SLE患者外周血单个核细胞雌激素受体、IL-10和IFN-γmRNA表达异常的研究及其相关性分析
|
摘要
目的：
检测系统性红斑狼疮患者未经刺激外周血单个核细胞雌激素受体，IL-10和IFN-γmRNA的表达水平并分析其相关性，探讨其在狼疮发病中的作用。
方法：
分离25例系统性红斑狼疮患者和15例正常人新鲜外周血单个核细胞，提取总RNA，利用半定量RT-PCR方法逆转录并扩增雌激素受体，IL-10和IFN-γ，通过凝胶图像扫描系统对PCR产物的电泳条带进行密度扫描。
结果：
1 病例组PBMCsER和IL-10mRNA表达水平高于正常对照组(P＜0.01)。SLE肾炎组和非肾炎组ER和IL 10mRNA表达水平均比对照组高(P＜0.05)。SLE肾炎组均稍高于非肾炎组，但差异没有统计学意义。
2 病例组PBMCsIFN-γmRNA表达水平高于正常对照组(P＜0.05)。SLE肾炎组IFN-γmRNA表达水平高于非肾炎组和正常对照组(P＜0.01)。SLE非肾炎组和正常对照组没有明显差别。
3 病例组PBMCsER(r=0.176，P＞0.05)，IL-10(r=0.197，P＞0.05)和IFN-γ(r=0.172，P＞0.05)mRNA表达水平与患者疾病活动指数均不相关。
4 病例组r=0.442(P＜0.05)和对照组r=0.557(P＜0.05)PBMCsERmRNA表达水平与IL-10mRNA表达水平均呈正相关。
天津医科大学硕士学位论文
5病例组产0.195(尸>0.05)和对照组r=0.169护)0.05)PBMCsERn1RNA
表达水平与IFN一YmRNA表达水平均不相关。
6病例组PBMCsIL一10(r=0.298，尸>0.05)和ER(厂0.193，尸>0.05)
mRNA表达水平与血清IgG均不相关。
结论:
SLE患者外周血单个核细胞存在雌激素受体，IL一10和IFN一YmRNA表达
异常，IL一10表达的上调可能与雌激素受体有关，这可能是性激素影响细胞因
子的作用机制之一。过量的IL一10和IFN一Y可能导致了SLE患者B细胞产生
大量自身抗体。IFN一Y产生的增高可能触发了炎症反应的发生，在狼疮肾炎发
生过程中起重要作用。
Objective:
To examine the mRNA expression of estrogen receptor, IL10 and IFN-y in unstimulated peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) and analyze their correlations, to investigate the role of estrogen receptor, IL10 and IFN-y in the pathogenesis of SLE.
Methods:
Isolating the fresh PBMCs from 25 women with SLE and 15 healthy women and extracting the total RNA followly. Then the mRNA expression of estrogen receptor, IL10 and IFN-y were measured semi quantitatively by reverse transcriptase-polymerase chain reaction (RT-PCR).
Results:
1. The mRNA expression of estrogen receptor and IL-10 in PBMCs of patients with SLE was significantly higher than that of healthy controls (P<0.01). There was no defference of the mRNA expression of estrogen receptor and IL-10 in PBMCs between SLE patients with nephritis and SLE patients without nephritis, though the former was higher than the latter, and both of them were higher than healthy controls (P<0.05).
2. The mRNA expression of IFN-y in PBMCs of patients with SLE was higher than that of healthy controls (.P<0.05) and that of SLE patients with nephritis was
higher than that of SLE patients without nephritis (P<0.01), There was no defference of the mRNA expression of IFN-y in PBMCs between SLE patients without nephritis and healthy controls.
3. There was no correlation between the mRNA expression of estrogen receptor and SLEDAI in patients with SLE, neither between IL-10 and SLEDAI, IFN-Y and SLEDAI.
4. There was positive correlation between the mRNA expression of estrogen receptor and IL-10 in patients with SLE (r=0.442, P<0.05) or healthy controls (r=0.557, />0.05).
5. There was no correlation between the mRNA expression of estrogen receptor and IFN-y in patients with SLE or healthy controls.
6. There was no correlation between the mRNA expression of estrogen receptor and the serum IgG in patients with SLE, nether between IL-10 and IgG.
Conclusion:
Our present findings suggest that there were mRNA expression of estrogen receptor, IL-10 and IFN-y abnormalities in patients with SLE. The expression of IL-10 maybe up-regulate by estrogen receptor and maybe that was one of the mechanisms how hormone affect the production of cytokines. Excessive IL-10 and IFN-y maybe resulte in autoantibody production by B cells in human SLE. The enhanced production of IFN-y by mononuclear cells may trigger inflammatory responses involving in the pathogenesis of SLE nephritis.
检测系统性红斑狼疮患者未经刺激外周血单个核细胞雌激素受体，IL-10和IFN-γmRNA的表达水平并分析其相关性，探讨其在狼疮发病中的作用。
方法：
分离25例系统性红斑狼疮患者和15例正常人新鲜外周血单个核细胞，提取总RNA，利用半定量RT-PCR方法逆转录并扩增雌激素受体，IL-10和IFN-γ，通过凝胶图像扫描系统对PCR产物的电泳条带进行密度扫描。
结果：
1 病例组PBMCsER和IL-10mRNA表达水平高于正常对照组(P＜0.01)。SLE肾炎组和非肾炎组ER和IL 10mRNA表达水平均比对照组高(P＜0.05)。SLE肾炎组均稍高于非肾炎组，但差异没有统计学意义。
2 病例组PBMCsIFN-γmRNA表达水平高于正常对照组(P＜0.05)。SLE肾炎组IFN-γmRNA表达水平高于非肾炎组和正常对照组(P＜0.01)。SLE非肾炎组和正常对照组没有明显差别。
3 病例组PBMCsER(r=0.176，P＞0.05)，IL-10(r=0.197，P＞0.05)和IFN-γ(r=0.172，P＞0.05)mRNA表达水平与患者疾病活动指数均不相关。
4 病例组r=0.442(P＜0.05)和对照组r=0.557(P＜0.05)PBMCsERmRNA表达水平与IL-10mRNA表达水平均呈正相关。
天津医科大学硕士学位论文
5病例组产0.195(尸>0.05)和对照组r=0.169护)0.05)PBMCsERn1RNA
表达水平与IFN一YmRNA表达水平均不相关。
6病例组PBMCsIL一10(r=0.298，尸>0.05)和ER(厂0.193，尸>0.05)
mRNA表达水平与血清IgG均不相关。
结论:
SLE患者外周血单个核细胞存在雌激素受体，IL一10和IFN一YmRNA表达
异常，IL一10表达的上调可能与雌激素受体有关，这可能是性激素影响细胞因
子的作用机制之一。过量的IL一10和IFN一Y可能导致了SLE患者B细胞产生
大量自身抗体。IFN一Y产生的增高可能触发了炎症反应的发生，在狼疮肾炎发
生过程中起重要作用。
Objective:
To examine the mRNA expression of estrogen receptor, IL10 and IFN-y in unstimulated peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) and analyze their correlations, to investigate the role of estrogen receptor, IL10 and IFN-y in the pathogenesis of SLE.
Methods:
Isolating the fresh PBMCs from 25 women with SLE and 15 healthy women and extracting the total RNA followly. Then the mRNA expression of estrogen receptor, IL10 and IFN-y were measured semi quantitatively by reverse transcriptase-polymerase chain reaction (RT-PCR).
Results:
1. The mRNA expression of estrogen receptor and IL-10 in PBMCs of patients with SLE was significantly higher than that of healthy controls (P<0.01). There was no defference of the mRNA expression of estrogen receptor and IL-10 in PBMCs between SLE patients with nephritis and SLE patients without nephritis, though the former was higher than the latter, and both of them were higher than healthy controls (P<0.05).
2. The mRNA expression of IFN-y in PBMCs of patients with SLE was higher than that of healthy controls (.P<0.05) and that of SLE patients with nephritis was
higher than that of SLE patients without nephritis (P<0.01), There was no defference of the mRNA expression of IFN-y in PBMCs between SLE patients without nephritis and healthy controls.
3. There was no correlation between the mRNA expression of estrogen receptor and SLEDAI in patients with SLE, neither between IL-10 and SLEDAI, IFN-Y and SLEDAI.
4. There was positive correlation between the mRNA expression of estrogen receptor and IL-10 in patients with SLE (r=0.442, P<0.05) or healthy controls (r=0.557, />0.05).
5. There was no correlation between the mRNA expression of estrogen receptor and IFN-y in patients with SLE or healthy controls.
6. There was no correlation between the mRNA expression of estrogen receptor and the serum IgG in patients with SLE, nether between IL-10 and IgG.
Conclusion:
Our present findings suggest that there were mRNA expression of estrogen receptor, IL-10 and IFN-y abnormalities in patients with SLE. The expression of IL-10 maybe up-regulate by estrogen receptor and maybe that was one of the mechanisms how hormone affect the production of cytokines. Excessive IL-10 and IFN-y maybe resulte in autoantibody production by B cells in human SLE. The enhanced production of IFN-y by mononuclear cells may trigger inflammatory responses involving in the pathogenesis of SLE nephritis.
引文
1 Rood M J, Van Der Veide E A, Ten Cate R, et al. Female sex hormones at the onset of systemic lupus erythematosus affect survival. Br J Rheumatol. 1998; 37(9): 1008-1010.
2 Wilder R L. Neuroimmunoendocrinology of the rheumatic diseases: past, present, and future. Ann N Y Acad Sci, 2002; 966: 13-19.
3 Askanase A D, Buyon J P. Reproductive health in SLE. Best Pratt Res Clin Rheumatol, 2002; 16(2): 265-280.
4 Suenaga R, Mitamura K, Evans M J, Abdou N I. Binding affinity and quantity of estrogen receptor in peripheral blood monocytes of patients with systemic lupus erythematosus. Lupus 1996; 5(3): 227-231.
5 Tsai M-J, Clark J M, Schrader W T, O'Malley B M. Mechanisms of action of hormones that act as transcription-regulatory factors. In: Wilson J D, Foster D W, Kronengerg H M, Larsen P R (eds). Williams Textbook of Endocrinology. W, B. Saunders: Philadelphia, PA, 1998, pp 55-94.
6 Kanda N, Tsuchida T, Tamaki K. Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patiente with systemic lupus erythematosus. Arhritis Rheum. 1999; 42(2): 328-337.
7 Karpuzoglu-Sahin E, Hissong B D, Ansar Ahmed S. Interferon-gamma level are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol, 2001; 52(1-2): 113-127.
8 Pottratz S T, Bellido T, Mocharla H, et al. 17beta-Estrodiol inhibits epression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest. 1994; 93(3): 944-950.
9 Sthoeger Z M, Zinger H, Mozes E. Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies. Ann Rheum Dis, 2003; 62(4): 341-346.
10 Csiszar A, Nagy, G, Gergely P. Increased interferon-gamma, IL-10 and decreased IL-4 mRNA expression in peripheral Blood mononuclear cells from patients with systemic lupus erythematosus. Clin Exp Immunol. 2000; 122(3): 464-470.
11 Chang D M, Su W L, Chu S J. The expression and significance of intracellular T helper cytokines in systemic lupus erythematosus. Immunol Invest. 2002; 31(1): 1-12.
12 Brenner C A, Tam A W, Nelson P A, et al. Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Biotechniques. 1989; 7(10): 1096-1103.
13 Kozbor D, Hyjek E, Wiaderkiewicz R, er al. Competitor mRNA fragments for quantitation of cytokine specific transcripts in cell lysates. Mol Immunol. 1993; 30(1): 1-7.
14 张乃峥．临床风湿病学．上海科学技术出版社．第一版．1999：201．
15 Nilsen E M, Krajci P, Scott H, Brandtzaeg P. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37(6): 766-776.
16 Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum. 1997; 40(5): 797-803.
17 Roubinian J, Talal N, Siiteri P K, et al. Sex hormone modulation of autoimmunity in NZB/NZW mice. Arthritis Rheum. 1979; 22(11): 1162-1169.
18 Folomeev M, Dougados M, Beaune J, et al. Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus. 1992; 1(3): 191-195.
19 武革，沈更新等．女性系统性红斑狼疮患者血清泌乳素与性激素水平关系的探讨．临床内科杂志．1999；16(3)：142-143．
20 张敏，张谊之等．女性SLE患者血清性激素水平研究．临床皮肤科杂志．2000：29(5)：269-270．
21 Cutolo M, Accardo S. Sex hormones, HLA and rheumatoid arthritis. Clin Exp Rheumatol. 1991;9(6): 641-646.
22 McMurray R W. Prolactin in murine systemic lupus erythematosus. Lupus. 2001; 10(10): 742-747.
23 Lahita R G. The role of sex hormones in SLE. Curr Opin Rheumatol. 1999; 11(5): 352-356.
24 McMurray R W, Keisler D, Izui S. Effects of parturition, suckling and pseudopregnancy on variables of disease activity in the B/W mouse model of systemic lupus erythematosus. J Rheumatol. 1993; 20(7): 1143-1151.
25 Suenaga R, Evans M J, Mitamura K, et al. Peripheral blood T cells and monocytes and B
cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998; 25(7): 1305-12.
26 Stimson WH. Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol. 1988; 28(3): 345-350.
27 Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol. 1998; 161(7): 3365-3374.
28 Bebo BF Jr, Schuster JC, Vandenbark AA, et al. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol. 1999; 162(1): 35-40.
29 Heery DM, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997; 387(6634): 733-736.
30 Gaub MP, Bellard M, Scheuer I, et al. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell. 1990; 63(6): 1267-1276.
31 张晓，陈顺乐．正常女性与女性SLE患者白细胞中雌激素受体含量比较．中山医科大学学报．1992；13(4)：73-74．
32 张晓，陈顺乐．SLE患者雌激素受体与睾酮及泌乳素的相关性研究．中山医科大学学报．1995：16(1)：63-65．
33 杜乾君，朱武．女性系统性红斑狼疮外周血单个核细胞雌激素受体及CD8抗原表达．中国现代医学杂志．2000，10(5)：15-16．
34 Roa R, Greenstein BD. Evidence for pleomorphism of estrogen receptor capacity and affinity in liver and thymus of immature BALB/c and (NZBxNZW) F1 mice, a model of systemic lupus erythematosus. Int J Immunopharmacol. 2000; 22(11): 897-903.
35 Lee SH. Validity of a histochemical estrogen receptor assay. Supported by the observation of a cellular response to steroid manipulation.J Histochem Cytochem. 1984; 32(3): 305-310.
36 Fishman J, Martucci C. Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab. 1980; 51(3): 611-615.
37 Jones S K. The effects of hormonal and other stimuli on cell-surface Ro/SSA antigen expression by human keratinocytes in vitro: their possible role in the induction of cutaneous lupus lesions.Br J Dermatol. 1992; 126(6): 554-560.
38 Shah N N, Faaland C A, Thomas T, et al. Estradiol analogues and polyamines alter the binding affinity of estrogen receptor(ER) with estrogen response element(ERE): Potential
implications for estrogenic action in lupus. Arthritis Rheum. 1996, 36(Suppl.): S109.
39 Lakshminarayanan S, Walsh S, Mohanraj M, et al. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus.J Rheumatol. 2001; 28(1): 102-108.
40 Funauchi M, Ikoma S, Enomoto H, et al. Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosus. Scand J Rheumatol. 1998; 27(3): 219-224.
41 Kruse N, Greif M, Moriabadi NF et al. Variations in cytokine mRNA expression during normal human pregnancy. Clin Exp Immunol. 2000; 119(2): 317-322.
42 Lazarus M, Hajeer AH, Turner D, et al. Genetic variation in the interleukin-10 gene promoter and systemic Iupus erythematosus. J Rheumatol. 1997; 24(12): 2314-2317.
43 Sanchez-Gurrero J, Karlson EW, Liang MH, et al. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum. 1997; 40(5): 804-808.
44 Walker P, Germond JE, Brown-Luedi M, et al. Sequence homologies in the region preceding the transcription initiation site of the liver estrogen-responsive vitellogenin and apoVLDⅡgenes. Nucletic Acids Res. 1984; 12(22): 8611-8626.
45 Beato M. Gene regulation by steroid hormones. Cell. 1989; 56(3): 335-344.
46 International Immunophamarmacology. 2001; 1(6): 983-93.
47 Carlsten H, Tarkowski A, Holmdahl R, et al. Oestrogen is a potent disease accelerator in SLE-prone MRL 1pr/Ipr mice. Clin Exp Immunol. 1990; 80(3): 467-473.
48 Kanda N, Tamaki K. Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999; 103(2 pt 1): 282-288.
49 Llorente L, Zon W, Lewy Y, et al. Role of interleukin-10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995; 181(3): 839-844.
50 Masutani K, Akahoshi M, Tsuruya K, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 2001; 44(9): 2097-2106.
51 Duits AJ, Bootsma H, Derksen RH, et al. Skewed distribution of IgG Fc receptor Ⅱa(CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995; 38(12): 1832-1836.
52 Ozmen L, Roman D, Fountoulakis M, et al. Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-γ receptor inhibits
the onset of glomerulonephritis. Eur J Immunol. 1995; 25(1): 6-12.
53 al-Janadi M, al-Balla S, al-Dalaan A, et al. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases.J Clin Immunol. 1993; 13(1): 58-67.
54 Masutani K, Akahoshi M, Tsuruya K, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum 2001; 44(9): 2097-2106.
55 Uhm WS, Na K, Song GW, et al. Cytokine balance in kidney tissue from lupus nephritis patients. Rheumatology(Oxford), 2003; 42(8): 935-938.
56 Mohan C, Shi Y, Laman JD, et al. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995; 154(3): 1470-1480.
57 Takahashi S, Fossati L, Iwamoto M, et al. Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest. 1996; 97(7): 1597-1604.
58 Huygen K, Palfliet K. Strain variation in interferon γ production of BCG-sensitized mice challenged with PPD. Cell Immunol. 1984; 85(1): 75-81.
59 Karpuzoglu-Sahin E, Hissong BD, Ansar Ahmed S. Interferon -gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol. 2001; 52(1-2): 113-127.
60 Fox HS, Bond BL, Parslow TG. Estrogen regulates the IF/q-γ promoter. J Immunol. 1991; 146(12): 4362-4367.
61 Matejuk A, Dwyer J, Zamora A et al. Evaluation of the 17beta-estradiol(17beta-E_2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray. Endocrinology. 2002; 143(1): 313-319.
62 Lelievre E, Sarrouilhe D, Morel F, et al. Preincubation of human resting T cell clones with interleukin 10 strongly enhances their ability to produce cytokines after stimulation. Cytokine. 1998; 10(11): 831-840.
63 Rider V, Foster RT, Evans M, et al. Gender differences in autoimmune disease: estrogen increases calcineurin expression in systemic lupus erythematosus. Clin Immunol Immunopathol. 1998; 89(2): 171-180.
2 Wilder R L. Neuroimmunoendocrinology of the rheumatic diseases: past, present, and future. Ann N Y Acad Sci, 2002; 966: 13-19.
3 Askanase A D, Buyon J P. Reproductive health in SLE. Best Pratt Res Clin Rheumatol, 2002; 16(2): 265-280.
4 Suenaga R, Mitamura K, Evans M J, Abdou N I. Binding affinity and quantity of estrogen receptor in peripheral blood monocytes of patients with systemic lupus erythematosus. Lupus 1996; 5(3): 227-231.
5 Tsai M-J, Clark J M, Schrader W T, O'Malley B M. Mechanisms of action of hormones that act as transcription-regulatory factors. In: Wilson J D, Foster D W, Kronengerg H M, Larsen P R (eds). Williams Textbook of Endocrinology. W, B. Saunders: Philadelphia, PA, 1998, pp 55-94.
6 Kanda N, Tsuchida T, Tamaki K. Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patiente with systemic lupus erythematosus. Arhritis Rheum. 1999; 42(2): 328-337.
7 Karpuzoglu-Sahin E, Hissong B D, Ansar Ahmed S. Interferon-gamma level are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol, 2001; 52(1-2): 113-127.
8 Pottratz S T, Bellido T, Mocharla H, et al. 17beta-Estrodiol inhibits epression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest. 1994; 93(3): 944-950.
9 Sthoeger Z M, Zinger H, Mozes E. Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies. Ann Rheum Dis, 2003; 62(4): 341-346.
10 Csiszar A, Nagy, G, Gergely P. Increased interferon-gamma, IL-10 and decreased IL-4 mRNA expression in peripheral Blood mononuclear cells from patients with systemic lupus erythematosus. Clin Exp Immunol. 2000; 122(3): 464-470.
11 Chang D M, Su W L, Chu S J. The expression and significance of intracellular T helper cytokines in systemic lupus erythematosus. Immunol Invest. 2002; 31(1): 1-12.
12 Brenner C A, Tam A W, Nelson P A, et al. Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Biotechniques. 1989; 7(10): 1096-1103.
13 Kozbor D, Hyjek E, Wiaderkiewicz R, er al. Competitor mRNA fragments for quantitation of cytokine specific transcripts in cell lysates. Mol Immunol. 1993; 30(1): 1-7.
14 张乃峥．临床风湿病学．上海科学技术出版社．第一版．1999：201．
15 Nilsen E M, Krajci P, Scott H, Brandtzaeg P. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37(6): 766-776.
16 Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum. 1997; 40(5): 797-803.
17 Roubinian J, Talal N, Siiteri P K, et al. Sex hormone modulation of autoimmunity in NZB/NZW mice. Arthritis Rheum. 1979; 22(11): 1162-1169.
18 Folomeev M, Dougados M, Beaune J, et al. Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus. 1992; 1(3): 191-195.
19 武革，沈更新等．女性系统性红斑狼疮患者血清泌乳素与性激素水平关系的探讨．临床内科杂志．1999；16(3)：142-143．
20 张敏，张谊之等．女性SLE患者血清性激素水平研究．临床皮肤科杂志．2000：29(5)：269-270．
21 Cutolo M, Accardo S. Sex hormones, HLA and rheumatoid arthritis. Clin Exp Rheumatol. 1991;9(6): 641-646.
22 McMurray R W. Prolactin in murine systemic lupus erythematosus. Lupus. 2001; 10(10): 742-747.
23 Lahita R G. The role of sex hormones in SLE. Curr Opin Rheumatol. 1999; 11(5): 352-356.
24 McMurray R W, Keisler D, Izui S. Effects of parturition, suckling and pseudopregnancy on variables of disease activity in the B/W mouse model of systemic lupus erythematosus. J Rheumatol. 1993; 20(7): 1143-1151.
25 Suenaga R, Evans M J, Mitamura K, et al. Peripheral blood T cells and monocytes and B
cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998; 25(7): 1305-12.
26 Stimson WH. Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol. 1988; 28(3): 345-350.
27 Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol. 1998; 161(7): 3365-3374.
28 Bebo BF Jr, Schuster JC, Vandenbark AA, et al. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol. 1999; 162(1): 35-40.
29 Heery DM, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997; 387(6634): 733-736.
30 Gaub MP, Bellard M, Scheuer I, et al. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell. 1990; 63(6): 1267-1276.
31 张晓，陈顺乐．正常女性与女性SLE患者白细胞中雌激素受体含量比较．中山医科大学学报．1992；13(4)：73-74．
32 张晓，陈顺乐．SLE患者雌激素受体与睾酮及泌乳素的相关性研究．中山医科大学学报．1995：16(1)：63-65．
33 杜乾君，朱武．女性系统性红斑狼疮外周血单个核细胞雌激素受体及CD8抗原表达．中国现代医学杂志．2000，10(5)：15-16．
34 Roa R, Greenstein BD. Evidence for pleomorphism of estrogen receptor capacity and affinity in liver and thymus of immature BALB/c and (NZBxNZW) F1 mice, a model of systemic lupus erythematosus. Int J Immunopharmacol. 2000; 22(11): 897-903.
35 Lee SH. Validity of a histochemical estrogen receptor assay. Supported by the observation of a cellular response to steroid manipulation.J Histochem Cytochem. 1984; 32(3): 305-310.
36 Fishman J, Martucci C. Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab. 1980; 51(3): 611-615.
37 Jones S K. The effects of hormonal and other stimuli on cell-surface Ro/SSA antigen expression by human keratinocytes in vitro: their possible role in the induction of cutaneous lupus lesions.Br J Dermatol. 1992; 126(6): 554-560.
38 Shah N N, Faaland C A, Thomas T, et al. Estradiol analogues and polyamines alter the binding affinity of estrogen receptor(ER) with estrogen response element(ERE): Potential
implications for estrogenic action in lupus. Arthritis Rheum. 1996, 36(Suppl.): S109.
39 Lakshminarayanan S, Walsh S, Mohanraj M, et al. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus.J Rheumatol. 2001; 28(1): 102-108.
40 Funauchi M, Ikoma S, Enomoto H, et al. Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosus. Scand J Rheumatol. 1998; 27(3): 219-224.
41 Kruse N, Greif M, Moriabadi NF et al. Variations in cytokine mRNA expression during normal human pregnancy. Clin Exp Immunol. 2000; 119(2): 317-322.
42 Lazarus M, Hajeer AH, Turner D, et al. Genetic variation in the interleukin-10 gene promoter and systemic Iupus erythematosus. J Rheumatol. 1997; 24(12): 2314-2317.
43 Sanchez-Gurrero J, Karlson EW, Liang MH, et al. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum. 1997; 40(5): 804-808.
44 Walker P, Germond JE, Brown-Luedi M, et al. Sequence homologies in the region preceding the transcription initiation site of the liver estrogen-responsive vitellogenin and apoVLDⅡgenes. Nucletic Acids Res. 1984; 12(22): 8611-8626.
45 Beato M. Gene regulation by steroid hormones. Cell. 1989; 56(3): 335-344.
46 International Immunophamarmacology. 2001; 1(6): 983-93.
47 Carlsten H, Tarkowski A, Holmdahl R, et al. Oestrogen is a potent disease accelerator in SLE-prone MRL 1pr/Ipr mice. Clin Exp Immunol. 1990; 80(3): 467-473.
48 Kanda N, Tamaki K. Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999; 103(2 pt 1): 282-288.
49 Llorente L, Zon W, Lewy Y, et al. Role of interleukin-10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995; 181(3): 839-844.
50 Masutani K, Akahoshi M, Tsuruya K, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 2001; 44(9): 2097-2106.
51 Duits AJ, Bootsma H, Derksen RH, et al. Skewed distribution of IgG Fc receptor Ⅱa(CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995; 38(12): 1832-1836.
52 Ozmen L, Roman D, Fountoulakis M, et al. Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-γ receptor inhibits
the onset of glomerulonephritis. Eur J Immunol. 1995; 25(1): 6-12.
53 al-Janadi M, al-Balla S, al-Dalaan A, et al. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases.J Clin Immunol. 1993; 13(1): 58-67.
54 Masutani K, Akahoshi M, Tsuruya K, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum 2001; 44(9): 2097-2106.
55 Uhm WS, Na K, Song GW, et al. Cytokine balance in kidney tissue from lupus nephritis patients. Rheumatology(Oxford), 2003; 42(8): 935-938.
56 Mohan C, Shi Y, Laman JD, et al. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995; 154(3): 1470-1480.
57 Takahashi S, Fossati L, Iwamoto M, et al. Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest. 1996; 97(7): 1597-1604.
58 Huygen K, Palfliet K. Strain variation in interferon γ production of BCG-sensitized mice challenged with PPD. Cell Immunol. 1984; 85(1): 75-81.
59 Karpuzoglu-Sahin E, Hissong BD, Ansar Ahmed S. Interferon -gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol. 2001; 52(1-2): 113-127.
60 Fox HS, Bond BL, Parslow TG. Estrogen regulates the IF/q-γ promoter. J Immunol. 1991; 146(12): 4362-4367.
61 Matejuk A, Dwyer J, Zamora A et al. Evaluation of the 17beta-estradiol(17beta-E_2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray. Endocrinology. 2002; 143(1): 313-319.
62 Lelievre E, Sarrouilhe D, Morel F, et al. Preincubation of human resting T cell clones with interleukin 10 strongly enhances their ability to produce cytokines after stimulation. Cytokine. 1998; 10(11): 831-840.
63 Rider V, Foster RT, Evans M, et al. Gender differences in autoimmune disease: estrogen increases calcineurin expression in systemic lupus erythematosus. Clin Immunol Immunopathol. 1998; 89(2): 171-180.