干扰素诱导基因LY6E在HIV-1慢性感染中调节单核细胞对LPS刺激应答的研究
发布时间：2019-05-21 17:10
【摘要】：人免疫缺陷病毒(human immunodeficiency virus, HIV)感染的特征是外周血、淋巴器官以及黏膜组织中的CD4+T细胞数量的渐进性耗竭。虽然HIV-1感染CD4+T细胞及其他的免疫细胞是病程发展的主要驱动力,但艾滋病以及疾病的转归不仅是病毒的致细胞病变效应所致,更是由于复杂的病毒-宿主间相互作用而最终导致,如免疫系统持续性活化以及T细胞稳态的失衡。其中,持续性免疫活化被认为是除了病毒复制水平之外决定疾病进展的重要因素。引起HIV-1相关免疫活化的因素很多,其中微生物产物从受损胃肠道黏膜转移到系统循环中是一个重要因素。虽然有效的抗逆转录病毒治疗(antiretroviral therapy, ART)能够较好地抑制HIV-1复制,但并不能降低免疫活化至正常水平。因此探究HIV-1感染中固有免疫系统的调控机制对于控制免疫活化及免疫干预治疗策略具有重要意义。 慢性感染中由于病原体相关分子模式(pathogen-associated molecular patterns, PAMP)对固有免疫细胞的长期刺激,导致持续的免疫活化,I型干扰素(type I interferon, IFN-I)大量产生,引起干扰素诱导基因(interferon-stimulated genes, ISGs)的表达上调。尽管大多数ISGs起到控制病毒复制的重要作用,但其中一些可能发挥补偿性的免疫抑制效应以限制病理性的功能失调进一步恶化。 本研究通过转录组芯片数据分析,发现淋巴细胞抗原6复合体E(lymphocyte antigen6complex, locus E, LY6E)在HIV-1进展者血液标本中的表达显著高于不进展者,并且能被IFN-a诱导表达上调。进一步检测感染者的单核细胞中LY6E的表达水平,发现其与CD4+T细胞数量降低、CD8+T细胞的免疫活化程度均密切相关,纵向随访表明LY6E表达高的病人病程进展更快。 为了进一步研究LY6E在单核细胞介导的固有免疫应答中的作用,通过短发夹RNA (short hairpin RNA, shRNA)或小干扰RNA (small interfering RNA,siRNA)技术沉默了单核细胞中的LY6E,结果表明单核细胞中的LY6E可负向调控CD14的表达,并导致LPS刺激引起的固有免疫应答减弱。 HIV-1慢性感染中,单核细胞中的LY6E上调水平与CD14的下调水平密切相关。体外实验表明,未治疗的感染者中LPS引起的单核细胞免疫应答要高于健康组和ART治疗组。而LY6E依然能够下调感染者单核细胞的CD14表达以及减弱LPS诱导的免疫应答水平。LY6E的免疫抑制效应在慢性感染期起到对过度免疫活化的代偿性平衡作用,虽然其抑制能力不足以使活化的单核细胞的高应答能力得以恢复到正常水平,但在一定程度上可以避免因过度活化造成宿主的病理损伤。 综上所述,本文发现了LY6E作为一个免疫调节基因,在HIV-1慢性感染中对LPS所致的固有免疫活化起到调控作用,是平衡单核细胞活化的一种负反馈机制,可作为免疫干预策略的一个新靶标。
[Abstract]:Human immunodeficiency virus (human immunodeficiency virus, HIV) infection is characterized by progressive depletion of CD4 T cells in peripheral blood, lymphoid organs and mucous membranes. Although HIV-1 infection with CD4 T cells and other immune cells is the main driving force of the course of disease, AIDS and the prognosis of the disease are not only caused by the cytopathic effect of the virus. It is also due to the complex virus-host interaction, such as the persistent activation of the immune system and the imbalance of T cell homeostasis. Among them, persistent immune activation is considered to be an important factor in determining disease progress in addition to virus replication level. There are many factors causing HIV-1 related immune activation, among which the transfer of microbial products from damaged gastrointestinal mucosa to systemic circulation is an important factor. Although effective antiretrovirus treatment of (antiretroviral therapy, ART) can inhibit HIV-1 replication, it can not reduce immune activation to normal level. Therefore, it is of great significance to explore the regulation mechanism of innate immune system in HIV-1 infection in order to control immune activation and immune intervention therapy strategy. In chronic infection, interferon I (type I interferon, IFN-I is produced in large numbers due to the long-term stimulation of innate immune cells by pathogen-associated molecular patterns, PAMP), which leads to continuous immune activation. The expression of interferon induced gene (interferon-stimulated genes, ISGs) was up-regulated. Although most ISGs play an important role in controlling viral replication, some of them may play a complementary immunosuppressive effect to limit the further deterioration of pathological dysfunction. In this study, through the analysis of microarray data of transcriptional group, it was found that the expression of E (lymphocyte antigen6complex, locus E, LY6E) in blood samples of HIV-1 progressive patients was significantly higher than that of non-progressive HIV-1 patients, and could be up-regulated by IFN-a. The expression of LY6E in monocytes of infected patients was further detected, and it was found that it was closely related to the decrease of the number of CD4 T cells and the degree of immune activation of CD8 T cells. Longitudinal follow-up showed that the patients with high expression of LY6E advanced faster in the course of disease. In order to further study the role of LY6E in monocyte-mediated innate immune response, LY6E, in monocytes was silenced by short hairpin RNA (short hairpin RNA, shRNA) or small interfering RNA (small interfering RNA,siRNA) technique. The results showed that LY6E in monocytes could negatively regulate the expression of CD14 and weaken the innate immune response induced by LPS stimulation. In chronic HIV-1 infection, the up-regulation of LY6E in monocytes is closely related to the down-regulation of CD14. In vitro experiments showed that the monocyte immune response induced by LPS in untreated infected patients was higher than that in healthy group and ART treatment group. However, LY6E can still down-regulate the expression of CD14 in monocytes and weaken the level of immune response induced by LPS. The immunosuppressive effect of Ly6E plays a compensative role in the stage of chronic infection. Although its inhibitory ability is not enough to restore the high response ability of activated monocytes to the normal level, to a certain extent, it can avoid the pathological damage of the host caused by excessive activation. In conclusion, we found that LY6E, as an immunomodulatory gene, plays a regulatory role in the intrinsic immune activation induced by LPS in HIV-1 chronic infection, and is a negative feedback mechanism to balance monocyte activation. It can be used as a new target of immune intervention strategy.
【学位授予单位】：南开大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R512.91
本文编号：2482248
[Abstract]:Human immunodeficiency virus (human immunodeficiency virus, HIV) infection is characterized by progressive depletion of CD4 T cells in peripheral blood, lymphoid organs and mucous membranes. Although HIV-1 infection with CD4 T cells and other immune cells is the main driving force of the course of disease, AIDS and the prognosis of the disease are not only caused by the cytopathic effect of the virus. It is also due to the complex virus-host interaction, such as the persistent activation of the immune system and the imbalance of T cell homeostasis. Among them, persistent immune activation is considered to be an important factor in determining disease progress in addition to virus replication level. There are many factors causing HIV-1 related immune activation, among which the transfer of microbial products from damaged gastrointestinal mucosa to systemic circulation is an important factor. Although effective antiretrovirus treatment of (antiretroviral therapy, ART) can inhibit HIV-1 replication, it can not reduce immune activation to normal level. Therefore, it is of great significance to explore the regulation mechanism of innate immune system in HIV-1 infection in order to control immune activation and immune intervention therapy strategy. In chronic infection, interferon I (type I interferon, IFN-I is produced in large numbers due to the long-term stimulation of innate immune cells by pathogen-associated molecular patterns, PAMP), which leads to continuous immune activation. The expression of interferon induced gene (interferon-stimulated genes, ISGs) was up-regulated. Although most ISGs play an important role in controlling viral replication, some of them may play a complementary immunosuppressive effect to limit the further deterioration of pathological dysfunction. In this study, through the analysis of microarray data of transcriptional group, it was found that the expression of E (lymphocyte antigen6complex, locus E, LY6E) in blood samples of HIV-1 progressive patients was significantly higher than that of non-progressive HIV-1 patients, and could be up-regulated by IFN-a. The expression of LY6E in monocytes of infected patients was further detected, and it was found that it was closely related to the decrease of the number of CD4 T cells and the degree of immune activation of CD8 T cells. Longitudinal follow-up showed that the patients with high expression of LY6E advanced faster in the course of disease. In order to further study the role of LY6E in monocyte-mediated innate immune response, LY6E, in monocytes was silenced by short hairpin RNA (short hairpin RNA, shRNA) or small interfering RNA (small interfering RNA,siRNA) technique. The results showed that LY6E in monocytes could negatively regulate the expression of CD14 and weaken the innate immune response induced by LPS stimulation. In chronic HIV-1 infection, the up-regulation of LY6E in monocytes is closely related to the down-regulation of CD14. In vitro experiments showed that the monocyte immune response induced by LPS in untreated infected patients was higher than that in healthy group and ART treatment group. However, LY6E can still down-regulate the expression of CD14 in monocytes and weaken the level of immune response induced by LPS. The immunosuppressive effect of Ly6E plays a compensative role in the stage of chronic infection. Although its inhibitory ability is not enough to restore the high response ability of activated monocytes to the normal level, to a certain extent, it can avoid the pathological damage of the host caused by excessive activation. In conclusion, we found that LY6E, as an immunomodulatory gene, plays a regulatory role in the intrinsic immune activation induced by LPS in HIV-1 chronic infection, and is a negative feedback mechanism to balance monocyte activation. It can be used as a new target of immune intervention strategy.
【学位授予单位】：南开大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R512.91
【参考文献】
相关期刊论文 前1条
1 ;Regulation of Toll-like receptor signaling in innate immunity[J];Science China(Life Sciences);2010年01期
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