【摘要】：背景：獲得性再生障礙性貧血(aplastic anemia, AA)為一類(lèi)以全血細(xì)胞減少和骨髓造血衰竭為特征的自身免疫性疾病。免疫介導(dǎo)的造血抑制是AA的主要發(fā)病機(jī)制。1 a,25-二羥維生素D3 [1a,25-Dihydroxyvitamin D3,1,25(OH)2D3]為維生素D的活性形式,除了調(diào)節(jié)機(jī)體鈣磷代謝外,近期研究發(fā)現(xiàn)其與維生素D受體(vitamin D receptor, VDR)結(jié)合后尚可發(fā)揮免疫調(diào)節(jié)效應(yīng)。已有研究證實(shí)1,25(OH)2D3和VDR在多種自身免疫性疾病發(fā)生發(fā)展中發(fā)揮關(guān)鍵作用,但其在A(yíng)A發(fā)病機(jī)制中的作用尚未明確。目的：本研究旨在檢測(cè)1,25(OH)2D3和VDR在A(yíng)A患者中的表達(dá),同時(shí)評(píng)價(jià)1,25(OH)2D3對(duì)AA患者外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cells, PBMCs)的作用,探討其在A(yíng)A發(fā)病機(jī)制中的作用,為AA的免疫抑制治療提供新的思路。方法：(1)通過(guò)ELISA方法檢測(cè)血漿中25(OH)D3的表達(dá),并進(jìn)一步分析25(OH)D3水平與AA患者各臨床參數(shù)之間的關(guān)系；(2)通過(guò)實(shí)時(shí)定量PCR的方法檢測(cè)PBMCs以及1,25(OH)2D3處理后的PBMCs中VDR mRNA的表達(dá)水平；(3)通過(guò)CCK-8的方法檢測(cè)1,25(OH)2D3對(duì)PBMCs增殖的影響；(4)將患者PBMCs用1,25(OH)2D3處理,未處理組作為對(duì)照。48小時(shí)后,采用ELISA的方法檢測(cè)培養(yǎng)上清中TNF-α IFN-γ IL-17A、IL-10和TGF-β1的水平變化,實(shí)時(shí)定量PCR的方法檢測(cè)T細(xì)胞相關(guān)轉(zhuǎn)錄因子T-bet. GATA3. RORyt和Foxp3 mRNA的表達(dá)變化,同時(shí)采用流式細(xì)胞術(shù)的方法檢測(cè)1,25(OH)2D3處理的PBMCs內(nèi)Thl (CD3+CD8-IFNy+)、Th2 (CD3+CD8-IL4+)、Tcl (CD3+CD8+IFNγ+)、Tc2 (CD3+CD8+IL4+)和Th17 (CD3+CD8-IL17+)細(xì)胞的比例變化。結(jié)果：(1)初治AA患者血漿25(OH)D3的水平與完全緩解患者、正常對(duì)照組無(wú)顯著差異；(2)AA患者血漿25(OH)D3的水平與血小板計(jì)數(shù)、自然殺傷T細(xì)胞(natural killer T cells, NKT)比例呈顯著正相關(guān),與B細(xì)胞比例呈負(fù)相關(guān)；(3)初治AA患者PBMCs VDR mRNA表達(dá)水平顯著低于正常對(duì)照組；(4)體外刺激實(shí)驗(yàn)顯示1,25(OH)2D3抑制AA患者PBMCs的增殖;(5)外源性1,25(OH)2D3的加入明顯抑制AA患者PBMCs分泌TNF-α、IFN-γ和IL-17A,并促進(jìn)TGF-β1的產(chǎn)生；(6)1,25(OH)2D3抑制Th1、Tc1和Th17細(xì)胞的極化,同時(shí)促進(jìn)Th2和Tc2細(xì)胞的極化,實(shí)時(shí)定量PCR的結(jié)果進(jìn)一步證實(shí)1,25(OH)2D3抑制AA患者PBMCs內(nèi)T-be、RORyt mRNA的表達(dá),同時(shí)促進(jìn)GATA3、Foxp3 mRNA的表達(dá)；(7)1,25(OH)2D3處理后正常對(duì)照組PBMCs中VDR mRNA的表達(dá)水平明顯上調(diào),AA患者卻無(wú)明顯變化。結(jié)論：初治AA患者PBMCs中VDR表達(dá)水平明顯降低,低表達(dá)的VDR可能使維生素D-VDR通路信號(hào)傳導(dǎo)減弱,從而導(dǎo)致AA的“高免疫”狀態(tài)。適量的補(bǔ)充維生素D可通過(guò)增強(qiáng)信號(hào)傳導(dǎo)來(lái)部分糾正AA免疫失耐受,有望成為一種新的輔助性治療策略。背景：再生障礙性貧血(aplastic anemia, AA)是一種少見(jiàn)的可嚴(yán)重危及患者生命的骨髓衰竭性疾病,目前對(duì)其發(fā)病機(jī)制的研究主要集中在免疫調(diào)節(jié)紊亂、造血微環(huán)境缺陷、造血干/祖細(xì)胞數(shù)量和(或)功能缺陷及遺傳易感性等方面。維生素D具有重要的免疫調(diào)節(jié)作用,其效應(yīng)的發(fā)揮依賴(lài)于與維生素D受體(vitamin D receptor, VDR)的結(jié)合。VDR基因位于第12號(hào)染色體,包含多個(gè)單核苷酸多態(tài)性(SNP)位點(diǎn)。研究發(fā)現(xiàn),VDR基因及其多態(tài)性與多種自身免疫性疾病的易感性相關(guān)。目前關(guān)于VDR基因多態(tài)性是否與AA發(fā)病相關(guān)尚未見(jiàn)報(bào)道。目的：本研究旨在探討VDR基因四個(gè)多態(tài)性位點(diǎn)(rs2228570、rs1544410、rs7975232和rs731236)與AA易感性的關(guān)系,并評(píng)價(jià)VDR基因多態(tài)性與AA嚴(yán)重程度、治療療效及晚期克隆演變等臨床特征的相關(guān)性。方法：采集AA患者和正常對(duì)照的外周血并提取DNA,采用聚合酶鏈反應(yīng)-連接酶檢測(cè)反應(yīng)(PCR-LDR)的方法檢測(cè)197例AA患者和135例健康對(duì)照rs1544410 (c.1024+283GA)、rs7975232 (c.1025-49GT)和rs731236(c.1056TC)的基因型。采用聚合酶鏈反應(yīng)-限制性片段長(zhǎng)度多態(tài)性(PCR-RFLP)方法檢測(cè)rs2228570(c.2TC)的基因型。應(yīng)用SPSS 17.0軟件統(tǒng)計(jì)分析VDR基因多態(tài)性位點(diǎn)與AA易感性、疾病嚴(yán)重程度、治療療效、克隆演變及其他臨床特征的相關(guān)性。結(jié)果：(1)VDR基因四個(gè)多態(tài)性位點(diǎn)的基因型均符合Hardy-Weinberg平衡。(2)VDR基因rs1544410、rs7975232和rs731236三個(gè)位點(diǎn)之間存在顯著的遺傳連鎖不平衡。 (3)在VDR基因的四個(gè)多態(tài)性位點(diǎn)中,AA患者rs1544410位點(diǎn)GG基因型和G等位基因頻率顯著高于正常對(duì)照組,而其他三個(gè)多態(tài)性位點(diǎn)與AA易感性無(wú)關(guān)。 (4)進(jìn)一步分析發(fā)現(xiàn)rs1544410和rs7975232位點(diǎn)與非重型AA的發(fā)病相關(guān),而rs2228570位點(diǎn)與重型AA的發(fā)病相關(guān)。 (5)AA患者rs2228570位點(diǎn)的基因型與治療療效相關(guān)：CC及CT基因型患者預(yù)后好于TT基因型者。(6)AA患者rs2228570位點(diǎn)的基因型與晚期克隆演變亦密切相關(guān)：TT基因型攜帶者更易于轉(zhuǎn)化為骨髓增生異常綜合征／急性髓系白血病,而CT基因型患者更易進(jìn)展為陣發(fā)性睡眠性血紅蛋白尿癥。結(jié)論：我們的研究結(jié)果表明,在中國(guó)人群中,VDR基因多態(tài)性與AA的易感性、疾病嚴(yán)重程度及預(yù)后密切相關(guān)。背景：獲得性再生障礙性貧血(aplastic anemia, AA)是一種自身反應(yīng)性T細(xì)胞攻擊靶器官骨髓所致的骨髓衰竭性疾病。IL-35為近年新發(fā)現(xiàn)的一種調(diào)節(jié)性細(xì)胞因子,是IL-12家族的新成員,主要由調(diào)節(jié)性T細(xì)胞(Tregs)分泌產(chǎn)生。目前認(rèn)為IL-35為T(mén)regs發(fā)揮免疫抑制作用的主要效應(yīng)分子。此外,IL-35尚可誘導(dǎo)T細(xì)胞分化為可分泌IL-35的誘導(dǎo)型調(diào)節(jié)性T細(xì)胞(iTR35),進(jìn)一步維持機(jī)體的免疫耐受狀態(tài)。越來(lái)越多的證據(jù)表明IL-35在調(diào)控機(jī)體免疫穩(wěn)態(tài)中發(fā)揮關(guān)鍵作用,但其在A(yíng)A中的表達(dá)情況以及是否參與AA的發(fā)病機(jī)制尚未明確。目的：本研究旨在檢測(cè)AA患者血漿中IL-35的表達(dá)情況,并評(píng)估IL-35對(duì)T細(xì)胞免疫反應(yīng)的作用,探討其在A(yíng)A發(fā)病機(jī)制中的作用,為基于IL-35的靶向治療提供理論依據(jù)。方法： (1)收集患者臨床資料；(2)通過(guò)ELISA方法檢測(cè)血漿中IL-35的表達(dá),并進(jìn)一步分析IL-35水平與AA患者各臨床參數(shù)之間的關(guān)系; (3)通過(guò)實(shí)時(shí)定量PCR的方法檢測(cè)外周血單個(gè)核細(xì)胞(PBMCs)中IL-35兩個(gè)亞基p35和EBI3 mRNA的表達(dá)水平； (4)通過(guò)Brdu摻入法檢測(cè)IL-35對(duì)PBMCs增殖的影響；(5)將患者和正常對(duì)照PBMCs用IL-35處理,未處理組作為對(duì)照。48小時(shí)后,采用ELISA的方法檢測(cè)培養(yǎng)上清中TNF-α IFN-γ、IL-17A. IL-10和TGF-β1的水平變化,流式細(xì)胞術(shù)和細(xì)胞計(jì)數(shù)相結(jié)合的方法檢測(cè)CD4+/CD8+T細(xì)胞、Thl (CD3+CD8-IFNy+)、Th2 ( CD3+CD8-IL4+)、Tcl (CD3+CD8+IFNy+)、Tc2 (CD3+CD8+IL4+)和Th17 ( CD3+CD8-IL17+)細(xì)胞的比例和絕對(duì)數(shù)變化,同時(shí)采用實(shí)時(shí)定量PCR的方法檢測(cè)T細(xì)胞相關(guān)轉(zhuǎn)錄因子T-bet、GATA3、RORγt和Foxp3 mRNA的表達(dá)變化。結(jié)果：(1)通過(guò)ELISA檢測(cè),我們發(fā)現(xiàn)初治AA患者血漿中IL-35的水平明顯低于完全緩解(CR)患者和正常對(duì)照組,而CR患者和正常對(duì)照組之間無(wú)顯著差異,進(jìn)一步分析發(fā)現(xiàn)IL-35水平與疾病的嚴(yán)重程度密切相關(guān)。(2)在初治AA患者,血漿IL-35的水平與血小板計(jì)數(shù)、中性粒細(xì)胞絕對(duì)值和網(wǎng)織紅細(xì)胞絕對(duì)值呈顯著正相關(guān),與淋巴細(xì)胞比例呈負(fù)相關(guān)。(3)實(shí)時(shí)定量PCR的結(jié)果顯示,初治重型AA患者p35和EBI3 mRNA表達(dá)水平低于正常對(duì)照組,而初治非重型AA與正常對(duì)照組之間無(wú)顯著差異。(4)體外刺激實(shí)驗(yàn)顯示IL-35能抑制AA患者PBMCs的增殖,進(jìn)而行細(xì)胞計(jì)數(shù)和流式細(xì)胞術(shù)發(fā)現(xiàn)IL-35能抑制CD4+和CD8+T細(xì)胞的增殖。(5)外源性IL-35的加入明顯抑制AA患者PBMCs分泌TNF-α IFN-γ和IL-17A,同時(shí)促進(jìn)TGF-β的產(chǎn)生。(6)IL-35抑制Th1、Tcl和Th17細(xì)胞的極化,同時(shí)促進(jìn)Th2和Tc2細(xì)胞的極化,實(shí)時(shí)定量PCR的結(jié)果證實(shí)IL-35抑制AA患者PBMCs內(nèi)T-bet和RORyt mRNA的表達(dá),同時(shí)促進(jìn)GATA3 mRNA的表達(dá),對(duì)Foxp3 mRNA的表達(dá)無(wú)明顯影響。結(jié)論：初治AA患者體內(nèi)IL-35的表達(dá)水平降低,且與疾病嚴(yán)重程度密切相關(guān),IL-35低表達(dá)可能致使Tregs失能,進(jìn)而導(dǎo)致AA的免疫失耐受狀態(tài),提示IL-35在A(yíng)A的發(fā)病機(jī)制中發(fā)揮關(guān)鍵作用。
[Abstract]:BACKGROUND: Acquired aplastic anemia (AA) is an autoimmune disease characterized by pancytopenia and bone marrow hematopoietic failure. Immune-mediated hematopoietic suppression is the main pathogenesis of AA. In addition to the regulation of calcium and phosphorus metabolism, recent studies have found that the binding of vitamin D receptor (VDR) with 1,25 (OH) 2D3 and VDR may play an important role in the pathogenesis of AA. Objective To detect the expression of 1,25 (OH) 2D3 and VDR in patients with AA, and to evaluate the effect of 1,25 (OH) 2D3 on peripheral blood mononuclear cells (PBMCs) in patients with AA, and to explore the role of 1,25 (OH) 2D3 in the pathogenesis of AA. The expression of VDR mRNA in PBMCs and PBMCs treated with 1,25 (OH) 2D3 was detected by real-time quantitative PCR; (3) The effect of 1,25 (OH) 2D3 on the proliferation of PBMCs was detected by CCK-8; (4) PBMCs were treated with 1,25 (OH) 2D3. After 48 hours, the levels of TNF-alpha IFN-gamma IL-17A, IL-10 and TGF-beta 1 in culture supernatant were detected by ELISA, and the expression of T-cell-related transcription factors T-bet.GATA3.RORyt and Foxp3 mRNA were detected by real-time quantitative PCR, and the expression of PBMC treated with 1,25(OH)2D3 was detected by flow cytometry. The proportion of Thl (CD3 + CD8 - IFNy +), Th2 (CD3 + CD8 - IL4 +), Tcl (CD3 + CD8 + IFN gamma +), Tc2 (CD3 + CD8 + IL4 +) and Th17 (CD3 + CD8 - IL17 +) cells changed within s. Results: (1) There was no significant difference in plasma 25 (OH) D3 levels and platelet counts, and natural killer T (NK) between AA patients and complete remission patients. The proportion of natural killer T cells (NKT) was significantly positively correlated with the proportion of B cells, and negatively correlated with the proportion of B cells; (3) The expression level of VDR mRNA in PBMCs of newly treated AA patients was significantly lower than that of normal controls; (4) In vitro stimulation test showed that 1,25 (OH) 2D3 inhibited the proliferation of PBMCs of AA patients; (5) Exogenous 1,25 (OH) 2D3 significantly inhibited the secretion of TNF-2 by PBMCs of AA patients. Alpha, IFN-gamma and IL-17A, and promote the production of TGF-beta 1; (6) 1,25 (OH) 2D3 inhibits the polarization of Th1, Tc 1 and Th17 cells, and promotes the polarization of Th2 and Tc2 cells. Real-time quantitative PCR further confirmed that 1,25 (OH) 2D3 inhibits the expression of T-be and RORyt mRNA in PBMCs of AA patients, and promotes the expression of GATA3 and Foxp3 mRNA; (7) 1,25 (OH) 2D3 treatment is positive. Conclusion: The expression of VDR in PBMCs of newly treated AA patients is significantly lower than that of control group, and the low expression of VDR may weaken the signal transduction of vitamin D-VDR pathway and lead to the "high immunity" state of AA. BACKGROUND: Aplastic anemia (AA) is a rare bone marrow failure disease that can seriously endanger the life of patients. Currently, studies on its pathogenesis mainly focus on immunomodulatory disorders, hematopoietic microenvironment defects, hematopoietic stem/progenitor. Vitamin D plays an important role in immune regulation. Its effect depends on binding to vitamin D receptor (VDR). VDR gene is located on chromosome 12 and contains multiple single nucleotide polymorphisms (SNP) loci. Objective: To investigate the relationship between the susceptibility to AA and the polymorphism of VDR gene (rs2228570, rs1544410, rs7975232 and rs731236), and to evaluate the relationship between the polymorphism of VDR gene and the severity and treatment of AA. Methods: DNA was extracted from peripheral blood of AA patients and normal controls, and the bases of rs1544410 (c. 1024 + 283GA), rs7975232 (c. 1025-49GT) and rs731236 (c. 1056TC) were detected by polymerase chain reaction-ligase assay (PCR-LDR) in 197 AA patients and 135 healthy controls. Genotype. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype of rs2228570 (c.2TC). The correlation between VDR gene polymorphism and AA susceptibility, disease severity, therapeutic efficacy, clonal evolution and other clinical features was analyzed by SPSS 17.0 software. (2) There was a significant genetic linkage imbalance among the three VDR loci, rs1544410, rs797523 2 and rs731236. (3) Among the four polymorphic loci of VDR gene, the frequency of GG genotype and G allele at rs1544410 locus in AA patients was significantly higher than that in normal controls, while the other three polymorphisms were higher. Further analysis revealed that rs1544410 and rs7975232 loci were associated with non-severe AA, while rs2228570 loci were associated with severe AA. (5) The genotype of rs2228570 locus in AA patients was associated with therapeutic efficacy: the prognosis of CC and CT genotypes was better than that of TT genotypes. (6) The rs2228570 locus in AA patients was associated with severe AA. Genotypes are also closely related to late clonal evolution: TT carriers are more likely to develop myelodysplastic syndrome/acute myeloid leukemia, while CT carriers are more likely to develop paroxysmal nocturnal hemoglobinuria. BACKGROUND: Acquired aplastic anemia (AA) is a bone marrow failure disease caused by autoreactive T cells attacking bone marrow of target organs. IL-35 is a newly discovered regulatory cytokine, a new member of the IL-12 family, mainly composed of regulatory T cells (Tregs). In addition, IL-35 can induce T cells to differentiate into inducible regulatory T cells (iTR35) secreting IL-35, which can further maintain the immune tolerance of the body. Objective: To detect the expression of IL-35 in plasma of AA patients and evaluate the effect of IL-35 on T cell immune response, and to explore its role in the pathogenesis of AA, so as to provide theoretical basis for targeted therapy based on IL-35. (3) The expression of IL-35 and EBI3 mRNA in peripheral blood mononuclear cells (PBMCs) was detected by real-time quantitative PCR; (4) The expression of IL-35 and EBI3 mRNA in PBMCs was detected by Brdu incorporation method; (4) The expression of IL-35 was detected by Brdu incorporation method. After 48 hours, the levels of TNF-alpha IFN-gamma, IL-17A.IL-10 and TGF-beta 1 in culture supernatant were detected by ELISA, and CD4+/CD8+T cells, Thl (CD3+CD8-IFNy+), Th2 (Th2+CD8-IFNy+) were detected by flow cytometry and cell counting. (CD3+CD8-IL4+), Tcl (CD3+CD8+IFNy+), Tc2 (CD3+CD8+IL4+) and Th17 (CD3+CD8-IL17+) cell ratios and absolute number changes, while real-time quantitative PCR method was used to detect T-bet, GATA3, ROR gamma T and Foxp3 mRNA expression changes. Results: (1) Through ELISA detection, we found that the plasma of newly treated AA patients with IL-35. The level of IL-35 was significantly lower than that of CR patients and normal control group, but there was no significant difference between CR patients and normal control group. Further analysis showed that the level of IL-35 was closely related to the severity of the disease. (2) In newly treated AA patients, the levels of IL-35 were significantly correlated with platelet count, neutrophil absolute value and reticulocyte absolute value. (3) Real-time quantitative PCR showed that the expression of p35 and EBI3 mRNA in newly treated severe AA patients was lower than that in the normal control group, but there was no significant difference between the newly treated non-severe AA patients and the normal control group. (4) In vitro stimulation test showed that IL-35 could inhibit the proliferation of PBMCs in AA patients, and then the cell count and flow. IL-35 could inhibit the proliferation of CD4+ and CD8+ T cells. (5) Exogenous IL-35 significantly inhibited the secretion of TNF-alpha IFN-gamma and IL-17A by PBMCs in AA patients, and promoted the production of TGF-beta. (6) IL-35 inhibited the polarization of Th1, Tcl and Th17 cells, and promoted the polarization of Th2 and Tc2 cells. Real-time quantitative PCR results confirmed that IL-35 inhibited the production of TNF-alpha IFN-gamma and IL-17A by PBMCs in AA patients. The expression of T-bet and RORyt mRNA in BMCs and GATA3 mRNA had no significant effect on the expression of Foxp3 mRNA. Conclusion: The expression of IL-35 in newly treated AA patients was decreased, which was closely related to the severity of the disease. The low expression of IL-35 may cause Tregs disability, which may lead to the immune intolerance of AA, suggesting that IL-35 may occur in AA. Play a key role in the disease mechanism.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R556.5

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