4+CD25+ regulatory T cells. Trends Immunol 2004;25(7):374-380.
44 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
45 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
46 Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21(4):589-601.
47 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cells development by the transcription factor Foxp3. Science,2003,299:1057-1061.
48 Roncador G et al. Analysis of FOXP3 protein expression in human CD4+CD25+regulatory T cells at the single-cell level. Eur J Immunol.2005 Jun;35(6):1681-91.
49 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.
50 Ehrenstein MR, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 2004;200(3):277-285.
51 Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2003;21(3):273-6.
52 Furuno K, et al. CD25+CD4+regulatory T cells in patients with Kawasaki disease. J Pediatr 2004;145(3):385-90.
53 Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002;109(1):131-40.
54 Fiocco U, et al. Early phenotypic activation of circulating helper memory T cells in scleroderma: correlation with disease activity. Annals of the Rheumatic Diseases 1993; 52:272-277.
53 Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 2007:56:334-44.
56 Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M. Increased expressionof TGF-beta receptors by scleroderma fibroblasts:evidence for contribution of autocrine TGF-beta signalling to scleroderma phenotype. J Invest Dermatol 1998; 110:47-51.
57 Agematsu K, Hokibara S, Nagumo H, Komiyama A. CD27:a memory B-cell marker. Immunol Today.2000 May;21(5):204-6.
58 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000; 165:5970-9.
5y Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
60 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
61 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004:50:1918-27.
62 Ng LG, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol.2004 Jul 15;173(2):807-17.
63 Rauch M, et al. Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells. PLoS ONE.2009;4(5):e5456. Epub 2009 May 6.
64 Carter RH, et al. Expression and Occupancy of BAFF-R on B Cells in Systemic Lupus Erythematosus. Arthritis Rheum.2005,52:3943-3954.
65 Matsushita T, et al. Elevated Serum BAFF Levels in Patients With Systemic Sclerosis:Enhanced BAFF Signaling in Systemic Sclerosis B Lymphocytes. Arthritis Rheum.2006,54:192-201.
66 刘翠杰等.系统性红斑狼疮病人外周血淋巴细胞CD38的表达.中国麻风皮肤病杂志.2001年9月第17卷第3期.162-163.
67 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000; 165:5970-9.
68 Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
69 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
1 Hayes MD, Lacey JV, Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D. Prevalence, incidence, survival and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:2246-2255.
2 Armando Gabrielli, M.D., Enrico V. Avvedimento, M.D., and Thomas Krieg, M.D. Mechanisms of Disease:Scleroderma. N Engl J Med 2009;360:1989-2003.
3 Denton CP et al. (2006) Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol 2:134-144.
4 Constans J, Gosse P, Pelegrin J-L, et al. Alteration of arterial distensibility in systemic scleorsis. J Int Med 1997;241:115-118.
5 Prescott RJ, Freemont AJ, Jones G, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992;166:255-63.
6 Perlish JS, Lemlich G, Fleischmajer R. Identification of collagen fibrils in scleroderma skin. J Invest Dermatol 1988;90:48-54.
7 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004;50:1918-27.
8 Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis:enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum.2006 Jan;54(1):192-201.
9 Duncan MR and Berman B (1991) Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin-6. J Invest Dermatol 97: 686-692.
10 Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996;22:709-35.
11 Zhou X et al. (2005) Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the 'scleroderma phenotype'. J Immunol 175: 4555-4560.
12 Carvalho D et al. (1996) IgG anti-endothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro:induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest 97:111-119.
13 Worda M et al. (2003) In vivo analysis of the apoptosisinducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorioallantoic membrane assay. Arthritis Rheum 48: 2605-2614.
14 Laplante P et al. (2005) Novel fibrogenic pathways are activated in response to endothelial apoptosis:implications in the pathophysiology of systemic sclerosis. J Immunol 174:5740-5749.
15 Baroni SS et al. (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667-2676.
16 Nishijima C et al. (2004) Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 138:357-363.
17 Kalogirou A, Gelou E, Zafiriou E, Mountantonakis S, Sakkas LI. Early T cell activation antigen in skin lesions in systemic sclerosis. Ann Rheum Dis 2003;62(Suppl 1):104.
18 Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen driven T cell disease? Arthritis Rheum 2004;50:1721-1733.
19 Sakkas LI et al. (1999) Increased levels of alternatively spliced interleukin 4 (IL-462) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn Lab Immunol 6: 660-664.
20 Fukasawa C et al. (2003) Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc):role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur J Immunol 33: 2792-2800.
21 Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease:the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol.2006 Dec;2(12):679-85.
22 Abraham DJ and Varga J (2005) Scleroderma:from cell and molecular mechanisms to disease models. Trends Immunol 26:587-595.
23 Kurasawa K et al. (2000) Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
24 Kurasawa K et al. (2000) Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
25 Fossiez F et al. (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
26 Murata M, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis:is systemic sclerosis a Th17 disease? J Dermatol Sci.2008 Jun;50(3):240-242.
27 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
28 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
29 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
30 Murata M, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis:is systemic sclerosis a Th17 disease? J Dermatol Sci.2008 Jun;50(3):240-242.
31 Deleuran B, Abraham DJ. Possible implication of the effector CD4+T-cell subpopulation TH17 in the pathogenesis of systemic scleroderma.Nat Clin Pract Rheumatol.2007 Dec;3(12):682-683.
I Armando Gabrielli, M.D., Enrico V. Avvedimento, M.D., and Thomas Krieg, M.D. Mechanisms of Disease:Scleroderma. N Engl J Med 2009;360:1989-2003.
3 唐福林主编.风湿免疫科医师效率手册.北京：中国协和医科大学出版社,2001.3：107-112.
4 Denton CP et al. (2006) Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol 2:134-144.
5 Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166:255-63.
0 Perlish JS, Lemlich G, Fleischmajer R. Identification of collagen fibrils in scleroderma skin. J Invest Dermatol 1988;90:48-54.
'Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen driven T cell disease? Arthritis Rheum 2004;50:1721-1733.
8 Kalogirou A, Gelou E, Zafiriou E, Mountantonakis S, Sakkas LI. Early T cell activation antigen in skin lesions in systemic sclerosis. Ann Rheum Dis 2003;62(Suppl 1):104.
9 Fukasawa C et al. Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc):role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur J Immunol 33: 2792-2800.
10 Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease:the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol.2006 Dec;2(12):679-85.
11 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
12 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
13 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
14 Miossec P. Interleukin-17 in rheumatoid arthritis:if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum 2003; 48:594-601.
15 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.
16 Kurasawa K et al. Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
17 Fossiez F et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
18 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
19 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
20 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.
21 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
22 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cells development by the transcription factor Foxp3. Science,2003,299:1057-1061.
" Roncador G et al. Analysis of FOXP3 protein expression in human CD4+CD25+regulatory T cells at the single-cell level. Eur J Immunol.2005 Jun;35(6):1681-91.
24 Agematsu K, Hokibara S, Nagumo H, Komiyama A. CD27:a memory B-cell marker. Immunol Today.2000 May;21(5):204-6.
25 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000;165:5970-9.
26 Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
27 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
28 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004;50:1918-27.
29 刘翠杰等.系统性红斑狼疮病人外周血淋巴细胞CD38的表达.中国麻风皮肤病杂志.2001年9月第17卷第3期.162-163.
30 Ng LG, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol.2004 Jul 15;173(2):807-17.
31 Rauch M, et al. Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells. PLoS ONE.2009;4(5):e5456. Epub 2009 May 6.
32 Carter RH, et al. Expression and Occupancy of BAFF-R on B Cells in Systemic Lupus Erythematosus. Arthritis Rheum.2005,52:3943-3954.
33 Matsushita T, et al. Elevated Serum BAFF Levels in Patients With Systemic Sclerosis:Enhanced BAFF Signaling in Systemic Sclerosis B Lymphocytes. Arthritis Rheum.2006,54:192-201.
34 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
35 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
36 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
37 Kotake S, Udagawa N, Takahashi N et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999; 103:1345-52.
38 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.
39 Kurasawa K et al. Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
40 Fossiez F et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
41 Fehervari Z, Sakaguchi S. CD4(+) Tregs and immune control. J Clin Invest 2004; 114(9):1209-1217.
42 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
43 Piccirillo CA, Thornton AM. Cornerstone of peripheral tolerance:naturally occurring CD4+CD25+ regulatory T cells. Trends Immunol 2004;25(7):374-380.
44 R.Y. Lan et al. Regulatory T cells:Development, function and role in autoimmunity. Autoimmunity Reviews 4 (2005) 351-363.
45 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol.2007 Apr;148(1):32-46.
46 Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21(4):589-601.
47 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cells development by the transcription factor Foxp3. Science,2003,299:1057-1061.
48 Roncador G et al. Analysis of FOXP3 protein expression in human CD4+CD25+regulatory T cells at the single-cell level. Eur J Immunol.2005 Jun;35(6):1681-91.
49 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.
50 Ehrenstein MR, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 2004;200(3):277-285.
51 Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2003;21(3):273-6.
52 Furuno K, et al. CD25+CD4+regulatory T cells in patients with Kawasaki disease. J Pediatr 2004;145(3):385-90.
53 Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002;109(1):131-40.
54 Fiocco U, et al. Early phenotypic activation of circulating helper memory T cells in scleroderma: correlation with disease activity. Annals of the Rheumatic Diseases 1993; 52:272-277.
53 Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 2007:56:334-44.
56 Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M. Increased expressionof TGF-beta receptors by scleroderma fibroblasts:evidence for contribution of autocrine TGF-beta signalling to scleroderma phenotype. J Invest Dermatol 1998; 110:47-51.
57 Agematsu K, Hokibara S, Nagumo H, Komiyama A. CD27:a memory B-cell marker. Immunol Today.2000 May;21(5):204-6.
58 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000; 165:5970-9.
5y Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
60 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
61 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004:50:1918-27.
62 Ng LG, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol.2004 Jul 15;173(2):807-17.
63 Rauch M, et al. Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells. PLoS ONE.2009;4(5):e5456. Epub 2009 May 6.
64 Carter RH, et al. Expression and Occupancy of BAFF-R on B Cells in Systemic Lupus Erythematosus. Arthritis Rheum.2005,52:3943-3954.
65 Matsushita T, et al. Elevated Serum BAFF Levels in Patients With Systemic Sclerosis:Enhanced BAFF Signaling in Systemic Sclerosis B Lymphocytes. Arthritis Rheum.2006,54:192-201.
66 刘翠杰等.系统性红斑狼疮病人外周血淋巴细胞CD38的表达.中国麻风皮肤病杂志.2001年9月第17卷第3期.162-163.
67 Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000; 165:5970-9.
68 Lindenau S, Scholze S, Odendahl M, Dorner T, Radbruch A, Burmester GR, Berek C. Aberrant activation of B cells in patients with rheumatoid arthritis. Ann N Y Acad Sci.2003 Apr;987:246-8. Review.
69 Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients withSjogren's syndrome. Arthritis Rheum 2002;46:2160-71.
1 Hayes MD, Lacey JV, Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D. Prevalence, incidence, survival and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:2246-2255.
2 Armando Gabrielli, M.D., Enrico V. Avvedimento, M.D., and Thomas Krieg, M.D. Mechanisms of Disease:Scleroderma. N Engl J Med 2009;360:1989-2003.
3 Denton CP et al. (2006) Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol 2:134-144.
4 Constans J, Gosse P, Pelegrin J-L, et al. Alteration of arterial distensibility in systemic scleorsis. J Int Med 1997;241:115-118.
5 Prescott RJ, Freemont AJ, Jones G, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992;166:255-63.
6 Perlish JS, Lemlich G, Fleischmajer R. Identification of collagen fibrils in scleroderma skin. J Invest Dermatol 1988;90:48-54.
7 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis:expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 2004;50:1918-27.
8 Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis:enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum.2006 Jan;54(1):192-201.
9 Duncan MR and Berman B (1991) Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin-6. J Invest Dermatol 97: 686-692.
10 Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996;22:709-35.
11 Zhou X et al. (2005) Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the 'scleroderma phenotype'. J Immunol 175: 4555-4560.
12 Carvalho D et al. (1996) IgG anti-endothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro:induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest 97:111-119.
13 Worda M et al. (2003) In vivo analysis of the apoptosisinducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorioallantoic membrane assay. Arthritis Rheum 48: 2605-2614.
14 Laplante P et al. (2005) Novel fibrogenic pathways are activated in response to endothelial apoptosis:implications in the pathophysiology of systemic sclerosis. J Immunol 174:5740-5749.
15 Baroni SS et al. (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667-2676.
16 Nishijima C et al. (2004) Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 138:357-363.
17 Kalogirou A, Gelou E, Zafiriou E, Mountantonakis S, Sakkas LI. Early T cell activation antigen in skin lesions in systemic sclerosis. Ann Rheum Dis 2003;62(Suppl 1):104.
18 Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen driven T cell disease? Arthritis Rheum 2004;50:1721-1733.
19 Sakkas LI et al. (1999) Increased levels of alternatively spliced interleukin 4 (IL-462) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn Lab Immunol 6: 660-664.
20 Fukasawa C et al. (2003) Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc):role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur J Immunol 33: 2792-2800.
21 Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease:the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol.2006 Dec;2(12):679-85.
22 Abraham DJ and Varga J (2005) Scleroderma:from cell and molecular mechanisms to disease models. Trends Immunol 26:587-595.
23 Kurasawa K et al. (2000) Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
24 Kurasawa K et al. (2000) Increased IL-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455-2463.
25 Fossiez F et al. (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593-2603.
26 Murata M, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis:is systemic sclerosis a Th17 disease? J Dermatol Sci.2008 Jun;50(3):240-242.
27 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
28 吴长有.Th17细胞：一种新的效应CD4+T细胞亚群.细胞与分子免疫学杂志.2006,22(6),695-697.
29 Hoeve MA, de Savage ND, BT et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006; 36:661-70.
30 Murata M, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis:is systemic sclerosis a Th17 disease? J Dermatol Sci.2008 Jun;50(3):240-242.
31 Deleuran B, Abraham DJ. Possible implication of the effector CD4+T-cell subpopulation TH17 in the pathogenesis of systemic scleroderma.Nat Clin Pract Rheumatol.2007 Dec;3(12):682-683.