TRAIL在Graves’病发病机制中作用的初步研究
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摘要
肿瘤坏死因子相关凋亡诱导配体(TNF related apoptosis inducing ligand,TRAIL,Apo-2L)为肿瘤坏死因子超家族的成员，同TNF-α和Fas配体(FasL)一样都属Ⅱ型跨膜蛋白，都有膜型及可溶型两种形式，都通过Ⅰ型跨膜蛋白受体胞质内的DD传导凋亡信号，在机体的免疫调节和肿瘤细胞凋亡及维护机体组织细胞稳态方面起重要的作用。自身免疫性甲状腺疾病(AITD)属器官特异性自身免疫病，主要包括Graves'病和桥本氏甲状腺炎。在这些疾病中细胞凋亡是一很重要的病理过程，而被受人们的关注。
目的：
(1)观察TRAIL在外周血单个核细胞(PBMC)中的表达。(2)检测经不同浓度T_3刺激后，体外培养的人外周血淋巴细胞TRAIL表达的及淋巴细胞的凋亡情况。(3)检测Graves病患者血清中可溶型TRAIL的。
方法：
1．免疫组织化学检测PBMC中TRAIL的表达情况。
2．流式细胞仪检测经不同浓度T_3(1×10~(-12)～1×10~8)刺激后淋巴细胞表面TRAIL的表达其凋亡。
3．收集50例Graves病患者、22例原发性甲状腺功能减低症(甲减)患者与40例健康人的血清标本，用酶联免疫吸附法(ELISA)
第四军医大学硕士学位论文
测定血清中的sTRAIL，同时测定患者的T3、T4、TSH、TGA七、
仰OAb水平。
结果:
1密度梯度离心法得到的PBMC中，TRAIL免疫反应阳性物
质分布于胞质内，核呈阴性反应。分离的PBMC中淋巴细胞占97.48
士3.43%，单核细胞占3.15土0.83%，TRAIL免疫反应阳性的淋巴
细胞占总数的26.31士3.18%，TRAIL免疫反应阳性的单核细胞
占总数的1.04士0.13%。
2 T3刺激后淋巴细胞TRAIL的表达情况
体外培养的人外周血淋巴细胞在1.0x10一，Zmo比与1.ox
10一“mo巩浓度T3刺激下，TRAIL表达率分别为16.78士3.84%、
18.n士3.04%，随着浓度的增加，TRAIL表达率明显增加，在毛
为1.0X10一10mo讥、1.Ox10、OUL与1.0xl0旧mo比时淋巴细
胞的TRAIL表达率分别为23.03士2.28%、28.01士1.37%、32.43
士3. 96%，其表达率于各浓度间差异明显(P<0.01)。
3 T3刺激后淋巴细胞的凋亡情况
体外培养的人外周血淋巴细胞在T3浓度为伪mOUL、1.ox
10一，ZmoFL、1 .0 X 10一“moUL、1.0 X 10一moljL、1.0X10一moFL
的刺激下其凋亡率分别为5.1士0.89%、12.53士2.00%、15.51士
2.45%、18.66士1.02%、22.76士2.43%、28.76士3.32%，各浓
度间差异明显(P<0.01)。
4血清sTRAIL检测结果
Graves病患者中的sTRAIL平均水平为2.23士0.46ng/m1，正
常对照组为0.80士0.07ng/ml，甲减组为1.02士1.45ng/m1。方差
分析结果示:组间存在统计学差异(F=5.54，P=0.005);组间比
较:Graves病组高于正常对照组(P二0.003)与甲减组(P=0.019)，
甲减组与正常对照组无差异(P二0.71)。三组间OR4及ORS未见
统计学差异。
结论:
l免疫组织化学SABC染色法显示正常人外周血分离的淋巴细胞
第四军医大学硕士学位论文
及单核细胞有TRA儿表达。
2一定浓度T3可以促进淋巴细胞TRAIL的表达及并促进其凋亡。
3 Graves病患者血清中sTRAIL水平明显升高。
至于T3促进淋巴细胞TRAIL的表达及凋亡的意义以及Graves
病sTRAIL升高的机制，有待深入研究。
TRAIL (Apo-2L) is one of members of the TNF super-family. Just like TNF-a and FasL, it belongs to type II membrane-bound protein, and has both membrane-bound and soluble forms and acts through type I membrane receptors that signal apoptosis through a cytoplasmic death domain, as the apoptosis plays an pivotal role in maintaining homeostasis of tissues. Autoimmune thyroid disease (AFTD) includes Graves' disease and Hashimoto' thyroiditis, while apoptosis has an important role in the pathogenesis of this kind of disease. Objects
(1)To observe the expression of TRAIL in PBMCs. (2) To investigate the level of serum soluble TRAIL in Graves' patients. (3).To investigate the expression of TRAIL on lymphocytes, and (4).To understand the effect of Triiodothyronine (T3) in different concentrations on the apoptosis of lymphocyte in vitro. Methods
The TRAIL immunoreactive substance was observed in PB
MCs hnmunohistochemically. Expression of TRAIL and apoptosis
of lymphocytes were tested by Flow cytometric analysis. Serum
soluble TRAIL was measured with sandwich enzyme-linked im
munosorbent assay in patients with Graves' disease (n=50), Prim ary hypothyroidism (n=22) and controls(n=40). At the same time,
T3, T4, TSH, TGAb and TPOAb were examined in all patients.
Results
1. The expression of TRAIL on PBMC :
The immunoreactive positive substance distributed in cytoplas ma, while it was negative on nuclei. The percentage of lymphoc yte and monocyte among PBMC were 97.48?.43% and 3.15 + 0.83 % respectively. The ratio of TRAIL immunoreactive lymphoc yte was 26.31+3.18)%, while that of monocytes was 1.04+0.13
2. The Effect of T3 in different concentrations on the expressi on of TRAIL in peripheral blood lymphocytes
The percentage of TRAIL positive lymphocyte were 16.78+3.8 4%, 18.11+3.04 %, 23.03+2.28 %, 28.01 + 1.37%, 32.43+3.96 % respectively when the lymphocyte were cultured in different c oncentrations of T3 (1X 10-12mol/L, 1X 10-11mol/L, 1X 10-10mol/L,
lX10-9mol/L, 1X10-8mol/L ). There were significant difference between all concentrations(P <0.05), except 10-12mol/L and 10-11m ol/L (P=0.605) .
3. The Effect of T3 in different concentrations on apoptosis of peripheral blood lymphocytes.
With the increasing of T3 hormone concentrations, the amou nt of apoptotic cells raised. The percentages of apoptotic cell w ere 5.1 + 0.89% , 12.53 + 2.00%, 15.51 + 2.45%, 18.66+1.02%, 22. 76+2.43%, 28. 76+3. 32% when T3 in different concentrations (0 mol/L, 1X 10-12mol/L, 1 X 10-10mol/L, 1X 10-10mol/L, 1 X 10-9mo 1/L, 1X 10-8mol/L ) were added into the culture media. There we re significantly different among groups. (P <0.01).
4. Serum sTRAIL level in thyroid diseases
The serum sTRAIL in the patients with GD were significantly higher than those in healthy controls(2.23+0.46ng/ml vs 0.80 + 0.07ng/ml , p<0.05) and those of hypothyroidism (1.02+1.45 ng/ ml, p<0.05) . The levels of serum soluble DR4 and DR5 in the patients with GD, hypothyroidism and healthy controls weren't di fferent. Conclusion:
The immunohistochemical work of this experiment indicated that TRAIL protein expressed in part of PBMC, especially in human peripheral blood lymphocytes, and T3 can up-regulate the expression of TRAIL and increase the apoptosis of lymphocytes in vitro when T3 is in certain extent of concentrations. As the clinic study, the level of sTRAIL was higher in Graves' disease than in hypothyroidism and control. All this data showed that TRAIL system may play an important role in the pathogenesis of Graves' disease. Further investigations are necessary to evaluate the significance of our results.
目的：
(1)观察TRAIL在外周血单个核细胞(PBMC)中的表达。(2)检测经不同浓度T_3刺激后，体外培养的人外周血淋巴细胞TRAIL表达的及淋巴细胞的凋亡情况。(3)检测Graves病患者血清中可溶型TRAIL的。
方法：
1．免疫组织化学检测PBMC中TRAIL的表达情况。
2．流式细胞仪检测经不同浓度T_3(1×10~(-12)～1×10~8)刺激后淋巴细胞表面TRAIL的表达其凋亡。
3．收集50例Graves病患者、22例原发性甲状腺功能减低症(甲减)患者与40例健康人的血清标本，用酶联免疫吸附法(ELISA)
第四军医大学硕士学位论文
测定血清中的sTRAIL，同时测定患者的T3、T4、TSH、TGA七、
仰OAb水平。
结果:
1密度梯度离心法得到的PBMC中，TRAIL免疫反应阳性物
质分布于胞质内，核呈阴性反应。分离的PBMC中淋巴细胞占97.48
士3.43%，单核细胞占3.15土0.83%，TRAIL免疫反应阳性的淋巴
细胞占总数的26.31士3.18%，TRAIL免疫反应阳性的单核细胞
占总数的1.04士0.13%。
2 T3刺激后淋巴细胞TRAIL的表达情况
体外培养的人外周血淋巴细胞在1.0x10一，Zmo比与1.ox
10一“mo巩浓度T3刺激下，TRAIL表达率分别为16.78士3.84%、
18.n士3.04%，随着浓度的增加，TRAIL表达率明显增加，在毛
为1.0X10一10mo讥、1.Ox10、OUL与1.0xl0旧mo比时淋巴细
胞的TRAIL表达率分别为23.03士2.28%、28.01士1.37%、32.43
士3. 96%，其表达率于各浓度间差异明显(P<0.01)。
3 T3刺激后淋巴细胞的凋亡情况
体外培养的人外周血淋巴细胞在T3浓度为伪mOUL、1.ox
10一，ZmoFL、1 .0 X 10一“moUL、1.0 X 10一moljL、1.0X10一moFL
的刺激下其凋亡率分别为5.1士0.89%、12.53士2.00%、15.51士
2.45%、18.66士1.02%、22.76士2.43%、28.76士3.32%，各浓
度间差异明显(P<0.01)。
4血清sTRAIL检测结果
Graves病患者中的sTRAIL平均水平为2.23士0.46ng/m1，正
常对照组为0.80士0.07ng/ml，甲减组为1.02士1.45ng/m1。方差
分析结果示:组间存在统计学差异(F=5.54，P=0.005);组间比
较:Graves病组高于正常对照组(P二0.003)与甲减组(P=0.019)，
甲减组与正常对照组无差异(P二0.71)。三组间OR4及ORS未见
统计学差异。
结论:
l免疫组织化学SABC染色法显示正常人外周血分离的淋巴细胞
第四军医大学硕士学位论文
及单核细胞有TRA儿表达。
2一定浓度T3可以促进淋巴细胞TRAIL的表达及并促进其凋亡。
3 Graves病患者血清中sTRAIL水平明显升高。
至于T3促进淋巴细胞TRAIL的表达及凋亡的意义以及Graves
病sTRAIL升高的机制，有待深入研究。
TRAIL (Apo-2L) is one of members of the TNF super-family. Just like TNF-a and FasL, it belongs to type II membrane-bound protein, and has both membrane-bound and soluble forms and acts through type I membrane receptors that signal apoptosis through a cytoplasmic death domain, as the apoptosis plays an pivotal role in maintaining homeostasis of tissues. Autoimmune thyroid disease (AFTD) includes Graves' disease and Hashimoto' thyroiditis, while apoptosis has an important role in the pathogenesis of this kind of disease. Objects
(1)To observe the expression of TRAIL in PBMCs. (2) To investigate the level of serum soluble TRAIL in Graves' patients. (3).To investigate the expression of TRAIL on lymphocytes, and (4).To understand the effect of Triiodothyronine (T3) in different concentrations on the apoptosis of lymphocyte in vitro. Methods
The TRAIL immunoreactive substance was observed in PB
MCs hnmunohistochemically. Expression of TRAIL and apoptosis
of lymphocytes were tested by Flow cytometric analysis. Serum
soluble TRAIL was measured with sandwich enzyme-linked im
munosorbent assay in patients with Graves' disease (n=50), Prim ary hypothyroidism (n=22) and controls(n=40). At the same time,
T3, T4, TSH, TGAb and TPOAb were examined in all patients.
Results
1. The expression of TRAIL on PBMC :
The immunoreactive positive substance distributed in cytoplas ma, while it was negative on nuclei. The percentage of lymphoc yte and monocyte among PBMC were 97.48?.43% and 3.15 + 0.83 % respectively. The ratio of TRAIL immunoreactive lymphoc yte was 26.31+3.18)%, while that of monocytes was 1.04+0.13
2. The Effect of T3 in different concentrations on the expressi on of TRAIL in peripheral blood lymphocytes
The percentage of TRAIL positive lymphocyte were 16.78+3.8 4%, 18.11+3.04 %, 23.03+2.28 %, 28.01 + 1.37%, 32.43+3.96 % respectively when the lymphocyte were cultured in different c oncentrations of T3 (1X 10-12mol/L, 1X 10-11mol/L, 1X 10-10mol/L,
lX10-9mol/L, 1X10-8mol/L ). There were significant difference between all concentrations(P <0.05), except 10-12mol/L and 10-11m ol/L (P=0.605) .
3. The Effect of T3 in different concentrations on apoptosis of peripheral blood lymphocytes.
With the increasing of T3 hormone concentrations, the amou nt of apoptotic cells raised. The percentages of apoptotic cell w ere 5.1 + 0.89% , 12.53 + 2.00%, 15.51 + 2.45%, 18.66+1.02%, 22. 76+2.43%, 28. 76+3. 32% when T3 in different concentrations (0 mol/L, 1X 10-12mol/L, 1 X 10-10mol/L, 1X 10-10mol/L, 1 X 10-9mo 1/L, 1X 10-8mol/L ) were added into the culture media. There we re significantly different among groups. (P <0.01).
4. Serum sTRAIL level in thyroid diseases
The serum sTRAIL in the patients with GD were significantly higher than those in healthy controls(2.23+0.46ng/ml vs 0.80 + 0.07ng/ml , p<0.05) and those of hypothyroidism (1.02+1.45 ng/ ml, p<0.05) . The levels of serum soluble DR4 and DR5 in the patients with GD, hypothyroidism and healthy controls weren't di fferent. Conclusion:
The immunohistochemical work of this experiment indicated that TRAIL protein expressed in part of PBMC, especially in human peripheral blood lymphocytes, and T3 can up-regulate the expression of TRAIL and increase the apoptosis of lymphocytes in vitro when T3 is in certain extent of concentrations. As the clinic study, the level of sTRAIL was higher in Graves' disease than in hypothyroidism and control. All this data showed that TRAIL system may play an important role in the pathogenesis of Graves' disease. Further investigations are necessary to evaluate the significance of our results.
引文
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48 Golstein J ,Dumont JE. Cytotoxic effects of iodide on thyroid cells :difference between rat thyroid FRTL25
cell and dog thyroid responsiveness[J]. J Endocrinol Invest, 1996, 19:119-128.
49 Pitsiavas V,Smerdely P, Li M, et al. Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat[J]. Eur J Endocrinol, 1997 ,137:89～98.
50. Bretz, J D, Arscott, P L , Myc A, et al .Inflammatory Cytokine Regulation of Fas-mediated Apoptosis in Thyroid Follicular Cells. J. Biol. Chem., 1999:274:25433-25438.
51 Giordano C, Stassi G, Maria RD, et al. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis[J]. Scinece, 1997, 275:960-963.
52 Stokes T A, Rymaszewski M, Arscott P L. et al .Constitutive Expression of FasL in Thyrocytes Science, Mar 1998; 279:2015
53 P Fiedler and H Eibel Antibody mAb33 from transduction laboratories detects human CD95L in ELISA but not in immunoblots. Cell Death Differ, 2000; 7: 126-128.
54 James R. Baker, Jr. Dying (Apoptosing?) for a Consensus on the Fas Death Pathway in the Thyroid J. Clin. Endocrinol. Metab, 1999; 84:2593-2595
55 Strokes TA, Rymaszewski M, Arscott PL, et al. Constitutive expression of FasL in thyrocytes(J)Science, 1998, 279:2015-025
56 张惠文 林汉华 陶德定．凋亡相关分子Fas和FasL在自身免疫性甲状腺炎发病中的作用．中华内分泌代谢杂志，2002，18：464-465．
57 Mitsiades N, Poulaki V, Tseleni-Balafouta S, et al. Fas ligand expression in thyroid follicular cells from patients with thionamide-treated Graves' disease. Thyroid, 2000: 10: 527-32.
58 Shimaoka Y, Hidaka Y, Okumura M, et al. Serum concentrationof soluble Fas in patients with autoimmune thyroid diseases(J). Thyroid,1998,8:43～47.
59 Bretz J, James R, Baker, Jr. Apoptosis and autoimmune thyroid disease: from TRAIL to thyroid destruction?[review][J] Clin Endocrinol(Oxf), 2001;55(1):1-11.
60 Bretz J, Rymaszewski M, Arscott P, et al TRAIL Death Pathway Expression and Induction in Thyroid Follicular Cells. J Biol Chem, 1999: 274(33) 23627-23632.
61 Mezosi E, Wang S H, Utsugi S, et al. Interleukin-lβ and Tumor Necrosis Factor (TNF)-α Sensitize Human Thyroid Epithelial Ceils to TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis through Increases in Procaspase-7 and Bid, and the Down-Regulation of p44/42 Mitogen-Activated Protein Kinase Activity J. Clin. Endocrinol. Metab, 2004; 89:250 - 257.
62 Bretz J, Mezosi E, Giordano TJ, et al. Inflammatory cytokine regulation of TRAIL-mediated apoptosis in thyroid epithelial cells. Cell Death Differ, 2002; 9(3): 274-286.
63 付建芳 姬求和 黄威权等．桥本甲状腺炎中 TRAIL及其死亡受体DR4，DR5的表达．第四军医大学学报，2002，23：920-923
64 Stassi G, Liberto D DJ, Todaro M, et al. Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. Nat Immunol, 2000; 1: 483-488.
65 Ansell JE. The blood in thyrotoxicosis. In: BravermanLE,
Utiger RD, eds. Werner and Ingbar' s the thyroid, 7th ed. Philadelphia: Lippincott-Raven; 1996, 637- 644
66 Grinblat J, Shohat B, Lewitus Z, et al. Quantitative and functional assessment of peripheral T lymphocytes in thyroid diseases. Acta Endocrinol, 1979, (Copenh). 90:52-61.
67 Wall JR, Gray B, Greenwood DM. Total and "activated" peripheral blood T-lymphocytes in patients with thyroid disorders. Acta Endocrinol (Copenh).1977, 85:753-759.
68 Griffith TS, Brunner T, Fletcher SM, et al. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science, 1995, 270 (5239): 1189 - 1192.
69 Kayagaki N, Yamaguchi N, Nakayama M, et al. Involvement of TNF-related apoptosis-inducing ligand in human CD4+T cell-mediated cytotoxicity. J Immunol, 1999, 162(5) :2639 - 2647.
70 Halaas O, Vik R, Ashkenazi A, et ,al .Lipopolysaccharide induces expression of APO2 Ligand/TRAIL in human monocytes and macrophages. Scand J Immunol, 2000, 51(3):244-250.
71 Pan G, O'Rourke K, ChinnaiyanAM, et al. The receptor for the cytotoxic ligand TRAIL. Science, 1997, 276(5309):111-113.
72 季军捷，卫立辛，李晓东，等．激活淋巴细胞中TRAIL及其受体表达的初步研究．第二军医大学学报，2002, 23 (7): 788-790.
73 Kayagaki N, Yamaguchi N, Nakayama M, et al. Type Ⅰ interferons(IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on
human T cells: a novel mechanism for the antitumor effects of type Ⅰ IFNs .J Exp Med, 1999, 189 (9): 1451 - 1460.
74 Judelson C, Privalsky ML. DNA recognition by normal and oncogenic thyroid hormone receptors. J Biol Chem. 1996, 271:10800 -10805.
75 Gandrillon O, Ferrand N, Michaille J-J, Roze L, ZileMH, Samarut J. c-erbAa/T3R and RARs control commitment of hematopoietic self-renewing progenitor cells to apoptosis or differentiation and are antagonized by the v-erbA oncogene. Oncogene. 1994, 9:749 - 758.
76 Brown aD, Wang Z, Kanamori A, Eliceiri B, Furlow JD, Schwartzman R. Amphibian metamorphosis: a complex program of gene expression changes controlled by the thyroid hormone. Recent Prog Horm Res. 1995, 50:309 - 315.
77 Arpin C, Pihlgren M, Fraichard A, et al. Effects of T3Ral and T3Ra2 Gene Deletion on T and B Lymphocyte Development. J Immunology, 2000, 164: 152- 160.
78 Mihara S, Suzuki N, Wakisaka S, et al. Effects of Thyroid Hormones on Apoptotic Cell Death of Human Lymphocytes. J Clin. Endocrinol. Metab. 1999 84(4): 1378-1385.
79 张雅萍 姬秋和 张万会等 桥本甲状腺炎组织中细胞凋亡相关蛋白表达的意义．中华医学杂志．2001，81(7)：432-434
80 Ludgate M, Jasani B, Ishii A, et al. Apoptosis in autoimmune and non-autoimmune thyroid disease [Eitorial], J Pathol 1997 182:123-124
81 Bellur S. Prabhakar, Rebecca S. et al. Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy Endocr Rev, 2003 24: 802-835.
82 Hammond LJ, Lowdell MW, Cerrano PG, et al .Analysis of apoptosis in relation to tissue destruction associated with Hashimoto's autoimmune thyroiditis. J Pathol, 1997, 182: 138-144.
83 Joahim F, Elke P, Matthas S, et al. Soluble fas is increased in hyperthyoidism independent of the underlying thyroid disease. J Clin Endocrinol Metab 2001,86:4250-4253
84 Wang CY, zhong WB, Chang TC, et al. Circulating Soluble fas ligand correlates with disease activity in Graves' hyperthyroidism. J Metab 2002,51, 769-773.
85 李影娜，李一，刘雪松等．检测可溶型TRAIL的ELISA的建立和初步应用．细胞与分子免疫学杂志，2003，19：190-191
86 Liabakk NB, Sundan A, Torp S, et al. Development, characterization and use of monoclonal antibodies against sTRAIL: measurement of sTRAIL by ELISA. J Immunol Methods, 2002, 259:119- 128.
87 Li-Hui Han, Wen-Sheng Sun, Chun-Hong Ma, et al. Detection of soluble TRAIL in HBV infected patients and its clinical implications. J WorldGastroenterol, 2002, 8:1077-1080.
88 Kayagaki N, Yamaguchi N, Nakayama M, et al. Type Ⅰ interferons(IFNs)regulate tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) expression on human T cells: a novel mechanism for the antitumor effects of type Ⅰ IFNs. J Exp Med, 1999, 189:1451-460.
89 潘中允主编 临床核医学 北京：原子能出版社，1994，442．
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40 Chneider, P., Thome, M., Burns, K., et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent
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41 Eremias, I., Kupatt, C., Baumann, B., et al. Inhibition of NF-kB activation attenuates apoptosis resistance in lymphoid cells. Blood, 1998, 91, 4624-4631.
42 Kandasamy K, Srinivasula S M, Alnemri E S, et al. Involvement of Proapoptotic Molecules Bax and Bak in Tumor Necrosis Factor-related Apoptosis-inducing Ligand(TRAIL)-induced Mitochondrial Disruption and Apoptosis: Differential Regulation of Cytochrome c and Smac/DIABLO Release. Cancer Res, 2003; 63:1712 - 1721.
43 Coclet J, Foureau F, Ketelbant P, et al. Cell population kinetics in dog and human adult thyroid. Clin Endocrinol (Oxf), 1989,31:655 -665.
44 Tanimoto C, Hirakawa S, Kawasaki H, et al. Apoptosis in thyroid diseases: a histochemical study. Endocr J, Apr 1995, 42: 193-201.
45 Hammound LJ, Lowdell MW, Cerrano PG, et al. Analysis of apoptosis in relation to tissue destruction associated with Hashimoto's autoimmune thyroiditis(J)Pathol, 1997, 182: 138-144.
46 Moore D, Ohene2Fianko D ,Garcia B ,et al. Apoptosis in thyroid neoplasms: relationship with p53 and bcl-2 expression[J]. Histopathology, 1998, 32:35-42.
47 Kawakami A, Eguchi K, Matsuoka N, et al. Thyroid stimulating hormone inhibits Fas antigen mediated apoptosis of human thyrocytes in vitro[J]. Endocrinology ,1996 ,137:3163-3169.
48 Golstein J ,Dumont JE. Cytotoxic effects of iodide on thyroid cells :difference between rat thyroid FRTL25
cell and dog thyroid responsiveness[J]. J Endocrinol Invest, 1996, 19:119-128.
49 Pitsiavas V,Smerdely P, Li M, et al. Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat[J]. Eur J Endocrinol, 1997 ,137:89～98.
50. Bretz, J D, Arscott, P L , Myc A, et al .Inflammatory Cytokine Regulation of Fas-mediated Apoptosis in Thyroid Follicular Cells. J. Biol. Chem., 1999:274:25433-25438.
51 Giordano C, Stassi G, Maria RD, et al. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis[J]. Scinece, 1997, 275:960-963.
52 Stokes T A, Rymaszewski M, Arscott P L. et al .Constitutive Expression of FasL in Thyrocytes Science, Mar 1998; 279:2015
53 P Fiedler and H Eibel Antibody mAb33 from transduction laboratories detects human CD95L in ELISA but not in immunoblots. Cell Death Differ, 2000; 7: 126-128.
54 James R. Baker, Jr. Dying (Apoptosing?) for a Consensus on the Fas Death Pathway in the Thyroid J. Clin. Endocrinol. Metab, 1999; 84:2593-2595
55 Strokes TA, Rymaszewski M, Arscott PL, et al. Constitutive expression of FasL in thyrocytes(J)Science, 1998, 279:2015-025
56 张惠文 林汉华 陶德定．凋亡相关分子Fas和FasL在自身免疫性甲状腺炎发病中的作用．中华内分泌代谢杂志，2002，18：464-465．
57 Mitsiades N, Poulaki V, Tseleni-Balafouta S, et al. Fas ligand expression in thyroid follicular cells from patients with thionamide-treated Graves' disease. Thyroid, 2000: 10: 527-32.
58 Shimaoka Y, Hidaka Y, Okumura M, et al. Serum concentrationof soluble Fas in patients with autoimmune thyroid diseases(J). Thyroid,1998,8:43～47.
59 Bretz J, James R, Baker, Jr. Apoptosis and autoimmune thyroid disease: from TRAIL to thyroid destruction?[review][J] Clin Endocrinol(Oxf), 2001;55(1):1-11.
60 Bretz J, Rymaszewski M, Arscott P, et al TRAIL Death Pathway Expression and Induction in Thyroid Follicular Cells. J Biol Chem, 1999: 274(33) 23627-23632.
61 Mezosi E, Wang S H, Utsugi S, et al. Interleukin-lβ and Tumor Necrosis Factor (TNF)-α Sensitize Human Thyroid Epithelial Ceils to TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis through Increases in Procaspase-7 and Bid, and the Down-Regulation of p44/42 Mitogen-Activated Protein Kinase Activity J. Clin. Endocrinol. Metab, 2004; 89:250 - 257.
62 Bretz J, Mezosi E, Giordano TJ, et al. Inflammatory cytokine regulation of TRAIL-mediated apoptosis in thyroid epithelial cells. Cell Death Differ, 2002; 9(3): 274-286.
63 付建芳 姬求和 黄威权等．桥本甲状腺炎中 TRAIL及其死亡受体DR4，DR5的表达．第四军医大学学报，2002，23：920-923
64 Stassi G, Liberto D DJ, Todaro M, et al. Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. Nat Immunol, 2000; 1: 483-488.
65 Ansell JE. The blood in thyrotoxicosis. In: BravermanLE,
Utiger RD, eds. Werner and Ingbar' s the thyroid, 7th ed. Philadelphia: Lippincott-Raven; 1996, 637- 644
66 Grinblat J, Shohat B, Lewitus Z, et al. Quantitative and functional assessment of peripheral T lymphocytes in thyroid diseases. Acta Endocrinol, 1979, (Copenh). 90:52-61.
67 Wall JR, Gray B, Greenwood DM. Total and "activated" peripheral blood T-lymphocytes in patients with thyroid disorders. Acta Endocrinol (Copenh).1977, 85:753-759.
68 Griffith TS, Brunner T, Fletcher SM, et al. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science, 1995, 270 (5239): 1189 - 1192.
69 Kayagaki N, Yamaguchi N, Nakayama M, et al. Involvement of TNF-related apoptosis-inducing ligand in human CD4+T cell-mediated cytotoxicity. J Immunol, 1999, 162(5) :2639 - 2647.
70 Halaas O, Vik R, Ashkenazi A, et ,al .Lipopolysaccharide induces expression of APO2 Ligand/TRAIL in human monocytes and macrophages. Scand J Immunol, 2000, 51(3):244-250.
71 Pan G, O'Rourke K, ChinnaiyanAM, et al. The receptor for the cytotoxic ligand TRAIL. Science, 1997, 276(5309):111-113.
72 季军捷，卫立辛，李晓东，等．激活淋巴细胞中TRAIL及其受体表达的初步研究．第二军医大学学报，2002, 23 (7): 788-790.
73 Kayagaki N, Yamaguchi N, Nakayama M, et al. Type Ⅰ interferons(IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on
human T cells: a novel mechanism for the antitumor effects of type Ⅰ IFNs .J Exp Med, 1999, 189 (9): 1451 - 1460.
74 Judelson C, Privalsky ML. DNA recognition by normal and oncogenic thyroid hormone receptors. J Biol Chem. 1996, 271:10800 -10805.
75 Gandrillon O, Ferrand N, Michaille J-J, Roze L, ZileMH, Samarut J. c-erbAa/T3R and RARs control commitment of hematopoietic self-renewing progenitor cells to apoptosis or differentiation and are antagonized by the v-erbA oncogene. Oncogene. 1994, 9:749 - 758.
76 Brown aD, Wang Z, Kanamori A, Eliceiri B, Furlow JD, Schwartzman R. Amphibian metamorphosis: a complex program of gene expression changes controlled by the thyroid hormone. Recent Prog Horm Res. 1995, 50:309 - 315.
77 Arpin C, Pihlgren M, Fraichard A, et al. Effects of T3Ral and T3Ra2 Gene Deletion on T and B Lymphocyte Development. J Immunology, 2000, 164: 152- 160.
78 Mihara S, Suzuki N, Wakisaka S, et al. Effects of Thyroid Hormones on Apoptotic Cell Death of Human Lymphocytes. J Clin. Endocrinol. Metab. 1999 84(4): 1378-1385.
79 张雅萍 姬秋和 张万会等 桥本甲状腺炎组织中细胞凋亡相关蛋白表达的意义．中华医学杂志．2001，81(7)：432-434
80 Ludgate M, Jasani B, Ishii A, et al. Apoptosis in autoimmune and non-autoimmune thyroid disease [Eitorial], J Pathol 1997 182:123-124
81 Bellur S. Prabhakar, Rebecca S. et al. Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy Endocr Rev, 2003 24: 802-835.
82 Hammond LJ, Lowdell MW, Cerrano PG, et al .Analysis of apoptosis in relation to tissue destruction associated with Hashimoto's autoimmune thyroiditis. J Pathol, 1997, 182: 138-144.
83 Joahim F, Elke P, Matthas S, et al. Soluble fas is increased in hyperthyoidism independent of the underlying thyroid disease. J Clin Endocrinol Metab 2001,86:4250-4253
84 Wang CY, zhong WB, Chang TC, et al. Circulating Soluble fas ligand correlates with disease activity in Graves' hyperthyroidism. J Metab 2002,51, 769-773.
85 李影娜，李一，刘雪松等．检测可溶型TRAIL的ELISA的建立和初步应用．细胞与分子免疫学杂志，2003，19：190-191
86 Liabakk NB, Sundan A, Torp S, et al. Development, characterization and use of monoclonal antibodies against sTRAIL: measurement of sTRAIL by ELISA. J Immunol Methods, 2002, 259:119- 128.
87 Li-Hui Han, Wen-Sheng Sun, Chun-Hong Ma, et al. Detection of soluble TRAIL in HBV infected patients and its clinical implications. J WorldGastroenterol, 2002, 8:1077-1080.
88 Kayagaki N, Yamaguchi N, Nakayama M, et al. Type Ⅰ interferons(IFNs)regulate tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) expression on human T cells: a novel mechanism for the antitumor effects of type Ⅰ IFNs. J Exp Med, 1999, 189:1451-460.
89 潘中允主编 临床核医学 北京：原子能出版社，1994，442．
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