碘过量对小鼠甲状腺炎发病影响的实验研究
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摘要
目的：本实验通过给予不同品系小鼠饮用碘过量水、Tg免疫及二者联合处理,观察两品系小鼠甲状腺形态功能的变化,脾淋巴细胞分泌细胞因子情况,炎症相关的趋化因子、凋亡相关的受体／配体在甲状腺内的表达及定位,以及甲状腺内炎症和凋亡相关基因的表达水平的变化。从而揭示不同环境因素单独和联合作用对诱发不同遗传背景个体自身免疫性甲状腺炎(AT)影响的差异,并且探讨AT时甲状腺内淋巴细胞浸润和上皮细胞凋亡的机制,为揭示人类自身免疫性甲状腺炎的病因和发病机制提供相关的实验依据。
方法：选用雌性、7-8周龄的NOD小鼠和BALB/c小鼠。两品系小鼠均随机分为4组：对照组(C)：饮去离子水；Tg组(Tg)：饮去离子水、在8周龄时给予每只鼠0.1mgTg皮下免疫,11周龄、15周龄加强免疫两次；碘过量组(HI)：饮用0.05%NaI水；碘过量+Tg组(HI+Tg)：饮0.05%NaI水,Tg免疫同Tg组。在小鼠16周龄时称体重、取血、处死全部小鼠,观察甲状腺组织大体形态并称重；采用HE染色观察甲状腺组织形态学变化；TUNEL法检测甲状腺滤泡上皮细胞凋亡情况；采用RIA法和ELISA法分别检测TT4、TgAb、TPOAb和TSH的水平；MTT法检测淋巴细胞增殖情况；ELISA法检测脾细胞培养上清中IL-4、IFN-γ、IL-10、IL-12的水平；免疫荧光染色观察甲状腺中CD3、CD22、CD31、Podoplanin、CCL21、CCR7、TRAIL、TRAIL-R2 (DR5)的表达及定位；采用SYBR Green实时荧光定量PCR法,检测甲状腺中炎症相关基因(CCL21、ICAM-1、CXCL10)和凋亡相关基因(TRAIL、TRAIL-sR1 (DR4))的表达水平。
结果：
1.甲状腺组织形态学变化：两品系小鼠HI组和HI+Tg组甲状腺较C组肿大,绝对和相对重量增加(P<0.01),出现滤泡扩张、胶质潴留。NOD小鼠这两组甲状腺内还可见呈灶性分布的淋巴细胞浸润,HI+Tg组伴局部纤维化。
2.血清激素与抗体水平：两品系小鼠HI组TT4水平较各自C组呈一定程度的下降,同时TSH水平升高；而Tg组和HI+Tg组TT4和TSH水平均较各自C组升高(P<0.01)。两品系小鼠Tg免疫后的两组有TgAb、TPOAb的生成(P<0.01)。
3.淋巴细胞增殖及脾细胞培养上清中细胞因子水平：体外给予Tg刺激后,除了BALB/c鼠HI组,两品系小鼠其余各实验组淋巴细胞,对特异性抗原Tg的刺激的增殖数量与C组比较升高(P<0.01)。细胞因子水平：NOD小鼠除HI组IL-4水平没有变化外,其余细胞因子(IL-10、IL-12、IFN-γ)水平在各实验组均较C组升高(P<0.05或0.01)；BALB/c小鼠HI组IL-4、IL-10和IFN-γ三种细胞因子水平与C组比无变化,其余两组这三种细胞因子水平升高(P<0.01),而IL-12在各实验组均表现为水平下降(P<0.01)。
4.甲状腺滤泡上皮细胞凋亡情况：两品系小鼠C组甲状腺中偶见弱阳性细胞。NOD小鼠HI和HI+Tg组可见大量阳性细胞,而Tg组和BALB/c小鼠各实验组较各自C组凋亡细胞数量略有增加。
5. TRAIL和受体在甲状腺内的表达：
免疫荧光染色结果：NOD小鼠C组甲状腺不见TRAIL和DR5的表达；Tg组有散在的TRAIL和DR5的表达；HI组二者的表达均增加；HI+Tg组甲状腺中TRAIL和DR5的表达进一步增加。TRAIL表达在甲状腺滤泡上皮细胞和浸润的炎细胞上,并且炎细胞上TRAIL的表达强度明显高于甲状腺滤泡上皮细胞；而DR5仅表达在甲状腺滤泡上皮细胞上。BALB/c小鼠各实验组均有少量TRAIL表达在甲状腺滤泡上皮细胞或浸润炎细胞上,但表达强度明显弱于NOD小鼠；各组均未见DR5的阳性表达。
基因表达结果：NOD小鼠TRAIL的表达在各实验组较C组均明显升高(P<0.01)；DR4的表达在HI和HI+Tg组明显升高(P<0.01),Tg组无明显变化。BALB/c小鼠TRAIL和DR4的表达在联合组明显升高(P<0.01),Tg组TRAIL的表达略有升高(P<0.05),其余与C组无异。
6.炎症相关因子在甲状腺内的表达：
免疫荧光染色结果：(1)C组甲状腺均未见CD3阳性细胞。NOD小鼠Tg组有散在CD3阳性细胞,HI和HI+Tg组可见大量CD3阳性淋巴细胞,HI+Tg组面积更大,且有纤维化出现。而BALB/c小鼠Tg组和HI组甲状腺内仅有零星CD3阳性细胞；HI+Tg组略有增加。BALB/c小鼠均未见CD22阳性细胞；NOD小鼠Tg组甲状腺有零星CD22阳性细胞,HI组未见, HI+Tg组甲状腺炎症区内有少量CD22阳性细胞。(2)NOD小鼠C组甲状腺未见CCL21和CCR7的阳性表达；Tg组也不见CCL21的阳性表达,但可见散在的CCR7阳性细胞；在HI组和联合组可见局部炎症区域有CCL21的强阳性表达,且在这些部位亦可见CCR7阳性细胞的聚集。CCL21的表达位于甲状腺的间质部分,呈管腔样。BALB/c小鼠各组甲状腺内均未见CCL21-CCR7的阳性表达。
基因表达结果：NOD小鼠ICAM1、CXCL10、CCL21 mRNA的表达在各实验组均较C组明显升高(P<0.01)；而BALB/c小鼠,仅HI组和HI+Tg组ICAM1和CXCL10 mRNA的表达较C组升高(P<0.05或0.01),其余组没变化,CCL21的表达在各实验组与C组无差异。
结论：
1.碘过量可诱发敏感小鼠发生EAT,而非敏感小鼠不发生,说明过量的碘摄入只是诱发HT的一个重要环境因素,遗传易感性是其发病的决定因素。
2.碘过量和Tg免疫均能诱发敏感品系小鼠发生EAT,但诱发途径不同。Tg作为自身抗原通过刺激机体自身免疫反应；而碘过量主要是通过对甲状腺细胞的损伤作用诱发EAT。Tg免疫和碘过量联合作用加重EAT的炎症程度。
3.两品系小鼠淋巴细胞对Tg刺激的反应不同。BALB/c小鼠细胞增殖反应好于NOD小鼠。NOD小鼠各实验组Th1和Th2细胞因子在互相竞争抑制作用中都有所升高,但升高水平都有限；而BALB/c小鼠Thl和Th2细胞因子的基础水平高于NOD小鼠,并且其Th2反应明显强于Thl反应。
4. TRAIL与受体DR4或DR5结合能促进AT甲状腺滤泡上皮细胞凋亡。TRAIL诱导的凋亡与炎症细胞浸润程度相关,但决定于死亡受体的表达水平,配体受体二者缺一不可。
5.趋化因子CCL21及受体CCR7在促进AT淋巴细胞浸润中有重要作用,当甲状腺受到致炎因子损害时,CCL21和CCR7作用能够趋化循环中的淋巴细胞向甲状腺内募集。
6. ICAM-1和CXCL10在甲状腺炎时基因表达水平升高,说明在炎细胞浸润过程中他们也发挥着黏附和趋化的作用。
Objective:In this experiment, we treated the different strain mice with drinking iodine excess water, Tg immunization and both. Then observed the thyroid morphology and function change, cytokines secretion by spleen lymphocytes, if and where inflammation and apoptosis related receptor/ligand emerged in thyroid, the level of inflammation and apoptosis related gene expressed in thytoid of both strain mice. Thus to reveal the distinct influence of environmental factors on inducing individuals with different genetic background to develop autoimmune thyroiditis (AT), investigate the mechanisms of lymphocytic infiltration in thyroid and epithelial cell apoptosis in AT and to provide experimental foundation for reveal etiological factor and pathogenesy of human autoimmune thyroiditis.
Methods:Female,7-8 weeks old NOD and BALB/c mice were used and randomly devided into four groups:control group (C):drank deionized water, Tg group (Tg): drank deionized water, immunized with 0.1 mg Tg to each mouse by subcutaneously injection at 8 weeks old and enhanced at 11 and 15 weeks old, iodine excess group (HI):received 0.05% NaI water, iodine excess+Tg group (HI+Tg):received 0.05% NaI water, Tg immunization was same as Tg group. At 16 weeks old, we weighed mice body weight, collected blood samples, observed the thyroid morphous and measured the weight of the thyroid after mice were sacrificed. HE staining was employed to observe the histopathology of thyroid, TUNEL was used to detect the apoptosis of thyroid follicle epithelial cells, RIA and ELISA were used respectively to detect TT4、TgAb、TPOAb and TSH level in serum. MTT method for lymphocytic proliferation, IL-4, IFN-y, IL-10, IL-12 levels in splenocyte culture supernatants were assayed by ELISA. Immunofluorescence staining to observe if and where CD3, CD22, CD31, Podoplanin, CCL21, CCR7, TRAIL and TRAIL-R2 (DR5) emerged in thyroid. SYBR Green real-time PCR was used to detect the levels of inflammation related genes (CCL21, ICAM-1 and CXCL10) and apoptosis related genes (TRAIL and TRAIL-sRl (DR4)) expression.
Results:
1. Morphology change of thyroid: for the mice of two strain, enlargement of the thyroid was observed in the HI and HI+Tg group than C group, the absolute and relative weight were increased (P<0.01), and enlarged follicular lumen with colloid accumulation was observed. For NOD mice thyroid of HI and HI+Tg group, focus lymphocytic infiltration was seen, partly fibrosis was also seen in HI+Tg group.
2. Hormore and autoantibodies leve in serum: for two strain mice, the HI group had a lower level of TT4 and a higher level of TSH compared with C group. But the level of TT4 and TSH in Tg and HI+Tg group were both higher than their C group (P<0.01). TgAb, TPOAb were producted in two groups performed Tg immunization (P<0.01).
3. Lymphocytic proliferation and cytokines level in splenocyte culture supernatants: after stimulated with Tg in vitro, compared with C group, lymphocytic proliferation increased in each experiment group of two strain mice (P<0.01) except HI group of BALB/c mice. Cytokines level:for NOD mice, cytokines level were all elevated in each experiment group to C group (P<0.05 or 0.01) except IL-4 level in HI group. For BALB/c mice, IL-4, IL-10 and IFN-γlevel elevated in Tg and HI+Tg group (P<0.01), no change in HI group, IL-12 level decreased in all experiment groups (P<0.01).
4. Apoptosis of thyroid follicle cells:C group thyroid of two strain mice have few weakly positive cells. For NOD mice, large amount of positive cells were observed in HI and HI+Tg groups, but for Tg group and experiment groups of BALB/c mice, postive cells were only a little more than C groups.
5. TRAIL and its receptor expression in thyroid:
Immunofluorescecce staining: In C group thyroid of NOD mice, TRAIL and DR5 were negative. Scattered TRAIL and DR5 positive expression in Tg group, their expression increased in HI group, and more in HI+Tg group. TRAIL was expressed on thyroid follicle epithelial cells and infiltrating inflammatory cells, the expression intension on inflammatory cells is stronger than on thyrocytes, DR5 located on thyroid follicular epithelial cells. For BALB/c mice, small amout of TRAIL expressed on thyrocytes or inflammatory cells in each experiment group, weaker than NOD mice. No DR5 expression in BALB/c mice.
Genetic expression:For NOD mice thyroid, TRAIL expression increased in all experiment groups (P<0.01), DR4 increased in HI and HI+Tg groups except Tg group (P<0.01). In BALB/c mice, TRAIL in Tg and HI+Tg group (P<0.05 and 0.01) and DR4 in HI+Tg group increased (P<0.01).
6. Inflammation related gene expression in thyroid:
Immunofluorescecce staining:(1) No CD3 positive cell in C group. For NOD mice thyroid, scattered CD3 positive cells in Tg group, large amount of CD3 positive cells were seen in HI and HI+Tg group and HI+Tg group has a bigger area and fibration was emerged. BALB/c mice, CD3 positive cells were very few in Tg and HI groups, a little more positive cells in HI+Tg group. No CD22 positive cells in BALB/c mice thyroid. NOD mice, two or three CD22 positive cells in Tg group, no CD22 positive cell in HI group, few CD22 positive cells in HI+Tg group. (2) CCL21 and CCR7 were negative in C group thyroid in NOD mice. CCR7 positive cells were scattered in Tg group but no CCL21 expression. In HI and HI+Tg group, we can see CCL21 strong positive expression in inflammation area and also has CCR7 positive cells there. The expression of CCL21 located in stroma and lumens like. BALB/c mice thyroid did not have CCL21 and CCR7 expression.
Genetic expression: ICAM1, CXCL10, CCL21 mRNA expression were all increased in three experiment groups compared with C group in NOD mice (P<0.01). For BALB/c mice, ICAM1, CXCL10 mRNA expression increased in HI and HI+Tg group (P<0.05 and 0.01), CCL21 expression did not change in BALB/c mice thyroid.
Conclusions:
1. Iodine excess can induce EAT in sensitive mice but not in non-sensitive mice, indicating that intake excessive iodine is only an important environmental factor; the genetic background determines the onset of HT.
2. Both iodine excess and Tg immunization can induce sensitive mice EAT, but by different ways. Tg as an autoantigen can stimulate the autoimmune response, iodine excess is mainly by thyrocytes damage to induce EAT. Tg immunization combine iodine excess aggravate inflammation in EAT.
3. Lymphocytes of two strain mice had different reaction to Tg stimulation. Cell proliferation reaction in BALB/ c mice was stronger than NOD mice. In NOD mice experiment groups, both Th1 and Th2 cytokines elevated under their competitive and inhibitive interactions though not significantly elevated. But for BALB/c mice, the basic level of Th1 and Th2 cytokines were higher than NOD mice and Th2 reaction was stronger than Th1 reaction.
4. TRAIL binding its receptors DR4 or DR5 can promote thyroid follicular epithelial cells apoptosis in AT. TRAIL induced apoptosis was positive correlation with the extent of inflammatory cells infiltration, but determined by the level of death receptors expression, ligand and receptor not a single one can be omitted.
5. Chemokine CCL21 and its receptor CCR7 are important in lymphocytic infiltration in AT. When thyroid suffer inflammation inducing factors, CCL21 with CCR7 can recruitment lymphocytes to thyroid from circulatory system.
6. ICAM-1 and CXCL10 expression increased in thyroiditis, indicating that they have adhesive attraction and chemotaxis during lymphocytic infiltration.
方法：选用雌性、7-8周龄的NOD小鼠和BALB/c小鼠。两品系小鼠均随机分为4组：对照组(C)：饮去离子水；Tg组(Tg)：饮去离子水、在8周龄时给予每只鼠0.1mgTg皮下免疫,11周龄、15周龄加强免疫两次；碘过量组(HI)：饮用0.05%NaI水；碘过量+Tg组(HI+Tg)：饮0.05%NaI水,Tg免疫同Tg组。在小鼠16周龄时称体重、取血、处死全部小鼠,观察甲状腺组织大体形态并称重；采用HE染色观察甲状腺组织形态学变化；TUNEL法检测甲状腺滤泡上皮细胞凋亡情况；采用RIA法和ELISA法分别检测TT4、TgAb、TPOAb和TSH的水平；MTT法检测淋巴细胞增殖情况；ELISA法检测脾细胞培养上清中IL-4、IFN-γ、IL-10、IL-12的水平；免疫荧光染色观察甲状腺中CD3、CD22、CD31、Podoplanin、CCL21、CCR7、TRAIL、TRAIL-R2 (DR5)的表达及定位；采用SYBR Green实时荧光定量PCR法,检测甲状腺中炎症相关基因(CCL21、ICAM-1、CXCL10)和凋亡相关基因(TRAIL、TRAIL-sR1 (DR4))的表达水平。
结果：
1.甲状腺组织形态学变化：两品系小鼠HI组和HI+Tg组甲状腺较C组肿大,绝对和相对重量增加(P<0.01),出现滤泡扩张、胶质潴留。NOD小鼠这两组甲状腺内还可见呈灶性分布的淋巴细胞浸润,HI+Tg组伴局部纤维化。
2.血清激素与抗体水平：两品系小鼠HI组TT4水平较各自C组呈一定程度的下降,同时TSH水平升高；而Tg组和HI+Tg组TT4和TSH水平均较各自C组升高(P<0.01)。两品系小鼠Tg免疫后的两组有TgAb、TPOAb的生成(P<0.01)。
3.淋巴细胞增殖及脾细胞培养上清中细胞因子水平：体外给予Tg刺激后,除了BALB/c鼠HI组,两品系小鼠其余各实验组淋巴细胞,对特异性抗原Tg的刺激的增殖数量与C组比较升高(P<0.01)。细胞因子水平：NOD小鼠除HI组IL-4水平没有变化外,其余细胞因子(IL-10、IL-12、IFN-γ)水平在各实验组均较C组升高(P<0.05或0.01)；BALB/c小鼠HI组IL-4、IL-10和IFN-γ三种细胞因子水平与C组比无变化,其余两组这三种细胞因子水平升高(P<0.01),而IL-12在各实验组均表现为水平下降(P<0.01)。
4.甲状腺滤泡上皮细胞凋亡情况：两品系小鼠C组甲状腺中偶见弱阳性细胞。NOD小鼠HI和HI+Tg组可见大量阳性细胞,而Tg组和BALB/c小鼠各实验组较各自C组凋亡细胞数量略有增加。
5. TRAIL和受体在甲状腺内的表达：
免疫荧光染色结果：NOD小鼠C组甲状腺不见TRAIL和DR5的表达；Tg组有散在的TRAIL和DR5的表达；HI组二者的表达均增加；HI+Tg组甲状腺中TRAIL和DR5的表达进一步增加。TRAIL表达在甲状腺滤泡上皮细胞和浸润的炎细胞上,并且炎细胞上TRAIL的表达强度明显高于甲状腺滤泡上皮细胞；而DR5仅表达在甲状腺滤泡上皮细胞上。BALB/c小鼠各实验组均有少量TRAIL表达在甲状腺滤泡上皮细胞或浸润炎细胞上,但表达强度明显弱于NOD小鼠；各组均未见DR5的阳性表达。
基因表达结果：NOD小鼠TRAIL的表达在各实验组较C组均明显升高(P<0.01)；DR4的表达在HI和HI+Tg组明显升高(P<0.01),Tg组无明显变化。BALB/c小鼠TRAIL和DR4的表达在联合组明显升高(P<0.01),Tg组TRAIL的表达略有升高(P<0.05),其余与C组无异。
6.炎症相关因子在甲状腺内的表达：
免疫荧光染色结果：(1)C组甲状腺均未见CD3阳性细胞。NOD小鼠Tg组有散在CD3阳性细胞,HI和HI+Tg组可见大量CD3阳性淋巴细胞,HI+Tg组面积更大,且有纤维化出现。而BALB/c小鼠Tg组和HI组甲状腺内仅有零星CD3阳性细胞；HI+Tg组略有增加。BALB/c小鼠均未见CD22阳性细胞；NOD小鼠Tg组甲状腺有零星CD22阳性细胞,HI组未见, HI+Tg组甲状腺炎症区内有少量CD22阳性细胞。(2)NOD小鼠C组甲状腺未见CCL21和CCR7的阳性表达；Tg组也不见CCL21的阳性表达,但可见散在的CCR7阳性细胞；在HI组和联合组可见局部炎症区域有CCL21的强阳性表达,且在这些部位亦可见CCR7阳性细胞的聚集。CCL21的表达位于甲状腺的间质部分,呈管腔样。BALB/c小鼠各组甲状腺内均未见CCL21-CCR7的阳性表达。
基因表达结果：NOD小鼠ICAM1、CXCL10、CCL21 mRNA的表达在各实验组均较C组明显升高(P<0.01)；而BALB/c小鼠,仅HI组和HI+Tg组ICAM1和CXCL10 mRNA的表达较C组升高(P<0.05或0.01),其余组没变化,CCL21的表达在各实验组与C组无差异。
结论：
1.碘过量可诱发敏感小鼠发生EAT,而非敏感小鼠不发生,说明过量的碘摄入只是诱发HT的一个重要环境因素,遗传易感性是其发病的决定因素。
2.碘过量和Tg免疫均能诱发敏感品系小鼠发生EAT,但诱发途径不同。Tg作为自身抗原通过刺激机体自身免疫反应；而碘过量主要是通过对甲状腺细胞的损伤作用诱发EAT。Tg免疫和碘过量联合作用加重EAT的炎症程度。
3.两品系小鼠淋巴细胞对Tg刺激的反应不同。BALB/c小鼠细胞增殖反应好于NOD小鼠。NOD小鼠各实验组Th1和Th2细胞因子在互相竞争抑制作用中都有所升高,但升高水平都有限；而BALB/c小鼠Thl和Th2细胞因子的基础水平高于NOD小鼠,并且其Th2反应明显强于Thl反应。
4. TRAIL与受体DR4或DR5结合能促进AT甲状腺滤泡上皮细胞凋亡。TRAIL诱导的凋亡与炎症细胞浸润程度相关,但决定于死亡受体的表达水平,配体受体二者缺一不可。
5.趋化因子CCL21及受体CCR7在促进AT淋巴细胞浸润中有重要作用,当甲状腺受到致炎因子损害时,CCL21和CCR7作用能够趋化循环中的淋巴细胞向甲状腺内募集。
6. ICAM-1和CXCL10在甲状腺炎时基因表达水平升高,说明在炎细胞浸润过程中他们也发挥着黏附和趋化的作用。
Objective:In this experiment, we treated the different strain mice with drinking iodine excess water, Tg immunization and both. Then observed the thyroid morphology and function change, cytokines secretion by spleen lymphocytes, if and where inflammation and apoptosis related receptor/ligand emerged in thyroid, the level of inflammation and apoptosis related gene expressed in thytoid of both strain mice. Thus to reveal the distinct influence of environmental factors on inducing individuals with different genetic background to develop autoimmune thyroiditis (AT), investigate the mechanisms of lymphocytic infiltration in thyroid and epithelial cell apoptosis in AT and to provide experimental foundation for reveal etiological factor and pathogenesy of human autoimmune thyroiditis.
Methods:Female,7-8 weeks old NOD and BALB/c mice were used and randomly devided into four groups:control group (C):drank deionized water, Tg group (Tg): drank deionized water, immunized with 0.1 mg Tg to each mouse by subcutaneously injection at 8 weeks old and enhanced at 11 and 15 weeks old, iodine excess group (HI):received 0.05% NaI water, iodine excess+Tg group (HI+Tg):received 0.05% NaI water, Tg immunization was same as Tg group. At 16 weeks old, we weighed mice body weight, collected blood samples, observed the thyroid morphous and measured the weight of the thyroid after mice were sacrificed. HE staining was employed to observe the histopathology of thyroid, TUNEL was used to detect the apoptosis of thyroid follicle epithelial cells, RIA and ELISA were used respectively to detect TT4、TgAb、TPOAb and TSH level in serum. MTT method for lymphocytic proliferation, IL-4, IFN-y, IL-10, IL-12 levels in splenocyte culture supernatants were assayed by ELISA. Immunofluorescence staining to observe if and where CD3, CD22, CD31, Podoplanin, CCL21, CCR7, TRAIL and TRAIL-R2 (DR5) emerged in thyroid. SYBR Green real-time PCR was used to detect the levels of inflammation related genes (CCL21, ICAM-1 and CXCL10) and apoptosis related genes (TRAIL and TRAIL-sRl (DR4)) expression.
Results:
1. Morphology change of thyroid: for the mice of two strain, enlargement of the thyroid was observed in the HI and HI+Tg group than C group, the absolute and relative weight were increased (P<0.01), and enlarged follicular lumen with colloid accumulation was observed. For NOD mice thyroid of HI and HI+Tg group, focus lymphocytic infiltration was seen, partly fibrosis was also seen in HI+Tg group.
2. Hormore and autoantibodies leve in serum: for two strain mice, the HI group had a lower level of TT4 and a higher level of TSH compared with C group. But the level of TT4 and TSH in Tg and HI+Tg group were both higher than their C group (P<0.01). TgAb, TPOAb were producted in two groups performed Tg immunization (P<0.01).
3. Lymphocytic proliferation and cytokines level in splenocyte culture supernatants: after stimulated with Tg in vitro, compared with C group, lymphocytic proliferation increased in each experiment group of two strain mice (P<0.01) except HI group of BALB/c mice. Cytokines level:for NOD mice, cytokines level were all elevated in each experiment group to C group (P<0.05 or 0.01) except IL-4 level in HI group. For BALB/c mice, IL-4, IL-10 and IFN-γlevel elevated in Tg and HI+Tg group (P<0.01), no change in HI group, IL-12 level decreased in all experiment groups (P<0.01).
4. Apoptosis of thyroid follicle cells:C group thyroid of two strain mice have few weakly positive cells. For NOD mice, large amount of positive cells were observed in HI and HI+Tg groups, but for Tg group and experiment groups of BALB/c mice, postive cells were only a little more than C groups.
5. TRAIL and its receptor expression in thyroid:
Immunofluorescecce staining: In C group thyroid of NOD mice, TRAIL and DR5 were negative. Scattered TRAIL and DR5 positive expression in Tg group, their expression increased in HI group, and more in HI+Tg group. TRAIL was expressed on thyroid follicle epithelial cells and infiltrating inflammatory cells, the expression intension on inflammatory cells is stronger than on thyrocytes, DR5 located on thyroid follicular epithelial cells. For BALB/c mice, small amout of TRAIL expressed on thyrocytes or inflammatory cells in each experiment group, weaker than NOD mice. No DR5 expression in BALB/c mice.
Genetic expression:For NOD mice thyroid, TRAIL expression increased in all experiment groups (P<0.01), DR4 increased in HI and HI+Tg groups except Tg group (P<0.01). In BALB/c mice, TRAIL in Tg and HI+Tg group (P<0.05 and 0.01) and DR4 in HI+Tg group increased (P<0.01).
6. Inflammation related gene expression in thyroid:
Immunofluorescecce staining:(1) No CD3 positive cell in C group. For NOD mice thyroid, scattered CD3 positive cells in Tg group, large amount of CD3 positive cells were seen in HI and HI+Tg group and HI+Tg group has a bigger area and fibration was emerged. BALB/c mice, CD3 positive cells were very few in Tg and HI groups, a little more positive cells in HI+Tg group. No CD22 positive cells in BALB/c mice thyroid. NOD mice, two or three CD22 positive cells in Tg group, no CD22 positive cell in HI group, few CD22 positive cells in HI+Tg group. (2) CCL21 and CCR7 were negative in C group thyroid in NOD mice. CCR7 positive cells were scattered in Tg group but no CCL21 expression. In HI and HI+Tg group, we can see CCL21 strong positive expression in inflammation area and also has CCR7 positive cells there. The expression of CCL21 located in stroma and lumens like. BALB/c mice thyroid did not have CCL21 and CCR7 expression.
Genetic expression: ICAM1, CXCL10, CCL21 mRNA expression were all increased in three experiment groups compared with C group in NOD mice (P<0.01). For BALB/c mice, ICAM1, CXCL10 mRNA expression increased in HI and HI+Tg group (P<0.05 and 0.01), CCL21 expression did not change in BALB/c mice thyroid.
Conclusions:
1. Iodine excess can induce EAT in sensitive mice but not in non-sensitive mice, indicating that intake excessive iodine is only an important environmental factor; the genetic background determines the onset of HT.
2. Both iodine excess and Tg immunization can induce sensitive mice EAT, but by different ways. Tg as an autoantigen can stimulate the autoimmune response, iodine excess is mainly by thyrocytes damage to induce EAT. Tg immunization combine iodine excess aggravate inflammation in EAT.
3. Lymphocytes of two strain mice had different reaction to Tg stimulation. Cell proliferation reaction in BALB/ c mice was stronger than NOD mice. In NOD mice experiment groups, both Th1 and Th2 cytokines elevated under their competitive and inhibitive interactions though not significantly elevated. But for BALB/c mice, the basic level of Th1 and Th2 cytokines were higher than NOD mice and Th2 reaction was stronger than Th1 reaction.
4. TRAIL binding its receptors DR4 or DR5 can promote thyroid follicular epithelial cells apoptosis in AT. TRAIL induced apoptosis was positive correlation with the extent of inflammatory cells infiltration, but determined by the level of death receptors expression, ligand and receptor not a single one can be omitted.
5. Chemokine CCL21 and its receptor CCR7 are important in lymphocytic infiltration in AT. When thyroid suffer inflammation inducing factors, CCL21 with CCR7 can recruitment lymphocytes to thyroid from circulatory system.
6. ICAM-1 and CXCL10 expression increased in thyroiditis, indicating that they have adhesive attraction and chemotaxis during lymphocytic infiltration.
引文
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