犬尿氨酸对体液免疫应答的影响及其机制的初步探讨
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摘要
自身免疫性疾病严重危害着人类的健康,其发病率呈现升高趋势。然而,目前临床上用于治疗自身免疫性疾病的药物,存在着诱发感染、肿瘤形成,尤其是弱的靶向性等副作用。急需寻找新的自身免疫性疾病的治疗策略。疫苗接种具有诱发抗原特异性免疫应答及形成长久免疫记忆的特点。因此,采用特异性抗原与致耐受性或抑制性佐剂联合免疫机体,诱导机体产生针对特异性抗原的免疫耐受或免疫抑制,是一种较为理想的治疗策略。多种诱发自身免疫性疾病形成的自身抗原已经被鉴别,但是,目前尚无合适的致耐受性或抑制性佐剂能被用于新的自身免疫性疾病的治疗策略。为了能确保新的治疗策略的顺利进行,需要探讨新的致耐受或抑制性佐剂及其作用机制。
犬尿氨酸是一种生理性物质,作为佐剂较其它外源性物质具有更好的安全性。在本论文中,首先,通过将犬尿氨酸与抗原(甲型肝炎病毒)联合免疫动物,阐明了在体内,犬尿氨酸具有作为抑制性佐剂的能力；ELISA数据表明犬尿氨酸可以显著性的下调甲型肝炎病毒诱导的特异性体液免疫应答,且在试验期内均具有较好的效果。B细胞是参与体液免疫应答的主要细胞,而且体外培养的B细胞在受到TD或TI抗原的刺激后,具有免疫球蛋白类别转化重排及向抗体分泌型的浆细胞分化的能力,所以,为体外研究体液免疫应答提供了一个很好的试验平台。随后,通过体外培养B淋巴细胞,并给予特定浓度犬尿氨酸+脂多糖处理,进一步阐明了在体外,犬尿氨酸同样具有作为抑制性佐剂的能力；ELISA结果表明特定浓度的犬尿氨酸能使脂多糖诱导的体液免疫应答明显下降。体内外的实验数据均表明犬尿氨酸是一种新型的抑制性佐剂,具有下调抗原免疫原性的能力。
MicroRNA在多种生理过程中发挥着重要作用,包括胚胎发育、肿瘤形成、细胞增殖、凋亡及分化、信号转导等。MicroRNA与其靶基因的相互作用是“中心法则”之外的一种基因表达调控方式。在生物体内,大约30-60%的基因表达受microRNA的调解,并且,也发现多种microRNA参与了B细胞末端分化过程。我们提出某种microRNA可能参与了犬尿氨酸抑制脂多糖诱导的体液免疫应答过程。Real-time PCR证实了犬尿氨酸能够引起microRNA30b (miR30b)的表达下调,而且其也可削弱脂多糖诱导的miR30b表达上调。ELISA数据进一步表明miR30b参与了脂多糖诱导的体液免疫应答,而且证明了miR30b参与了犬尿氨酸抑制脂多糖诱导的体液免疫应答过程。
在RNA沉默复合体中,microRNA通过2-7个核酸种子序列与靶基因3'UTR的互补序列结合,导致靶基因的直接降解或稳定性减弱,进而达到抑制靶基因的表达。通过荧光素霉双报告系统,human Bach2mRNA和human Foxo3mRNA均被证明为miR30b的靶基因：Western blot分析也表明,在人正常B淋巴细胞中,miR30b能够下调human Bach2和human Foxo3的蛋白表达水平;同时也证实了在犬尿氨酸抑制脂多糖诱导的体液免疫应答过程中,miR30b可以影响human Bach2和human Foxo3的蛋白表达水平。
Bach2作为一种转录抑制子参与B细胞末端分化的调控,已经被众多学者接受。Foxo3是FOXO转录因子家族成员之一；广泛分布于多种细胞,包括T细胞、B细胞和树突状细胞；其除了在细胞存活、增殖、凋亡、代谢、应急反应、衰老、维持机体内环境稳态等生理过程中发挥着重要作用,还在调节免疫应答方面起着一定的作用。由于尚无商品化的human Foxo3蛋白,我们利用基因重组技术成功构建了pcDNA3.1(+)-human Foxo3过表达质粒,并利用human Foxo3的过表达、敲除探讨了其对犬尿氨酸抑制脂多糖诱导的体液免疫应答的影响,以及其在miR30b影响脂多糖诱导的体液免疫应答过程中发挥的作用。ELISA数据表明human Foxo3蛋白参与了miR30b影响脂多糖诱导的体液免疫应答的过程。
本论文证实了犬尿氨酸能够抑制抗原诱导的体液免疫应答及削弱抗原免疫原性；在体外培养的B淋巴细胞中,miR30b参与了犬尿氨酸作为抑制性佐剂发挥作用的过程；并且也证实了human Bach2mRNA和human Foxo3mRNA均为miR30b的靶基因;另外,也证实了human Foxo3参与了miR30b影响脂多糖诱导的体液免疫应答的过程。这些数据表明犬尿氨酸是一种有效的抑制性佐剂,为新的自身免疫性疾病的治疗策略提供了一种新型的抑制性佐剂。
There is a seriously effect of autoimmune diseases on human health. The data showed that the incidence of autoimmune diseases is gradually trend to increase. However, there are many side effects of the currently-used therapeutic strategies, including immunosuppressive agents, cytokines, and TNF-a antagonists, such as causing tumors, infection, as well as delayed dysfunction, and especially reduced targeting effectiveness. Thus, a novel strategy is required to improve therapeutic effects. Vaccination against autoimmune diseases is a feasible strategy because vaccines induce immune response memory and the antigen specificity. Recovering tolerance or down-regulating the immune response to non-harmful antigens is a better ideal way to treat autoimmune diseases through administrating a mixture of special antigen with adjuvant that decreases the strength of the immune response. Recent medical advances have included determining the self-antigens for various autoimmune diseases. However, no suitable adjuvant is available to direct the immune response toward tolerance or suppression. Thus, it is difficult to find novel tolerogenic/suppressive adjuvants and to understand their biological mechanisms of action for a successful new therapeutic strategy.
Kynurenine (Kyn), an endogenous substance, is safer than exogenous substances when considered as a vaccine adjuvant. In this thesis, firstly, we evaluated whether Kyn could serve as a novel tolerogenic or suppressive adjuvant to decrease the humoral immune responses against hepatitis A virus (HAV) in the ICR mouse model in vivo. The data showed that Kyn significantly decreased HAV immunogenicity when co-administered with HAV and that the effect appeared throughout the test period. B cells play a key role in the humoral immune response. In addition to the experimental animal model, B cell terminal differentiation also can be studied successfully in vitro, because B cells are capable of both immunoglobulin class switch recombination and differentiation toward antibody-secreting plasma cells in response to a TD stimulus or a T1-related signal such as lipopolysaccharide (LPS). B cell responses in vitro thus provide a controlled system to investigate the humoral immune response on both a cellular and molecular level. Subsequently, the function of Kyn as a novel suppressive adjuvant in vitro was evaluated by stimulating B cells with the mixture of Kyn and LPS. The results showed that Kyn (100μM/1000μM) impaired IgM generation compared to that induced by LPS alone. These findings suggest that Kyn is able to attenuate the antigenic immunogenicity, and that can serve as a novel and effective suppressive adjuvant for vaccines.
MicroRNAs play important and broad roles in a wide variety of biological processes, including embryogenesis, carcinogenesis, proliferation and apoptosis, differentiation and signal transduction. The interaction between microRNA and its target gene is a regulation of gene expression except for 'Central Dogma of Molecular Biology'. It has been estimated that30-60%of the genes in a given genome are regulated in this manner. Furthermore, several microRNAs were identified involving in the progress of B cell terminal differentiation. We provide the hypothesis that some microRNA involves in the progress of Kyn-mediated suppressive humoral immune responses induced by LPS. In this study, we analyzed the contribution of microRNAs to the process of humoral immune responses suppressed by Kyn, and found that, in the presence of Kyn, the level of microRNA30b (miR30b) was significantly decreased compared to that in the corresponding control group. We also demonstrated that miR30b played a critical role in the process of Kyn-mediated suppression of IgM responses induced by LPS.
In the RNA-induced silencing complex, microRNA down-regulates the expression of the target gene either by direct degradation or destabilization and eventually suppresses translation of the target through binding to the target sequence in the3'UTR via the2-7nucleotide seed region. Our results demonstrated that human Bach2and human Foxo3were novel targets of miR30b through Dual-Luciferase Reporter Assay System. Next, the results were further strengthened by reducing the protein levels of human Bach2and human Foxo3by miR30b in normal human B cells through Western blot assay. At same time, we also demonstrated that there are effects of miR30b on the protein levels of human Bach2and human Foxo3in the process of Kyn-mediated suppression of IgM responses induced by LPS.
Bach2, a transcriptional repressor, is well known for the regulation of B cell terminal differentiation. Foxo3is one of the members of the FOXO transcription factor family, exists in a variety of cells such as T cell, B cell and dendritic cell, and plays a role in many physiological processes, including cell survival, proliferation, apoptosis, metabolism, emergency response, aging, maintaining homeostasis and immune response. Since there is no commercial human Foxo3 protein, we successfully constructed recombination plasmid of pcDNA3.1(+)-human Foxo3, and evaluated that the effect of Foxo3on the process of IgM responses induced by LPS in normal human B cells treated with Kyn or miR30b on the basis of it. The data of ELISA showed that human Foxo3plays an important role in the process of miR30b-mediated humarol immune responses.
In conclusion, our data demonstrate that Kyn can suppress the humoral immune responses induced by special antigen and attenuate antigenic immunogenicity. In B cells in vitro, miR30b plays an important role in Kyn-mediated suppression of IgM responses induced by LPS. Bach2and Foxo3were novel targets of miR30b. In addition, we also successfully constructed the recombination plasmid of pcDNA3.1(+)-human Foxo3, and demonstrate that Foxo3plays an important role in the process of miR30b-mediated humarol immune responses. These findings suggest that Kyn can serve as a novel and effective suppressive adjuvant for vaccines.
犬尿氨酸是一种生理性物质,作为佐剂较其它外源性物质具有更好的安全性。在本论文中,首先,通过将犬尿氨酸与抗原(甲型肝炎病毒)联合免疫动物,阐明了在体内,犬尿氨酸具有作为抑制性佐剂的能力；ELISA数据表明犬尿氨酸可以显著性的下调甲型肝炎病毒诱导的特异性体液免疫应答,且在试验期内均具有较好的效果。B细胞是参与体液免疫应答的主要细胞,而且体外培养的B细胞在受到TD或TI抗原的刺激后,具有免疫球蛋白类别转化重排及向抗体分泌型的浆细胞分化的能力,所以,为体外研究体液免疫应答提供了一个很好的试验平台。随后,通过体外培养B淋巴细胞,并给予特定浓度犬尿氨酸+脂多糖处理,进一步阐明了在体外,犬尿氨酸同样具有作为抑制性佐剂的能力；ELISA结果表明特定浓度的犬尿氨酸能使脂多糖诱导的体液免疫应答明显下降。体内外的实验数据均表明犬尿氨酸是一种新型的抑制性佐剂,具有下调抗原免疫原性的能力。
MicroRNA在多种生理过程中发挥着重要作用,包括胚胎发育、肿瘤形成、细胞增殖、凋亡及分化、信号转导等。MicroRNA与其靶基因的相互作用是“中心法则”之外的一种基因表达调控方式。在生物体内,大约30-60%的基因表达受microRNA的调解,并且,也发现多种microRNA参与了B细胞末端分化过程。我们提出某种microRNA可能参与了犬尿氨酸抑制脂多糖诱导的体液免疫应答过程。Real-time PCR证实了犬尿氨酸能够引起microRNA30b (miR30b)的表达下调,而且其也可削弱脂多糖诱导的miR30b表达上调。ELISA数据进一步表明miR30b参与了脂多糖诱导的体液免疫应答,而且证明了miR30b参与了犬尿氨酸抑制脂多糖诱导的体液免疫应答过程。
在RNA沉默复合体中,microRNA通过2-7个核酸种子序列与靶基因3'UTR的互补序列结合,导致靶基因的直接降解或稳定性减弱,进而达到抑制靶基因的表达。通过荧光素霉双报告系统,human Bach2mRNA和human Foxo3mRNA均被证明为miR30b的靶基因：Western blot分析也表明,在人正常B淋巴细胞中,miR30b能够下调human Bach2和human Foxo3的蛋白表达水平;同时也证实了在犬尿氨酸抑制脂多糖诱导的体液免疫应答过程中,miR30b可以影响human Bach2和human Foxo3的蛋白表达水平。
Bach2作为一种转录抑制子参与B细胞末端分化的调控,已经被众多学者接受。Foxo3是FOXO转录因子家族成员之一；广泛分布于多种细胞,包括T细胞、B细胞和树突状细胞；其除了在细胞存活、增殖、凋亡、代谢、应急反应、衰老、维持机体内环境稳态等生理过程中发挥着重要作用,还在调节免疫应答方面起着一定的作用。由于尚无商品化的human Foxo3蛋白,我们利用基因重组技术成功构建了pcDNA3.1(+)-human Foxo3过表达质粒,并利用human Foxo3的过表达、敲除探讨了其对犬尿氨酸抑制脂多糖诱导的体液免疫应答的影响,以及其在miR30b影响脂多糖诱导的体液免疫应答过程中发挥的作用。ELISA数据表明human Foxo3蛋白参与了miR30b影响脂多糖诱导的体液免疫应答的过程。
本论文证实了犬尿氨酸能够抑制抗原诱导的体液免疫应答及削弱抗原免疫原性；在体外培养的B淋巴细胞中,miR30b参与了犬尿氨酸作为抑制性佐剂发挥作用的过程；并且也证实了human Bach2mRNA和human Foxo3mRNA均为miR30b的靶基因;另外,也证实了human Foxo3参与了miR30b影响脂多糖诱导的体液免疫应答的过程。这些数据表明犬尿氨酸是一种有效的抑制性佐剂,为新的自身免疫性疾病的治疗策略提供了一种新型的抑制性佐剂。
There is a seriously effect of autoimmune diseases on human health. The data showed that the incidence of autoimmune diseases is gradually trend to increase. However, there are many side effects of the currently-used therapeutic strategies, including immunosuppressive agents, cytokines, and TNF-a antagonists, such as causing tumors, infection, as well as delayed dysfunction, and especially reduced targeting effectiveness. Thus, a novel strategy is required to improve therapeutic effects. Vaccination against autoimmune diseases is a feasible strategy because vaccines induce immune response memory and the antigen specificity. Recovering tolerance or down-regulating the immune response to non-harmful antigens is a better ideal way to treat autoimmune diseases through administrating a mixture of special antigen with adjuvant that decreases the strength of the immune response. Recent medical advances have included determining the self-antigens for various autoimmune diseases. However, no suitable adjuvant is available to direct the immune response toward tolerance or suppression. Thus, it is difficult to find novel tolerogenic/suppressive adjuvants and to understand their biological mechanisms of action for a successful new therapeutic strategy.
Kynurenine (Kyn), an endogenous substance, is safer than exogenous substances when considered as a vaccine adjuvant. In this thesis, firstly, we evaluated whether Kyn could serve as a novel tolerogenic or suppressive adjuvant to decrease the humoral immune responses against hepatitis A virus (HAV) in the ICR mouse model in vivo. The data showed that Kyn significantly decreased HAV immunogenicity when co-administered with HAV and that the effect appeared throughout the test period. B cells play a key role in the humoral immune response. In addition to the experimental animal model, B cell terminal differentiation also can be studied successfully in vitro, because B cells are capable of both immunoglobulin class switch recombination and differentiation toward antibody-secreting plasma cells in response to a TD stimulus or a T1-related signal such as lipopolysaccharide (LPS). B cell responses in vitro thus provide a controlled system to investigate the humoral immune response on both a cellular and molecular level. Subsequently, the function of Kyn as a novel suppressive adjuvant in vitro was evaluated by stimulating B cells with the mixture of Kyn and LPS. The results showed that Kyn (100μM/1000μM) impaired IgM generation compared to that induced by LPS alone. These findings suggest that Kyn is able to attenuate the antigenic immunogenicity, and that can serve as a novel and effective suppressive adjuvant for vaccines.
MicroRNAs play important and broad roles in a wide variety of biological processes, including embryogenesis, carcinogenesis, proliferation and apoptosis, differentiation and signal transduction. The interaction between microRNA and its target gene is a regulation of gene expression except for 'Central Dogma of Molecular Biology'. It has been estimated that30-60%of the genes in a given genome are regulated in this manner. Furthermore, several microRNAs were identified involving in the progress of B cell terminal differentiation. We provide the hypothesis that some microRNA involves in the progress of Kyn-mediated suppressive humoral immune responses induced by LPS. In this study, we analyzed the contribution of microRNAs to the process of humoral immune responses suppressed by Kyn, and found that, in the presence of Kyn, the level of microRNA30b (miR30b) was significantly decreased compared to that in the corresponding control group. We also demonstrated that miR30b played a critical role in the process of Kyn-mediated suppression of IgM responses induced by LPS.
In the RNA-induced silencing complex, microRNA down-regulates the expression of the target gene either by direct degradation or destabilization and eventually suppresses translation of the target through binding to the target sequence in the3'UTR via the2-7nucleotide seed region. Our results demonstrated that human Bach2and human Foxo3were novel targets of miR30b through Dual-Luciferase Reporter Assay System. Next, the results were further strengthened by reducing the protein levels of human Bach2and human Foxo3by miR30b in normal human B cells through Western blot assay. At same time, we also demonstrated that there are effects of miR30b on the protein levels of human Bach2and human Foxo3in the process of Kyn-mediated suppression of IgM responses induced by LPS.
Bach2, a transcriptional repressor, is well known for the regulation of B cell terminal differentiation. Foxo3is one of the members of the FOXO transcription factor family, exists in a variety of cells such as T cell, B cell and dendritic cell, and plays a role in many physiological processes, including cell survival, proliferation, apoptosis, metabolism, emergency response, aging, maintaining homeostasis and immune response. Since there is no commercial human Foxo3 protein, we successfully constructed recombination plasmid of pcDNA3.1(+)-human Foxo3, and evaluated that the effect of Foxo3on the process of IgM responses induced by LPS in normal human B cells treated with Kyn or miR30b on the basis of it. The data of ELISA showed that human Foxo3plays an important role in the process of miR30b-mediated humarol immune responses.
In conclusion, our data demonstrate that Kyn can suppress the humoral immune responses induced by special antigen and attenuate antigenic immunogenicity. In B cells in vitro, miR30b plays an important role in Kyn-mediated suppression of IgM responses induced by LPS. Bach2and Foxo3were novel targets of miR30b. In addition, we also successfully constructed the recombination plasmid of pcDNA3.1(+)-human Foxo3, and demonstrate that Foxo3plays an important role in the process of miR30b-mediated humarol immune responses. These findings suggest that Kyn can serve as a novel and effective suppressive adjuvant for vaccines.
引文
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