【摘要】：第一部分DOCK8缺陷狀態(tài)下濾泡輔助T細(xì)胞產(chǎn)生IL-21調(diào)節(jié)Ig E的機(jī)制研究背景:高Ig E綜合征(Hyper-Ig E syndrome,HIES)是一組常染色體遺傳的原發(fā)性免疫缺陷病,其中常染色體隱性遺傳(AR)的DOCK8免疫缺陷綜合癥(Dedicator of cytokinesis 8immunodeficiency syndrome,DIDS;OMIM 243700)是一種以特應(yīng)性皮炎、反復(fù)、慢性皮膚病毒感染和呼吸道感染癥狀、血清lg E升高和嗜酸性粒細(xì)胞增多為特征的原發(fā)性免疫缺陷疾病。DOCK8基因定位于人類9號(hào)染色體p24.3,其編碼的DOCK8蛋白可激活Rho-GTP酶,從而調(diào)節(jié)諸多細(xì)胞功能,尤其是肌動(dòng)蛋白細(xì)胞骨架調(diào)控、影響細(xì)胞遷移活動(dòng)。DOCK8缺陷患者罹患聯(lián)合免疫缺陷,但B細(xì)胞介導(dǎo)的抗體缺陷最為突出,其中尤以Ig E水平急劇升高較為明顯,目前機(jī)制未知。目的:分析中國(guó)的DOCK8缺陷綜合征患兒臨床表現(xiàn)及免疫功能,采用臨床樣本與DOCK8-KO小鼠模型探究DOCK8蛋白缺陷對(duì)Ig E水平的影響及其機(jī)制。方法:采用高通量測(cè)序及流式細(xì)胞術(shù)對(duì)疑似高Ig E綜合征的患兒進(jìn)行診斷,確立DOCK8缺陷診斷后進(jìn)行淋巴細(xì)胞免疫功能評(píng)估,分析患兒及健康同齡對(duì)照外周血濾泡輔助T細(xì)胞數(shù)量和功能改變,以及其相關(guān)功能分子IL-21水平,實(shí)時(shí)熒光定量檢測(cè)Bcl-6及Blimp-1 m RNA表達(dá)。運(yùn)用TALEN技術(shù)建立DOCK8-KO小鼠模型并對(duì)其免疫功能進(jìn)行評(píng)估,分析濾泡輔助T細(xì)胞數(shù)量功能改變,以及其相關(guān)功能分子ICOS、PD-1、Bcl-6及IL-21水平,對(duì)DOCK8-KO小鼠進(jìn)行IL-21替代治療并觀察其對(duì)免疫功能的修復(fù)效應(yīng)。進(jìn)一步構(gòu)建OVA誘導(dǎo)哮喘DOCK8-KO小鼠模型并對(duì)其進(jìn)行IL-21補(bǔ)充治療,解析其治療機(jī)制。結(jié)果:1.7例DOCK8免疫缺陷患兒,2男5女,高Ig E綜合征NIH評(píng)分均高于40分,表現(xiàn)為反復(fù)頑固的病毒感染,肺炎,血清Ig E異常增高和嗜酸性粒細(xì)胞增多等現(xiàn)象。針對(duì)DOCK8單基因的高通量測(cè)序分析顯示7例患兒發(fā)生不同程度的大片段缺失突變、移碼突變或錯(cuò)義突變,均為尚未報(bào)道過(guò)的新發(fā)突變。其中P1患兒為19-48號(hào)外顯子雜合性大片段缺失并伴有移碼突變(c.5842 del G,c 5843CA p.A1948fs X1953),P2患兒11號(hào)外顯子純合性缺失,12-33號(hào)外顯子雜合性缺失,P3-4患兒為移碼突變(c.3152del G p.S1051fs X1093)和錯(cuò)義突變(c.5175GC p.E1725D),P5患兒為2號(hào)外顯子純合性缺失,1號(hào),3-39號(hào)外顯子雜合性缺失,P6患兒為7號(hào)外顯子純合性缺失,8-10號(hào)外顯子雜合性缺失,P7患兒為移碼突變(c.1278-1279 del TG p.V427fs X435)。7例患兒完成流式細(xì)胞術(shù)及Western檢測(cè),外周血單個(gè)核細(xì)胞均無(wú)DOCK8蛋白表達(dá)�；純和庵苎狢D4+T細(xì)胞、記憶B細(xì)胞和記憶T細(xì)胞均有不同程度降低。T細(xì)胞刪除環(huán)(TRECs)、淋巴細(xì)胞增殖水平和NK細(xì)胞的細(xì)胞毒殺傷功能均明顯低于正常同齡兒童。外周血調(diào)節(jié)性B細(xì)胞水平低下,而調(diào)節(jié)性T細(xì)胞,CD4+T細(xì)胞產(chǎn)生細(xì)胞因子IL-17、IL-4及IFN-γ水平均正常。DOCK8患兒濾泡輔助T細(xì)胞占CD4+T細(xì)胞比率與正常人相比無(wú)統(tǒng)計(jì)學(xué)差異,但絕對(duì)值卻明顯低于正常對(duì)照。尤其是Tfh細(xì)胞分泌的IL-21明顯下降。2.(1)運(yùn)用TALEN技術(shù)建立DOCK8-KO小鼠,DOCK8-KO小鼠較WT小鼠的血清Ig E、血液及脾臟中的Ig E+B細(xì)胞有升高趨勢(shì),并有統(tǒng)計(jì)學(xué)差異。DOCK8-KO小鼠的濾泡輔助T細(xì)胞相關(guān)功能分子出現(xiàn)不同程度的下降,其中細(xì)胞因子IL-21水平下降極為明顯,Tfh細(xì)胞分化的主要調(diào)節(jié)轉(zhuǎn)錄因子Bcl-6,以及Tfh細(xì)胞的功能分子PD-1、ICOS水平均不同程度降低。(2)采用傳統(tǒng)劑量四分之一的低劑量OVA成功誘導(dǎo)DOCK8-KO小鼠哮喘模型,模型小鼠出現(xiàn)明顯的肺功能異常,血清Ig E水平升高,嗜酸性粒細(xì)胞增多等過(guò)敏特征。OVA誘導(dǎo)的DOCK8-KO及WT小鼠Ig E+B細(xì)胞水平均有升高現(xiàn)象,但前者升高的水平是后者的數(shù)倍,其中血清總Ig E及OVA特異性Ig E水平升高尤為明顯。經(jīng)OVA誘導(dǎo)的DOCK8-KO小鼠IL-21水平隨之進(jìn)一步下降,而經(jīng)OVA誘導(dǎo)的WT小鼠則沒有明顯改變。另外,OVA誘導(dǎo)的DOCK8-KO小鼠脾臟記憶性Tfh細(xì)胞,Tfh細(xì)胞分化的主要調(diào)節(jié)轉(zhuǎn)錄因子Bcl-6,以及Tfh細(xì)胞的功能分子PD-1、ICOS均出現(xiàn)明顯降低。3.(1)使用重組小鼠IL-21細(xì)胞因子(20ng/d×3-6天)對(duì)DOCK8-KO小鼠進(jìn)行替代治療,發(fā)現(xiàn)KO小鼠血清Ig E水平幾乎能夠回復(fù)到正常水平,脾臟Tfh細(xì)胞及其分化的主要調(diào)節(jié)轉(zhuǎn)錄因子Bcl-6,以及Tfh細(xì)胞的功能分子PD-1和ICOS均能不同程度的回升至接近正常水平,治療效應(yīng)十分明顯。(2)采用IL-21治療OVA誘導(dǎo)的小鼠模型,WT小鼠的Ig E水平雖有回復(fù),但總體治療效果不如DOCK8-KO小鼠明顯。經(jīng)OVA誘導(dǎo)的DOCK8-KO小鼠經(jīng)過(guò)IL-21治療其Ig E水平能夠回復(fù)到正常水平,并且Tfh細(xì)胞及其主要調(diào)節(jié)轉(zhuǎn)錄因子Bcl-6,以及Tfh細(xì)胞的功能分子PD-1,ICOS均能不同程度的回升至正常水平。結(jié)論:DOCK8缺陷引起Tfh細(xì)胞發(fā)育分化障礙,IL-21分泌降低,可能是導(dǎo)致B細(xì)胞對(duì)過(guò)敏原反應(yīng)失控,產(chǎn)生大量功能性Ig E的根本原因。第二部分IKKβ缺陷對(duì)NF-κB入核的影響背景:IKBKB基因突變是一種特殊的聯(lián)合免疫缺陷病,以反復(fù)細(xì)菌、病毒、真菌感染為主要表現(xiàn),大部分病人會(huì)出現(xiàn)不同程度鵝口瘡、支氣管炎及肺炎,并伴有慢性腹瀉、生長(zhǎng)發(fā)育遲緩、腦出血、癲癇、臍炎、臍帶脫落延遲等現(xiàn)象。IKBKB基因定位于人類8號(hào)染色體p11.2,其編碼的IKKβ蛋白是IκB kinase的亞單位之一,主要參與NF-κB通路激活過(guò)程,活化的IKK磷酸化IκBα(NF-κB的抑制劑),磷酸化的IκBα不斷降解,使其對(duì)NF-κB的抑制功能減弱,后者則可以自由出入細(xì)胞核并激活參與炎癥及免疫反應(yīng)的各種基因。目的:分析一例IKBKB突變患兒臨床表現(xiàn)、蛋白表達(dá)、基因突變及免疫功能。探討395位點(diǎn)氨基酸磷酸化對(duì)NF-κB入核影響及通路功能的影響及機(jī)制。方法:患兒男,17歲,生后2月齡開始出現(xiàn)反復(fù)呼吸道感染,腹瀉及低體重。采用高通量測(cè)序發(fā)現(xiàn)基因突變,并用一代測(cè)序驗(yàn)證,采用流式細(xì)胞術(shù)及免疫印跡法檢測(cè)IKKβ蛋白。采用流式細(xì)胞術(shù)分析淋巴細(xì)胞功能,EMSA方法檢測(cè)核內(nèi)NF-κB水平。制備395位點(diǎn)定點(diǎn)變異細(xì)胞系,以去除該位點(diǎn)磷酸化,探討其對(duì)IKKβ蛋白穩(wěn)定性的影響機(jī)制。結(jié)果:高通量測(cè)序顯示IKBKB基因發(fā)生錯(cuò)義突變(c.1183TC,p.Y395H),為尚未報(bào)道的新發(fā)突變。一代測(cè)序驗(yàn)證確認(rèn)為該位點(diǎn)突變,流式細(xì)胞術(shù)及免疫印跡法均未能檢測(cè)到IKKβ蛋白表達(dá)。免疫功能評(píng)估中發(fā)現(xiàn)患兒記憶B細(xì)胞極度低下,調(diào)節(jié)性T細(xì)胞缺如,淋巴細(xì)胞增殖水平明顯受損。調(diào)節(jié)性B細(xì)胞升高,而CD4+T細(xì)胞表達(dá)細(xì)胞因子IL-17、IL-4、IL-21及IFN-γ均處于正常下限,NK細(xì)胞的細(xì)胞毒殺傷功能及TCRVβ多樣性正常�；純杭�(xì)胞核內(nèi)NF-κB蛋白較正常人明顯降低,提示基因突變導(dǎo)致進(jìn)入細(xì)胞核的NF-κB水平減少。進(jìn)一步發(fā)現(xiàn)395位點(diǎn)突變導(dǎo)致磷酸化位點(diǎn)消失后IKKβ降解速率增快,蛋白穩(wěn)定性下降。結(jié)論:確診1例極為罕見的PID病例——IKBKB缺陷,為全球范圍內(nèi)報(bào)道的第10例患兒。IKKβ的395位點(diǎn)發(fā)生的錯(cuò)義突變?yōu)樯形磮?bào)道過(guò)的新發(fā)突變。首次闡明該位點(diǎn)是IKKβ蛋白重要的磷酸化位點(diǎn),由酪氨酸突變?yōu)榻M氨酸造成的氨基酸改變會(huì)導(dǎo)致磷酸化位點(diǎn)丟失,降解增快,從而最終影響NF-κB入核。
[Abstract]:In the first part of the DOCK8 deficiency, follicular assisting T cells to produce the mechanism of IL-21 regulation of Ig E: high Ig E syndrome (Hyper-Ig E syndrome, HIES) is a group of autosomal primary immunodeficiency diseases, including the autosomal recessive inheritance (AR) Yndrome, DIDS; OMIM 243700) is a primary immunodeficiency disease characterized by atopic dermatitis, recurrent, chronic skin virus infection and respiratory infection. The.DOCK8 gene of serum LG E and eosinophils is a primary immunodeficiency disease, which is located on the human chromosome 9 of human chromosome p24.3, and its encoded DOCK8 protein activates the Rho-GTP enzyme, thus regulating many of them. The cell function, especially the actin cytoskeleton regulation, affects the joint immunodeficiency in the cell migration.DOCK8 deficiency patients, but the B cell mediated antibody defects are most prominent, especially the rapid rise of Ig E level, and the present mechanism is unknown. Objective: to analyze the clinical manifestation and immunity of children with DOCK8 deficiency syndrome in China. Function, using clinical samples and DOCK8-KO mouse model to explore the effect of DOCK8 protein deficiency on the level of Ig E and its mechanism. Methods: high throughput sequencing and flow cytometry were used to diagnose children with suspected high Ig E syndrome, and the lymphocyte immune function evaluation was established after the diagnosis of DOCK8 defect, and the children and the healthy same age control were analyzed. The number and function of T cells were assisted by peripheral blood follicles, as well as the IL-21 level of its related functional molecules, and the expression of Bcl-6 and Blimp-1 m RNA were detected by real time fluorescence. The TALEN technique was used to establish the DOCK8-KO mouse model and evaluate its immune function. The function of the follicle assisted T cells was changed, and the related functional molecules ICOS, PD-1, Bcl were analyzed. At the level of -6 and IL-21, the DOCK8-KO mice were treated with IL-21 replacement therapy and their effects on the immune function were observed. Further construction of OVA induced asthma DOCK8-KO mice model and IL-21 supplementation were carried out to analyze the therapeutic mechanism. Results: 1.7 cases of DOCK8 immunodeficiency children, 2 men and 5 women, and high Ig E syndrome NIH score were all higher than 40 points. For repeated stubborn virus infection, pneumonia, abnormal increase of serum Ig E and eosinophils. High throughput sequencing analysis of DOCK8 single gene showed that 7 children had different degrees of large fragment deletion, code mutation or missense mutation, all of which were unreported new mutations. Among them, children with P1 were exon 19-48. C.5842 del G, C 5843CA p.A1948fs X1953, loss of homozygosity in exon 11 of P2 children, loss of heterozygosity in exon 12-33 of children with P2 (c.3152del G, c.3152del G p.S1051fs) and missense mutations were found in children with exon 2, 1 and 3-39. The heterozygosity of exon was absent, the children of P6 were homozygous deletion of exon 7 and heterozygosity in exon 8-10, and P7 children were transferred code mutation (c.1278-1279 del TG p.V427fs X435) with.7 cases complete flow cytometry and Western detection, and peripheral blood mononuclear cells had no DOCK8 egg white expression. The.T cell deletion ring (TRECs) was reduced to some extent, the proliferation level of lymphocyte and the cytotoxic function of NK cells were significantly lower than those of normal age children. The regulatory B cells in peripheral blood were low, and regulatory T cells, CD4+T cells produced cytokine IL-17, IL-4 and IFN- gamma water were normal.DOCK8 children with follicular auxiliary T. There was no statistical difference in the ratio of cell CD4+T cells to normal people, but the absolute value was significantly lower than that of normal controls. Especially, the IL-21 secreted by Tfh cells significantly decreased.2. (1) using TALEN technology to establish DOCK8-KO mice, the Ig E of the DOCK8-KO mice and the Ig E+B cells in the blood and spleen, and the statistical difference between the DOCK8-KO mice and the WT mice. The follicle assisted T cell related functional molecules in different.DOCK8-KO mice decreased to varying degrees, in which the level of cytokine IL-21 decreased significantly, the main regulating transcription factor Bcl-6 of Tfh cell differentiation, and the PD-1 of Tfh cells, the level of ICOS were reduced in varying degrees. (2) the low dose OVA of traditional dose 1/4 was used. The DOCK8-KO mouse asthma model was successfully induced. The model mice had obvious abnormal pulmonary function, the level of serum Ig E increased, the eosinophil increased, and the level of Ig E+B cells in DOCK8-KO and WT mice induced by.OVA was increased, but the level of the former was several times that of the latter, and the serum total Ig E and OVA specificity Ig. The level of horizontal elevation was particularly obvious. The IL-21 level of DOCK8-KO mice induced by OVA was further decreased, while the WT mice induced by OVA did not change obviously. In addition, the OVA induced DOCK8-KO mouse spleen memory Tfh cells, the main regulating transcription factor Bcl-6 of the Tfh cell differentiation, and the functional molecular PD-1 of the Tfh cells were significantly reduced. 3. (1) the recombinant mouse IL-21 cytokine (20ng/d x 3-6 days) was used to replace the DOCK8-KO mice. It was found that the serum Ig E level of the KO mice could almost revert to the normal level. The spleen Tfh cells and the main regulating transcription factor Bcl-6 of the splenic Tfh cells, as well as the Tfh cell functional molecules PD-1 and ICOS were all able to recover to the normal level to the normal level. Level, treatment effect is very obvious. (2) the use of IL-21 to treat OVA induced mouse model, WT mice Ig E level although there is a response, but the overall treatment effect is not as obvious as DOCK8-KO mice. OVA induced DOCK8-KO mice after IL-21 treatment of Ig E level can be back to normal levels, and Tfh cells and the main regulation of transcription factors, And the functional molecules of Tfh cells, PD-1, and ICOS can rise to the normal level in varying degrees. Conclusion: DOCK8 defects cause the development and differentiation of Tfh cells and the decrease of IL-21 secretion, which may be the root cause of the uncontrolled reaction of the B cells to the allergen reaction and the production of a large number of functional Ig E. The background of the influence of the second part IKK beta defect on NF- nuclear B is: Gene mutation is a special kind of joint immunodeficiency disease, which is characterized by repeated bacteria, virus and fungal infection. Most patients have different degrees of thrush, bronchitis and pneumonia, accompanied by chronic diarrhea, growth retardation, cerebral hemorrhage, epilepsy, cord inflammation, and delay of umbilical cord abscission. The.IKBKB gene is located in human 8. P11.2, its encoded IKK beta protein is one of the subunits of I kappa B kinase, which is mainly involved in the activation process of NF- kappa B pathway, and activated IKK phosphorylation I kappa B alpha (NF- kappa B). Objective: to analyze the clinical manifestation, protein expression, gene mutation and immune function of a patient with IKBKB mutation. The effect and mechanism of the 395 site amino acid phosphorylation on NF- kappa B nucleation and pathway function. Methods: children, 17 years old, 2 month old after birth, recurrent respiratory infection, diarrhea and low weight. High throughput sequencing IKK beta protein was detected by flow cytometry and immunoblotting. Flow cytometry and immunoblotting were used to detect IKK beta protein. Flow cytometry was used to analyze lymphocyte function and EMSA method was used to detect the level of NF- kappa B. The site directed mutated cell line of 395 loci was prepared to remove the phosphorylation of the site and the mechanism of its effect on the stability of IKK beta protein was discussed. Result: high throughput sequencing showed that the IKBKB gene occurred missense mutation (c.1183TC, p.Y395H), which was a new mutation that had not been reported. One generation sequencing verification confirmed the mutation of the site. The expression of IKK beta protein was not detected by flow cytometry and immunoblotting. The immune function evaluation found that the children's memory B cells were extremely low, and the regulatory T cells were absent. The level of lymphocyte proliferation was significantly impaired. Regulatory B cells were elevated, while CD4+T cells expressed cytokine IL-17, IL-4, IL-21 and IFN- gamma in the normal lower limit. The cytotoxic function of NK cells and the diversity of TCRV beta were normal. The protein of NF- kappa B in the nucleus of the children was lower than that of the normal human, suggesting that the gene mutation leads to NF- kappa B. IKK beta degradation rate increased rapidly and protein stability decreased after the 395 site mutation resulted in the disappearance of phosphorylation sites. Conclusion: 1 cases of extremely rare cases of IKBKB were diagnosed, and the missense mutation of the 395 site of.IKK beta in tenth cases of.IKK was reported worldwide for the first time. This site is an important phosphorylation site for IKK beta protein. The amino acid change caused by mutation of tyrosine to histidine leads to the loss of phosphorylation sites and the rapid degradation of the amino acid, which ultimately affects the nucleation of NF- kappa B.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R725.9

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