免疫相關(guān)血細(xì)胞減少癥患者外周血淋巴細(xì)胞線粒體DNA D-環(huán)區(qū)多態(tài)性研究
發(fā)布時間：2018-09-11 09:45
【摘要】：目的:第一部分:在血液系統(tǒng)的疾病中,我們常常最需要診斷的一類為全血細(xì)胞減少癥,而其中免疫相關(guān)血細(xì)胞減少癥(IRP)作為以骨髓衰竭為表現(xiàn)的疾病體系被細(xì)分出來,近年來研究表明其發(fā)病機(jī)制是由于機(jī)體受到某種未知病原的刺激后,樹突細(xì)胞亞群作為主要的呈遞抗原率先出現(xiàn)異常,隨后傳遞至T淋巴細(xì)胞,再導(dǎo)致下游的B淋巴細(xì)胞在功能、數(shù)量及亞群等各方面出現(xiàn)不同程度的異常,從而形成自身抗體,而這類自身抗體可以專門針對骨髓的造血細(xì)胞,它們可以通過封閉造血細(xì)胞膜上的功能蛋白、或通過激活補(bǔ)體原位溶血、亦或可通過介導(dǎo)巨噬細(xì)胞吞噬等多種途徑導(dǎo)致骨髓的造血細(xì)胞增殖分化被抑制,最終導(dǎo)致機(jī)體無效造血,骨髓出現(xiàn)衰竭[35]。所以盡快的正確診斷,將IRP與其他不同種類、不同治療方案的全血細(xì)胞減少癥鑒別出來至關(guān)重要。近年來大量的實驗研究都集中在細(xì)胞核內(nèi)的基因組遺傳物質(zhì)與血液疾病的是否存在相關(guān)性,本試驗檢測的線粒體DNA中的D-環(huán)區(qū)著眼于細(xì)胞核外DNA的突變與免疫性血液系統(tǒng)疾病是否同樣存在相關(guān)性,立志于為疾病的臨床診斷與發(fā)病機(jī)制提供新的思路。線粒體作為高等動物細(xì)胞內(nèi)除細(xì)胞核外的唯一含有DNA的細(xì)胞器,且不依賴基因組進(jìn)行復(fù)制、轉(zhuǎn)錄及翻譯。盡管如此,但是當(dāng)線粒體DNA長期在氧化磷酸化中裸露時卻極其容易被周圍的氧自由基等物質(zhì)所損傷,這主要是由于其缺乏有效的抗氧化修復(fù)機(jī)制,大量研究表明其同樣缺乏與組蛋白的有效結(jié)合,因此無法獲得組蛋白保護(hù),導(dǎo)致線粒體DNA的與細(xì)胞核DNA相比,遠(yuǎn)高于10倍以上。目前大量研究也表明,線粒體DNA的損傷氧化與腫瘤的發(fā)病風(fēng)險、疾病的預(yù)后、人類糖尿病等慢性疾病以及人類衰老等多方面存在相關(guān)性。此外,線粒體DNA的變異還會影響線粒體呼吸鏈功能的障礙從而導(dǎo)致機(jī)體多種免疫相關(guān)性疾病發(fā)生。其中的D-環(huán)區(qū)位于線粒體DNA的t RNApro與t RNAphe之間(nt16024-nt575)總長度約為1120bp左右,為線粒體DNA主要的非編碼區(qū)域,是線粒體DNA內(nèi)最大的遺傳變異區(qū)域,D-環(huán)區(qū)還是線粒體DNA復(fù)制與轉(zhuǎn)錄的調(diào)控區(qū),以及線粒體DNA的輕鏈與重鏈的開始位點也均在D-環(huán)區(qū),因此近年來對該區(qū)域的探索成為對線粒體DNA研究的重點區(qū)域。單核苷酸多態(tài)性(SNP),研究認(rèn)為其在DNA序列的變異中是極為常見的,在高等動物的基因組內(nèi)變異頻率通�？绳e1%,它主要是由于DNA序列上單個核甘酸的變化導(dǎo)致的基因組序列的多態(tài)性,比例在已知的所有多態(tài)性中占有90%以上。因此SNP被認(rèn)為與物種的多樣性、與藥物治療個體差異、與某些疾病的易感性均存在相關(guān)因素。由于人類的基因組是存在連鎖不平衡的,所以,盡管大多數(shù)的SNP不會直接的影響到對基因產(chǎn)物的表達(dá),但是其依舊會被大多數(shù)學(xué)者當(dāng)成遺傳標(biāo)記的一個類別來深入研究,當(dāng)某些可以導(dǎo)致疾病的基因其在功能上或在結(jié)構(gòu)上產(chǎn)生變化時,我能仍可以將SNP用于定位這些臨近的基因或基因組。如果SNP恰好位于某些基因的啟動子中,其功能起著對該基因進(jìn)行編碼及調(diào)控時,那么此時的SNP就有可能會對此基因造成影響。而本次將要研究的D-環(huán)區(qū)域線粒體DNA復(fù)制的控制區(qū)、線粒體DNA的輕鏈及重鏈的復(fù)制起始點以及承擔(dān)調(diào)控線粒體DNA轉(zhuǎn)錄和復(fù)制的重要區(qū)域,其遺傳上的高度多態(tài)性勢必會對線粒體產(chǎn)生一定的影響。因此我們進(jìn)行了對免疫相關(guān)性血細(xì)胞減少癥(IRP)患者外周血淋巴細(xì)胞線粒體DNA(mtDNA)D-環(huán)區(qū)多態(tài)性的意義、與免疫指標(biāo)相關(guān)性以及與患者骨髓及外周血細(xì)胞形態(tài)學(xué)特征相關(guān)性的研究。第二部分:幼淋巴細(xì)胞白血病(prolymphocytic leukemia,PLL)為一種特殊類型的淋巴細(xì)胞白血病,一般認(rèn)為屬罕見的慢性淋巴細(xì)胞白血病的變異型,但也有人認(rèn)為是急淋的一種(Ⅱ型)。Auer小體是急性髓系白血病一個具有診斷意義的形態(tài)學(xué)特征,其在急性髓系白血病的檢出、分布情況及與療效的關(guān)系有診斷性的臨床意義。而我們此次探討的是在幼淋巴細(xì)胞白血病細(xì)胞的胞漿中出現(xiàn)了形態(tài)學(xué)類似Auer小體的Auer小體樣內(nèi)含物的特征。方法:第一部分:1.提取43例初治IRP患者及41例正常對照者外周血淋巴細(xì)胞的線粒體DNA,對所有樣本的D-環(huán)區(qū)域采用PCR擴(kuò)增的方法,并通過正向及反向直接測序?qū)ζ銬-環(huán)區(qū)域的PCR擴(kuò)增產(chǎn)物基因序列進(jìn)行檢測,將檢測出的結(jié)果與人線粒體DNA文庫記錄的劍橋序列以及mt DB數(shù)據(jù)庫的Polymorphic Sites子數(shù)據(jù)庫相關(guān)數(shù)據(jù)庫進(jìn)行對比。2.利用流式細(xì)胞術(shù)(FACS)檢測43例初治IRP患者的骨髓造血細(xì)胞CD15+、Gly Co A+細(xì)胞以及CD34+細(xì)胞膜表面抗體的陽性率(Ig G與Ig M)3.利用流式細(xì)胞術(shù)(FACS)檢測43例初治IRP患者的外周血B淋巴細(xì)胞及T淋巴細(xì)胞亞群陽性率4.利用瑞氏染色法對43例初治IRP患者的骨髓涂片,計數(shù)200個骨髓細(xì)胞,分別記錄其骨髓的小粒、油滴、增生程度、粒紅系比例及病態(tài)造血情況、淋巴細(xì)胞比例、巨核細(xì)胞數(shù)量以及血小板等5.利用利用瑞氏染色法對43例初治IRP患者的外周血涂片,計數(shù)100個白細(xì)胞,分別記錄其粒細(xì)胞比例、成熟紅細(xì)胞、淋巴細(xì)胞比例、單核細(xì)胞比例以及血小板等第二部分:用顯微鏡觀察骨髓細(xì)胞形態(tài)學(xué)、細(xì)胞化學(xué)染色的特點,用流式細(xì)胞術(shù)檢測骨髓細(xì)胞的免疫表型,用電鏡掃描分析其成份。結(jié)果:1.43例IRP患者的外周血淋巴細(xì)胞線粒體DNA D-環(huán)區(qū)中共有110個變異位點,其中62個為多態(tài)位點(SNP),48個為突變位點,其中14個位點為數(shù)據(jù)庫中未提及的新突變位點。2.110個變異位點中共發(fā)現(xiàn)516個堿基改變,最主要改變是410個堿基置換,常見的堿基置換為T/C(184/410)和A/G(113/410)3.110個變異位點中高頻變異位點73和263,其變異率為43/43,位點311的變異率為32/43,位點310和16224的變異率為27/43,16519的變異率為25/43,位點489和16362為24/43。4.IRP患者外周血淋巴細(xì)胞線粒體DNA D-環(huán)區(qū)多態(tài)性與該類患者骨髓單個核細(xì)胞的相關(guān)性統(tǒng)計中發(fā)現(xiàn),以年齡18歲為界的35例成年組中其淋巴細(xì)胞線粒體DNA D-環(huán)區(qū)多態(tài)性與患者骨髓單個核細(xì)胞的CD15Ig M、Gly Co A+細(xì)胞Ig M、CD34+細(xì)胞Ig G、CD34+細(xì)胞Ig M存在顯著正相關(guān)性。5.骨髓細(xì)胞形態(tài)學(xué)提示為幼淋巴細(xì)胞白血病,部分胞漿中見有Auer小體樣內(nèi)含物,細(xì)胞化學(xué)染色及流式細(xì)胞術(shù)分析亦為B淋巴細(xì)胞,電鏡掃描其為基質(zhì)密度增高,內(nèi)部結(jié)構(gòu)消失的變性線粒體。結(jié)論:1.IRP患者外周血淋巴細(xì)胞的線粒體DNA D-環(huán)區(qū)存在高頻突變。2.最主要的堿基改變類型為T/C以及A/G3.高頻突變位點分別為73、263、311、310、16224、16519、489以及163624.且在成年組(年齡≥18歲)中與骨髓單個核細(xì)胞膜結(jié)合自身抗體顯著正相關(guān),可能是免疫相關(guān)性血細(xì)胞減少癥發(fā)病機(jī)制中的重要環(huán)節(jié)。5.在淋巴系統(tǒng)的腫瘤細(xì)胞胞漿中變性的線粒體經(jīng)瑞氏染色后可呈現(xiàn)Auer小體樣內(nèi)含物。Auer小體在形態(tài)學(xué)上是非常有價值的發(fā)現(xiàn),但不能僅通過形態(tài)學(xué)觀察,還應(yīng)結(jié)合其他相關(guān)檢查進(jìn)一步對白血病細(xì)胞的類別分型。
[Abstract]:OBJECTIVE: PART I: In hematological diseases, pancytopenia is the most frequently diagnosed type, in which immune-associated hematocytopenia (IRP) is subdivided as a disease system characterized by bone marrow failure. Recent studies have shown that the pathogenesis of IRP is stimulated by an unknown pathogen. After that, dendritic cell subsets as the main presenting antigens first appear abnormal, then transmit to T lymphocytes, and then lead to the downstream B lymphocytes in the function, number and subsets of abnormalities in varying degrees, thus forming autoantibodies, which can be specifically targeted at bone marrow hematopoietic cells, they can pass through Blockade of functional proteins on hematopoietic cell membranes, activation of complement in situ hemolysis, or mediation of macrophage phagocytosis may lead to inhibition of bone marrow hematopoietic cell proliferation and differentiation, resulting in invalid hematopoiesis and bone marrow failure [35]. In recent years, a large number of experimental studies have focused on whether there is a correlation between genomic genetic material in the nucleus and blood diseases. The D-loop region of mitochondrial DNA detected in this study focuses on whether mutations in extranuclear DNA and immune hematological diseases exist as well. Mitochondria are the only DNA-containing organelles in the cells of higher animals other than the nucleus and are not dependent on the genome for replication, transcription and translation. Oxygen free radicals and other substances around the damage, mainly due to its lack of effective antioxidant repair mechanism, a large number of studies have shown that it is also lack of effective binding with histone, so it can not obtain histone protection, resulting in mitochondrial DNA and nuclear DNA compared to much more than 10 times. In addition, the variation of mitochondrial DNA also affects the function of mitochondrial respiratory chain and leads to the occurrence of many immune-related diseases. The D-ring region of mitochondrial DNA is located in the t RN of mitochondrial DNA. The total length between Apro and t RNAphe (nt16024-nt575) is about 1120 bp, which is the main non-coding region of mitochondrial DNA, the largest genetic variation region in mitochondrial DNA, the D-loop region or the regulatory region of mitochondrial DNA replication and transcription, as well as the starting sites of light and heavy strands of mitochondrial DNA in recent years. Single nucleotide polymorphism (SNP) is considered to be very common in the variation of DNA sequences. The frequency of variation in the genome of higher animals is usually? 1%. It is mainly due to the polymorphism of the genome sequence caused by the change of single nucleotide glycine in the DNA sequence. SNP is considered to be associated with species diversity, individual differences in drug treatment, and susceptibility to certain diseases. Since the human genome is linked to disequilibrium, most SNPs do not directly affect the expression of gene products, but their dependence. I can still use SNPs to locate adjacent genes or genomes when certain genes that cause disease change functionally or structurally. If SNPs happen to be located in the promoters of certain genes, their function plays a role in that gene. The high genetic polymorphisms in the D-loop region, the starting point for the replication of light and heavy strands of mitochondrial DNA, and the important regions responsible for the regulation of mitochondrial DNA transcription and replication are bound to occur. Therefore, we have studied the significance of D-loop polymorphism of peripheral blood lymphocyte mitochondrial DNA (mtDNA) in patients with immune-associated hematopenia (IRP), the correlation between D-loop polymorphism and immune indices, and the correlation between D-loop polymorphism and morphological characteristics of bone marrow and peripheral blood cells. Prolymphocytic leukemia (PLL) is a special type of lymphocytic leukemia. It is generally considered to be a rare variant of chronic lymphocytic leukemia, but it is also considered to be a type (type II) of acute lymphocytic leukemia. Auer body is a diagnostic morphological feature of acute myeloid leukemia, which is found in acute myeloid leukemia. Detection, distribution and relationship with therapeutic effect have diagnostic clinical significance. We are exploring the characteristics of Auer body-like inclusions in the cytoplasm of immature lymphoblastic leukemia cells. The mitochondrial DNA of the cells was amplified by PCR in the D-loop region of all samples. The PCR product gene sequences of the D-loop region were detected by direct forward and reverse sequencing. The results were related to the Cambridge sequence recorded by the human mitochondrial DNA library and the Polymorphic Sites subdatabase of the MT DB database. Flow cytometry (FACS) was used to detect the positive rates of CD15 +, Gly Co A + cells and CD34 + cell membrane surface antibodies (Ig G and Ig M) of bone marrow hematopoietic cells in 43 patients with newly diagnosed IRP. Flow cytometry (FACS) was used to detect the positive rates of B lymphocytes and T lymphocyte subsets in 43 patients with newly diagnosed IRP. Bone marrow smears of 43 patients with primary IRP were counted by color method. 200 bone marrow cells were counted. The granules, oil droplets, degree of proliferation, ratio of granulogenous erythroid system and pathological hematopoiesis, ratio of lymphocyte, number of megakaryocyte and platelet were recorded. Peripheral blood smears of 43 patients with primary IRP were counted by Rayleigh staining and 100 white blood cells were counted. The proportion of granulocytes, mature red blood cells, lymphocytes, monocytes and platelets were recorded. Part 2: Morphology and cytochemical staining of bone marrow cells were observed under microscope. Immunophenotype of bone marrow cells was detected by flow cytometry, and their components were analyzed by electron microscopy. Results: 1.43 patients with IRP There were altogether 110 mutation sites in the mitochondrial DNA D-loop region of peripheral blood lymphocytes, of which 62 were polymorphic sites (SNP) and 48 were mutation sites. Of these sites, 14 were new mutation sites not mentioned in the database. A total of 516 base changes were found in the 2.110 mutation sites. The main change was 410 base substitution, and the common base substitution was T/C (T/C). The mutation rates of 73 and 263 of 184/410 and A/G (113/410) 3.110 loci were 43/43, 32/43 for locus 311, 27/43 for loci 310 and 16224, 25/43 for loci 16519, 24/43.4 for loci 489 and 1616622. Mitochondrial DNA D-loop polymorphism in peripheral blood lymphocytes of patients with IRP and bone marrow of these patients According to the correlation statistics of mononuclear cells, there was a significant positive correlation between lymphocyte mitochondrial DNA D-loop polymorphism and CD15Ig M, Gly Co A + cell Ig M, CD34 + cell Ig G, CD34 + cell Ig M of bone marrow mononuclear cells in 35 adult patients aged 18 years. There were some Auer body-like inclusions in the cytoplasm. Cytochemical staining and flow cytometry analysis also showed that B lymphocytes were denatured mitochondria with increased matrix density and disappeared internal structure. The high-frequency mutations were 73,263,311,310,16224,16519,489 and 163624 respectively. In the adult group (age < 18 years old), the high-frequency mutations were positively correlated with autoantibodies binding to bone marrow mononuclear cell membrane, which may be an important link in the pathogenesis of immune-associated hematocytopenia. 5. Auer bodies are very valuable morphological findings, but not only through morphological observation, but also should be combined with other related examinations to further classify leukemia cells.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R558.2
本文編號：2236337
[Abstract]:OBJECTIVE: PART I: In hematological diseases, pancytopenia is the most frequently diagnosed type, in which immune-associated hematocytopenia (IRP) is subdivided as a disease system characterized by bone marrow failure. Recent studies have shown that the pathogenesis of IRP is stimulated by an unknown pathogen. After that, dendritic cell subsets as the main presenting antigens first appear abnormal, then transmit to T lymphocytes, and then lead to the downstream B lymphocytes in the function, number and subsets of abnormalities in varying degrees, thus forming autoantibodies, which can be specifically targeted at bone marrow hematopoietic cells, they can pass through Blockade of functional proteins on hematopoietic cell membranes, activation of complement in situ hemolysis, or mediation of macrophage phagocytosis may lead to inhibition of bone marrow hematopoietic cell proliferation and differentiation, resulting in invalid hematopoiesis and bone marrow failure [35]. In recent years, a large number of experimental studies have focused on whether there is a correlation between genomic genetic material in the nucleus and blood diseases. The D-loop region of mitochondrial DNA detected in this study focuses on whether mutations in extranuclear DNA and immune hematological diseases exist as well. Mitochondria are the only DNA-containing organelles in the cells of higher animals other than the nucleus and are not dependent on the genome for replication, transcription and translation. Oxygen free radicals and other substances around the damage, mainly due to its lack of effective antioxidant repair mechanism, a large number of studies have shown that it is also lack of effective binding with histone, so it can not obtain histone protection, resulting in mitochondrial DNA and nuclear DNA compared to much more than 10 times. In addition, the variation of mitochondrial DNA also affects the function of mitochondrial respiratory chain and leads to the occurrence of many immune-related diseases. The D-ring region of mitochondrial DNA is located in the t RN of mitochondrial DNA. The total length between Apro and t RNAphe (nt16024-nt575) is about 1120 bp, which is the main non-coding region of mitochondrial DNA, the largest genetic variation region in mitochondrial DNA, the D-loop region or the regulatory region of mitochondrial DNA replication and transcription, as well as the starting sites of light and heavy strands of mitochondrial DNA in recent years. Single nucleotide polymorphism (SNP) is considered to be very common in the variation of DNA sequences. The frequency of variation in the genome of higher animals is usually? 1%. It is mainly due to the polymorphism of the genome sequence caused by the change of single nucleotide glycine in the DNA sequence. SNP is considered to be associated with species diversity, individual differences in drug treatment, and susceptibility to certain diseases. Since the human genome is linked to disequilibrium, most SNPs do not directly affect the expression of gene products, but their dependence. I can still use SNPs to locate adjacent genes or genomes when certain genes that cause disease change functionally or structurally. If SNPs happen to be located in the promoters of certain genes, their function plays a role in that gene. The high genetic polymorphisms in the D-loop region, the starting point for the replication of light and heavy strands of mitochondrial DNA, and the important regions responsible for the regulation of mitochondrial DNA transcription and replication are bound to occur. Therefore, we have studied the significance of D-loop polymorphism of peripheral blood lymphocyte mitochondrial DNA (mtDNA) in patients with immune-associated hematopenia (IRP), the correlation between D-loop polymorphism and immune indices, and the correlation between D-loop polymorphism and morphological characteristics of bone marrow and peripheral blood cells. Prolymphocytic leukemia (PLL) is a special type of lymphocytic leukemia. It is generally considered to be a rare variant of chronic lymphocytic leukemia, but it is also considered to be a type (type II) of acute lymphocytic leukemia. Auer body is a diagnostic morphological feature of acute myeloid leukemia, which is found in acute myeloid leukemia. Detection, distribution and relationship with therapeutic effect have diagnostic clinical significance. We are exploring the characteristics of Auer body-like inclusions in the cytoplasm of immature lymphoblastic leukemia cells. The mitochondrial DNA of the cells was amplified by PCR in the D-loop region of all samples. The PCR product gene sequences of the D-loop region were detected by direct forward and reverse sequencing. The results were related to the Cambridge sequence recorded by the human mitochondrial DNA library and the Polymorphic Sites subdatabase of the MT DB database. Flow cytometry (FACS) was used to detect the positive rates of CD15 +, Gly Co A + cells and CD34 + cell membrane surface antibodies (Ig G and Ig M) of bone marrow hematopoietic cells in 43 patients with newly diagnosed IRP. Flow cytometry (FACS) was used to detect the positive rates of B lymphocytes and T lymphocyte subsets in 43 patients with newly diagnosed IRP. Bone marrow smears of 43 patients with primary IRP were counted by color method. 200 bone marrow cells were counted. The granules, oil droplets, degree of proliferation, ratio of granulogenous erythroid system and pathological hematopoiesis, ratio of lymphocyte, number of megakaryocyte and platelet were recorded. Peripheral blood smears of 43 patients with primary IRP were counted by Rayleigh staining and 100 white blood cells were counted. The proportion of granulocytes, mature red blood cells, lymphocytes, monocytes and platelets were recorded. Part 2: Morphology and cytochemical staining of bone marrow cells were observed under microscope. Immunophenotype of bone marrow cells was detected by flow cytometry, and their components were analyzed by electron microscopy. Results: 1.43 patients with IRP There were altogether 110 mutation sites in the mitochondrial DNA D-loop region of peripheral blood lymphocytes, of which 62 were polymorphic sites (SNP) and 48 were mutation sites. Of these sites, 14 were new mutation sites not mentioned in the database. A total of 516 base changes were found in the 2.110 mutation sites. The main change was 410 base substitution, and the common base substitution was T/C (T/C). The mutation rates of 73 and 263 of 184/410 and A/G (113/410) 3.110 loci were 43/43, 32/43 for locus 311, 27/43 for loci 310 and 16224, 25/43 for loci 16519, 24/43.4 for loci 489 and 1616622. Mitochondrial DNA D-loop polymorphism in peripheral blood lymphocytes of patients with IRP and bone marrow of these patients According to the correlation statistics of mononuclear cells, there was a significant positive correlation between lymphocyte mitochondrial DNA D-loop polymorphism and CD15Ig M, Gly Co A + cell Ig M, CD34 + cell Ig G, CD34 + cell Ig M of bone marrow mononuclear cells in 35 adult patients aged 18 years. There were some Auer body-like inclusions in the cytoplasm. Cytochemical staining and flow cytometry analysis also showed that B lymphocytes were denatured mitochondria with increased matrix density and disappeared internal structure. The high-frequency mutations were 73,263,311,310,16224,16519,489 and 163624 respectively. In the adult group (age < 18 years old), the high-frequency mutations were positively correlated with autoantibodies binding to bone marrow mononuclear cell membrane, which may be an important link in the pathogenesis of immune-associated hematocytopenia. 5. Auer bodies are very valuable morphological findings, but not only through morphological observation, but also should be combined with other related examinations to further classify leukemia cells.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R558.2
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