Th1/Th2细胞在自身免疫性甲状腺疾病发生机制中作用的研究
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摘要
目的:自身免疫性甲状腺疾病(autoimmune thyroid disease AITD)中Graves病(Graves' disease GD)和桥本氏甲状腺炎(Hashimoto's thyroiditis HT)是最常见的类型。依据产生的细胞因子(cytokine CK)的不同,辅助性T细胞(Th)主要分为Thl和Th2两类。Thl细胞分泌的细胞因子主要包括有白介素-2 (IL-2)、肿瘤坏死因子-α(tumor necrosis factor TNF-α);Th2细胞分泌的细胞因子主要包括白介素-4 (IL-4)、白介素-5(IL-5)。本文选择了临床确诊的GD与HT患者,利用观察性研究的方法,分析自身免疫性甲状腺疾病患者血清中Thl及Th2型细胞因子水平,探讨Thl/Th2细胞免疫平衡偏移以及Thl/Th2细胞免疫平衡在自身免疫性甲状腺疾病发生中的作用,同时观察细胞因子能否成为自身免疫性甲状腺疾病诊断的指标。
方法:选取2007年8月至2008年3月在我院就诊的未经治疗的初诊AITD患者,其中GD患者45例、HT患者30例。另选20例体检合格的健康人作为正常对照组。所有入选的研究对象均抽取清晨空腹静脉血,两小时内利用放射免疫法测定游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、抗甲状腺球蛋白抗体(TGAb)、抗甲状腺微粒体抗体(TMAb),采用免疫放射法测定超敏促甲状腺激素(sTSH),剩余血清放置于-200C冰箱保存,5个月内所有剩余血清采用酶联免疫吸附试验法(ELISA)检测患者和健康人(对照组)血清中Thl型细胞因子白介素2 (IL-2)和Th2型细胞因子白介素5(IL-5)的水平并进行统计学分析。
结果:
1 GD组以及HT组中的TGAb和TMAb均较对照组明显增高,均为P<0.01。HT组TGAb与TMAb浓度较GD组高,P<0.05。
2细胞因子在GD中的表达在GD患者中,IL-2与正常对照组相比无显著差异(P>0.05),而IL-5水平与其余两组相比有显著差异性(P<0.05)。
3细胞因子在HT中的表达HT组患者血清IL-2水平明显高于GD组和对照组(P<0.05),而IL-5水平与其余两组相比无显著差异性(P>0.05)。
4各组中的IL-2/IL-5比值情况
GD组患者血清IL-2/IL-5比值降低,而HT组患者血清IL-2/IL-5比值增高,且二者相比有统计学差异,p<0.05。
结论:
1 TGAb与TMAb对于GD以及HT的诊断有重要价值,其中对于HT的诊断价值更为重要。
2 Th2型细胞因子参与了GD的致病过程,GD是以Th2细胞免疫占优势为主的。
3 Th1型细胞因子参与了HT的致病过程,HT是以Th1细胞免疫占优势为主的。
OBJECT: The present classification of autoimmune thyroid disease (AITD) includes principally chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) and Graves’disease (GD). CD4+T helper precursor cells differentiate into two distinct subpopulations, Th1 andTh2. Th1 cells mainly secrete interleukine-2 (IL-2), IFN-γ, and TNF-α; Th2 cells mainly secrete interleukine-4(IL-4) and interleukine-5 (IL-5). Choosing GD and HT patients as research object, we analysis the serum concentrations of the Th1/Th2 cytokines interleukine-2 and interleukine-5 in patients AITD with and investigate the relationship between the imbalance of Th1/Th2 cytokines and the pathogenesis of AITD.
METHODS: Chose 20 normal as controls, 75 patients were studied. 45 patients suffered from GD, 30 patients suffered from HT from Aug. 2007 to Feb. 2008 in the third affiliated hospital of Nanchang university. The serum concentrations of free triiodothyronine (FT3), free thyroxin (FT4) ,thyrotropic-stimulating hormone (TSH), thyroglobulin antibody(TGAb) and thyroid microsome antibody (TMAb)were assayed by radioimmunoassay (RIA) and the serum concentrations of thyrotropic-stimulating hormone (TSH) were assayed by immunoradioassay . The serum concentrations of IL-2 and IL-5,representative cytokines of Th1 and Th2 cells respectively,were assayed by enzyme-linked immunosorbent assay (ELISA). All data were analysis by statistics methods.
RESULTS: (1) Compare with controls, the serum concentrations of TGAb and TMAb in GD and HT groups were remarkably increased (P<0.01); Compare with GD group, the concentration of TGAb and TMAb in HT group were remarkably increased (P<0.05). (2) Compare with HT group and controls, the concentration of IL-5 in GD group were remarkably increased (P<0.05). (3) Compare with GD group, the concentration of IL-2 in HT group were remarkably increased (P<0.05). (4) Compare with GD group, the ratio of IL-2/IL-5 in HT group were remarkably increased (P<0.05).
CONCLUSIONS: (1) TGAb and TMAb play a very important role in the diagnosis of GD and HT, especially in the HT. (2) A Th1 pattern of immune response of characteristic cellular immunity is dominant in HT, whereas the predominance Th2 cytokines in GD indicates a humoral pattern of immune reaction.
方法:选取2007年8月至2008年3月在我院就诊的未经治疗的初诊AITD患者,其中GD患者45例、HT患者30例。另选20例体检合格的健康人作为正常对照组。所有入选的研究对象均抽取清晨空腹静脉血,两小时内利用放射免疫法测定游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、抗甲状腺球蛋白抗体(TGAb)、抗甲状腺微粒体抗体(TMAb),采用免疫放射法测定超敏促甲状腺激素(sTSH),剩余血清放置于-200C冰箱保存,5个月内所有剩余血清采用酶联免疫吸附试验法(ELISA)检测患者和健康人(对照组)血清中Thl型细胞因子白介素2 (IL-2)和Th2型细胞因子白介素5(IL-5)的水平并进行统计学分析。
结果:
1 GD组以及HT组中的TGAb和TMAb均较对照组明显增高,均为P<0.01。HT组TGAb与TMAb浓度较GD组高,P<0.05。
2细胞因子在GD中的表达在GD患者中,IL-2与正常对照组相比无显著差异(P>0.05),而IL-5水平与其余两组相比有显著差异性(P<0.05)。
3细胞因子在HT中的表达HT组患者血清IL-2水平明显高于GD组和对照组(P<0.05),而IL-5水平与其余两组相比无显著差异性(P>0.05)。
4各组中的IL-2/IL-5比值情况
GD组患者血清IL-2/IL-5比值降低,而HT组患者血清IL-2/IL-5比值增高,且二者相比有统计学差异,p<0.05。
结论:
1 TGAb与TMAb对于GD以及HT的诊断有重要价值,其中对于HT的诊断价值更为重要。
2 Th2型细胞因子参与了GD的致病过程,GD是以Th2细胞免疫占优势为主的。
3 Th1型细胞因子参与了HT的致病过程,HT是以Th1细胞免疫占优势为主的。
OBJECT: The present classification of autoimmune thyroid disease (AITD) includes principally chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) and Graves’disease (GD). CD4+T helper precursor cells differentiate into two distinct subpopulations, Th1 andTh2. Th1 cells mainly secrete interleukine-2 (IL-2), IFN-γ, and TNF-α; Th2 cells mainly secrete interleukine-4(IL-4) and interleukine-5 (IL-5). Choosing GD and HT patients as research object, we analysis the serum concentrations of the Th1/Th2 cytokines interleukine-2 and interleukine-5 in patients AITD with and investigate the relationship between the imbalance of Th1/Th2 cytokines and the pathogenesis of AITD.
METHODS: Chose 20 normal as controls, 75 patients were studied. 45 patients suffered from GD, 30 patients suffered from HT from Aug. 2007 to Feb. 2008 in the third affiliated hospital of Nanchang university. The serum concentrations of free triiodothyronine (FT3), free thyroxin (FT4) ,thyrotropic-stimulating hormone (TSH), thyroglobulin antibody(TGAb) and thyroid microsome antibody (TMAb)were assayed by radioimmunoassay (RIA) and the serum concentrations of thyrotropic-stimulating hormone (TSH) were assayed by immunoradioassay . The serum concentrations of IL-2 and IL-5,representative cytokines of Th1 and Th2 cells respectively,were assayed by enzyme-linked immunosorbent assay (ELISA). All data were analysis by statistics methods.
RESULTS: (1) Compare with controls, the serum concentrations of TGAb and TMAb in GD and HT groups were remarkably increased (P<0.01); Compare with GD group, the concentration of TGAb and TMAb in HT group were remarkably increased (P<0.05). (2) Compare with HT group and controls, the concentration of IL-5 in GD group were remarkably increased (P<0.05). (3) Compare with GD group, the concentration of IL-2 in HT group were remarkably increased (P<0.05). (4) Compare with GD group, the ratio of IL-2/IL-5 in HT group were remarkably increased (P<0.05).
CONCLUSIONS: (1) TGAb and TMAb play a very important role in the diagnosis of GD and HT, especially in the HT. (2) A Th1 pattern of immune response of characteristic cellular immunity is dominant in HT, whereas the predominance Th2 cytokines in GD indicates a humoral pattern of immune reaction.
引文
[1] Caturegli P, Kimura H, Rocchi R, et al. Autoimmune Thyroid Diseases. [J] Current Opinion in Rheumatology 2007, 19:44–48
[2]Elenkov U. Glucocorticoids and the Thl/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-46
[3]仲人前.自身免疫病研究:挑战与机遇并存.[J]国外医学临床生物化学与检验学分册,2003,24(6):311-312
[4] Ruggeri RM, Barresi G, Sciacchitano S, et al. Immunoexpression of the CD30 Ligand/CD30 and IL-6/IL-6R Signals in Thyroid Autoimmune Diseases. [J] Histol Histopathol 2006; 21(3): 249-256.
[5] Brand OJ, Lowe CE, Heward JM, et al. Association of the Interleukin-2 receptor Alpha (IL-2Rα)/CD25 Gene Region with Graves’Disease Using a Multilocus Test and Tag SNPs. [J] Clinical Endocrinology 2007;66: 508–512
[6] Gianoukakis AG, Raymond S, King CS, et al. Immunoglobulin G from Patients with Graves’ Disease Induces Interleukin-16 and RANTES Expression in Cultured Human Thyrocytes: A Putative Mechanism for T-Cell Infiltration of the Thyroid in Autoimmune Disease. [J] Endocrinology 2006; 147(4): 1941–1949
[7]Patibandla SA, Prabhakar BS, Autoimmunity to the Thyroid Stimulating Hormone Receptor [J] Adv Neuroimmunol, 1996, 6(4):347-357
[8] Weetman AP. Autoimmune Thyroiditis: Predisposition and Pathogenesis. [J]Clin Endocrinol, 1992,475-480
[9] Chen RH, Chang CT. Proinflammatory Cytokine Gene Polymorphisms among Hashimoto's Thyroiditis Patients. [J] Clin Lab Anal. 2006; 20(6): 260-265.
[10] Ito C, Watanabe M, Okuda N, et al. Association Between the Severity of Hashimoto’s disease and the Functional +874A/T Polymorphism in the Interferon-γGene. [J] Endocrine Journal. 2006; 53(4), 473-478.
[11] Charles A Janeway. Immunobiology,2001 by Garland Publishing
[12] Kopp P. the TSH Receptor and its Role in Thyroid Disease. [J] Cell Mol Life Sci, 2001, 58:1301-1322
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[14] Weetman AP. Cellular Immune Responses in Autoimmune Thyroid Disease. [J] Clin Endocrinol.2004; 61 (4):405-413
[15] Oppenheim Y, Ban Y, Tomer Y, Interferon induced Autoimmune Thyroid Disease (AITD): a model for human autoimmunity. [J] Autoimmune Rev.2 004,Jul; 3(5):388-393
[16] Dagia NM, Harii N, Meli AE, et al. Phenyl methimazole inhibits TNF-alpha-induced VCAM-1expression in an IFN regulatory factor-I-dependent manner and reduces monocytic cell adhesion to endothelial cells. [J] Immunol.2004; 173(3):2041-2049
[17] Drugarin D, Negru S, Koreck A, et al. The patern of a Th1 cytokine in autoimmune thyroiditis. [J] lmmunol Lett.2000;71(2):73-77
[18] Phenekos C, Vryonidou A, Gritzapis AD, et al. Thl and Th2 serum cytokine profiles characterize patients with Hashimoto's thyroiditis (Thl) and Graves' disease (Th2). [J] Neuroimmunomodulation.2004; 11(4):209-213
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[22] Weibin W, Fengying L. Autoantibodies Highly Increased in Patients with Thyroid Dysfunction. [J] Cellular & Molecular Immunology 2007; 4:233-236
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[1] Caturegli P, Kimura H, Rocchi R, et al. Autoimmune Thyroid Diseases. [J] Current Opinion in Rheumatology 2007, 19:44–48
[2] Mosmann TR, Cherwinski H, Bond MW, et al. Two Types of Murine helper T Cell Clone. I. Definition According to Profiles of Lymphokine Activities and Secreted Proteins. [J] J Immunol 1986; 136:2348-2357.
[3] Mosmann TR, Coffman RL. TH1 and TH2 Cells: Different patterns of Lymphokine Secretion Lead to Different Functional Properties. [J] Annu Rev Immunol 1989; 7:145-173.
[4] 唐亚梅 ,陈志衡 ,唐爱国等. Thl/Th2型细胞因子失衡与自身免疫性甲状腺疾病的关系研究. 中国医师杂志, 2005; 7(7):876-878.
[5] Ruggeri RM, Barresi G, Sciacchitano S, et al. Immunoexpression of the CD30 Ligand/CD30 and IL-6/IL-6R Signals in Thyroid Autoimmune Diseases. [J] Histol Histopathol 2006; 21(3): 249-256.
[6] Brand OJ, Lowe CE, Heward JM, et al. Association of the Interleukin-2 receptor Alpha (IL-2Rα)/CD25 Gene Region with Graves’Disease Using a Multilocus Test and Tag SNPs. [J] Clinical Endocrinology 2007;66: 508–512
[7] Gianoukakis AG, Raymond S, King CS, et al. Immunoglobulin G from Patients with Graves’ Disease Induces Interleukin-16 and RANTES Expression in Cultured Human Thyrocytes: A Putative Mechanism for T-Cell Infiltration of the Thyroid in Autoimmune Disease. [J] Endocrinology 2006; 147(4): 1941–1949
[8] Chen KM, Wei YZ, Sharp GC, et al. Decreasing TNFαResults in Less Fibrosis and Earlier Resolution of Granulomatous Experimental Autoimmune Thyroiditis. [J] Leukoc Biol. 2007; 81(1): 306–314.
[9] Chen RH, Chang CT. Proinflammatory Cytokine Gene Polymorphisms among Hashimoto's Thyroiditis Patients. [J] Clin Lab Anal. 2006; 20(6): 260-265.
[10] Ito C, Watanabe M, Okuda N, et al. Association Between the Severity of Hashimoto’s disease and the Functional +874A/T Polymorphism in the Interferon-γGene. [J] Endocrine Journal. 2006; 53(4), 473-478.
[11] Drexhage HA. Are There More than Antibodies to the Thyroid-Stimulating Hormone Receptor that Meet the Eye in Graves’ disease? [J] Endocrinology. 2006; 147(1): 9–12
[12] Han R, Smith TJ. T Helper Type 1 and Type 2 Cytokines Exert Divergent Influence on the Induction of Prostaglandin E2 and Hyaluronan Synthesis by Interleukin-1β in Orbital Fibroblasts: Implications for the Pathogenesis of Thyroid-associated Ophthalmopathy. [J] Endocrinology.2006; 147:13–19
[13] Feldon SE, Park DJ, O’Loughlin CW, et al. Autologous T-Lymphocytes Stimulate Proliferation of Orbital Fibroblasts Derived from Patients with Graves’ Ophthalmopathy. [J]Investigative Ophthalmology and Visual Science. 2005;46:3913-3921
[14] Xia N, Zhou S, Liang Y, et al. CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy. [J]. Int J Mol Med. 2006; 17(5): 911-916
[15] Hiromatsu Y, Yang D, Bad T, et al. Cytokine Profile in Eye Muscle Tissue and Orbital Fat Tissue from Patients with Thyroid-associated Ophthalmopathy [J] Clin Endocrinol Metab, 2000,85:1194-1199.
[2]Elenkov U. Glucocorticoids and the Thl/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-46
[3]仲人前.自身免疫病研究:挑战与机遇并存.[J]国外医学临床生物化学与检验学分册,2003,24(6):311-312
[4] Ruggeri RM, Barresi G, Sciacchitano S, et al. Immunoexpression of the CD30 Ligand/CD30 and IL-6/IL-6R Signals in Thyroid Autoimmune Diseases. [J] Histol Histopathol 2006; 21(3): 249-256.
[5] Brand OJ, Lowe CE, Heward JM, et al. Association of the Interleukin-2 receptor Alpha (IL-2Rα)/CD25 Gene Region with Graves’Disease Using a Multilocus Test and Tag SNPs. [J] Clinical Endocrinology 2007;66: 508–512
[6] Gianoukakis AG, Raymond S, King CS, et al. Immunoglobulin G from Patients with Graves’ Disease Induces Interleukin-16 and RANTES Expression in Cultured Human Thyrocytes: A Putative Mechanism for T-Cell Infiltration of the Thyroid in Autoimmune Disease. [J] Endocrinology 2006; 147(4): 1941–1949
[7]Patibandla SA, Prabhakar BS, Autoimmunity to the Thyroid Stimulating Hormone Receptor [J] Adv Neuroimmunol, 1996, 6(4):347-357
[8] Weetman AP. Autoimmune Thyroiditis: Predisposition and Pathogenesis. [J]Clin Endocrinol, 1992,475-480
[9] Chen RH, Chang CT. Proinflammatory Cytokine Gene Polymorphisms among Hashimoto's Thyroiditis Patients. [J] Clin Lab Anal. 2006; 20(6): 260-265.
[10] Ito C, Watanabe M, Okuda N, et al. Association Between the Severity of Hashimoto’s disease and the Functional +874A/T Polymorphism in the Interferon-γGene. [J] Endocrine Journal. 2006; 53(4), 473-478.
[11] Charles A Janeway. Immunobiology,2001 by Garland Publishing
[12] Kopp P. the TSH Receptor and its Role in Thyroid Disease. [J] Cell Mol Life Sci, 2001, 58:1301-1322
[13] Weetman AP. Autoimmune Thyroid Disease. Autoimmunity.2 004; 37 (4): 337-340
[14] Weetman AP. Cellular Immune Responses in Autoimmune Thyroid Disease. [J] Clin Endocrinol.2004; 61 (4):405-413
[15] Oppenheim Y, Ban Y, Tomer Y, Interferon induced Autoimmune Thyroid Disease (AITD): a model for human autoimmunity. [J] Autoimmune Rev.2 004,Jul; 3(5):388-393
[16] Dagia NM, Harii N, Meli AE, et al. Phenyl methimazole inhibits TNF-alpha-induced VCAM-1expression in an IFN regulatory factor-I-dependent manner and reduces monocytic cell adhesion to endothelial cells. [J] Immunol.2004; 173(3):2041-2049
[17] Drugarin D, Negru S, Koreck A, et al. The patern of a Th1 cytokine in autoimmune thyroiditis. [J] lmmunol Lett.2000;71(2):73-77
[18] Phenekos C, Vryonidou A, Gritzapis AD, et al. Thl and Th2 serum cytokine profiles characterize patients with Hashimoto's thyroiditis (Thl) and Graves' disease (Th2). [J] Neuroimmunomodulation.2004; 11(4):209-213
[19] 候健,王东星,胥军民.白细胞介素5人类细胞因子手册.上海同济大学出版社,1996.65-77、100-123.
[20] Kiyoshi T. Molecular biology intelligence unit interleukin-5 and its receptor system:from genes to disease. Landes company, 1995, 32-34.
[21] 陶征,吴洁,李连喜.自身免疫性甲状腺疾病甲状腺自身抗体的临床研究.江苏大学学报(医学版),2004,14( 2):123- 125
[22] Weibin W, Fengying L. Autoantibodies Highly Increased in Patients with Thyroid Dysfunction. [J] Cellular & Molecular Immunology 2007; 4:233-236
[23] Suzuki S, Mitsunaga M, Miyoshi M, et al. Cytophilic antithyroglobulin antibody and antibody-dependent monocyte-mediated cytotoxicity in Hashimoto's thyroiditis. [J] Clin Endocrinol Metab.1980; 51(3):446-53
[24] McLachlan SM, Rapoport B, Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies? [J] Thyroid.20 04;14(7):510-20
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