發(fā)布時(shí)間：2018-05-09 12:45

  本文選題：特發(fā)性炎癥性肌病 + 髓樣樹突狀細(xì)胞�。� 參考：《山東大學(xué)》2015年博士論文

【摘要】：研究背景皮肌炎(dermatomyositis,DM)是一種公認(rèn)的獲得性骨骼肌自身免疫性疾病,為特發(fā)性炎癥性肌病(idiopathic inflammatory myopathies, IIMs)的一個(gè)亞型,臨床上以亞急性進(jìn)展的近端肌無力、特征性皮疹以及病理上肌肉組織炎癥細(xì)胞浸潤和束周肌纖維萎縮為主要特征,到目前為止,其免疫病理機(jī)制尚未得到完全闡明。Ⅰ型干擾素(type Ⅰ interferon, IFN-I)在紅斑狼瘡、干燥綜合征等自身免疫性疾病中發(fā)揮著重要作用。而今,Ⅰ型干擾素在特發(fā)性炎癥性疾病固有免疫中的作用機(jī)制也越來越受到重視。能夠分泌和產(chǎn)生大量Ⅰ型干擾素的漿細(xì)胞樣樹突狀細(xì)胞(plasmacytoid dendritic cells, pDCs),以往的研究證實(shí),廣泛地分布于皮肌炎患者肌肉組織中的肌內(nèi)膜和肌束膜內(nèi)。而Ⅰ型干擾素的產(chǎn)生依賴于各種受體和信號(hào)因子,并通過外源性和內(nèi)源性兩種途徑來誘導(dǎo)激活,外源性誘導(dǎo)途徑主要見于病毒感染,由Toll樣受體(Toll-like receptors, TLRs)識(shí)別相應(yīng)的病毒核酸成分,而誘導(dǎo)Ⅰ型干擾素的產(chǎn)生；內(nèi)源性激活途徑主要由視黃酸誘導(dǎo)基因-Ⅰ(retinoic acidnducible gene I, RIG-I)介導(dǎo),通過核酸與蛋白復(fù)合物(內(nèi)源性自身免疫復(fù)合物),誘導(dǎo)生成Ⅰ型干擾素。TLRs和RIG-I作為IFN-I產(chǎn)生通路中的重要受體,在DM肌肉組織中是否同時(shí)表達(dá),且以何種TLR表達(dá)為主,pDCs又通過何種機(jī)制產(chǎn)生大量的Ⅰ型干擾素,在國內(nèi)外尚無報(bào)道。本課題通過免疫組化、雙重免疫熒光、蛋白免疫印跡定量等實(shí)驗(yàn)方法,充分探討TLRs和RIG-I在皮肌炎患者肌肉組織中內(nèi)源性Ⅰ型干擾素生成中的作用機(jī)制。第一部分樹突狀細(xì)胞在特發(fā)性炎癥性肌病中的分布特點(diǎn)目的分析樹突狀細(xì)胞在DM、多發(fā)性肌炎(polymyositis, PM)和包涵體肌炎(inclusion body myositis, IBM)患者肌肉組織中的分布特點(diǎn),以初步探討髓樣樹突狀細(xì)胞(myeloid dendritic cell, mDCs)和pDCs在IIM發(fā)病中的免疫作用機(jī)制。方法總結(jié)分析進(jìn)行肌肉活檢的IIM患者27例,其中DM10例、PM10例、IBM4例和正常對照組3例。總結(jié)IIM患者的臨床資料和病理學(xué)特點(diǎn),所有活檢肌肉組織均行蘇木素-伊紅染色(hematoxylin-eosin, HE)和血樹突狀細(xì)胞抗原1(blood dendritic cell antigen 1, BDCA-1)和BDCA-2免疫組織化學(xué)染色。結(jié)果mDCs在DM、PM和IBM患者的肌肉組織中的血管周圍和炎性浸潤處,均有明顯的陽性表達(dá)。pDCs在DM中有明顯的陽性表達(dá),但在PM和IBM中呈現(xiàn)出無或僅有微弱的非特異性表達(dá)。10例DM患者中有8例患者可見到pDCs的顯著浸潤,主要分布在筋膜和寬大肌束膜內(nèi)血管周圍及肌內(nèi)膜炎細(xì)胞浸潤處。正常對照組未見mDCs和pDCs的陽性表達(dá)。結(jié)論樹突狀細(xì)胞可能參與IIM中炎性細(xì)胞浸潤和肌纖維破壞,在IIM的免疫病理機(jī)制中發(fā)揮重要作用,尤其是pDCs在DM的特異性表達(dá),提示pDCs與DM的特征性免疫病理密切相關(guān)。第二部分Toll樣受體和視黃醇誘導(dǎo)基因-Ⅰ在皮肌炎免疫病理機(jī)制中的作用研究目的明確包括TLR-3、TLR-4、TLR-7和TLR-9在內(nèi)的TLRs和RIG-I在皮肌炎中的表達(dá)特點(diǎn),并結(jié)合TLRs和RIG-I的功能探討其在皮肌炎免疫病理中的作用。方法選取行肌肉活檢的患者31例,其中DM組20例,對照組11例,包括PM4例,面肩肱型肌營養(yǎng)不良(facioscapulohumeral muscular dystrophy, FSHD)4例和正常對照組3例；全部活檢標(biāo)本均行HE染色及TLR-3、TLR-4、TLR-7、TLR-9和RIG-I免疫組化染色,應(yīng)用Western-blot定量檢測肌肉組織中TLR-3、TLR-4、 TLR-7、TLR-9和RIG-I的表達(dá)含量。結(jié)果免疫組化染色顯示TLR-3和RIG-I在DM組的束周萎縮處有明顯的表達(dá),而在DM和PM組的炎性浸潤處和壞死再生纖維中,僅有輕微的非特異性表達(dá),在FSHD組和正常對照組未見其表達(dá),RIG-I在DM組筋膜中的炎性浸潤處可見陽性表達(dá)；TLR-4和TLR-9在DM、PM和FSHD組的炎性浸潤處均有明顯的表達(dá),而在正常對照組未見其表達(dá),TLR-9在DM組筋膜中的炎性浸潤處可見陽性表達(dá)；TLR-7僅在9例DM患者及少數(shù)PM患者的炎性浸潤處可見的陽性表達(dá),而在其他DM/PM中,以及FSHD的炎性浸潤處未見表達(dá),TLR-7在所有患者肌肉組織中的神經(jīng)纖維上可見強(qiáng)陽性表達(dá)。Western-blot定量分析提示,TLR-3和RIG-I在DM中的表達(dá)明顯上調(diào),與各對照組相比具有統(tǒng)計(jì)學(xué)意義(p0.05); TLR-9在DM中的表達(dá)明顯上調(diào),與各對照組相比,具有顯著的統(tǒng)計(jì)學(xué)意義(p0.05); TLR-4在DM、PM和FSHD各組患者肌肉中的的蛋白表達(dá),之間比較無顯著差異(p0.05), TLR-4在DM組的蛋白表達(dá)與正常對照組比較,存在統(tǒng)計(jì)學(xué)差異(p0.05); TLR-7在DM組中的表達(dá)上調(diào),與其他對照組相比有統(tǒng)計(jì)學(xué)差異(p0.05)。結(jié)論RIG-I和TLR-3在DM中束周萎縮處的特異性分布,提示它們在DM的特征性免疫病理束周萎縮的形成過程中起重要作用。TLR-9在DM的肌肉組織中的表達(dá)含量明顯上調(diào),提示其在DM的免疫病理機(jī)制過程中有重要的參與作用。第三部分Toll樣受體和視黃酸誘導(dǎo)基因-Ⅰ在皮肌炎患者肌肉組織中內(nèi)源性Ⅰ型干擾素生成中的作用目的通過檢測pDCs與TLR-3、TLR-4、TLR-7、TLR-9和RIG-I的共表達(dá),以探討DM患者肌肉組織中內(nèi)源性IFN-I的生成機(jī)制。方法選取行肌肉活檢的患者31例,其中DM組20例,對照組11例,包括PM4例,FSHD4例和正常對照組3例；全部活檢標(biāo)本均行TLR-3、TLR-4、TLR-7、TLR-9和RIG-I免疫熒光染色,用雙重免疫熒光方法檢測DM肌肉標(biāo)本中漿細(xì)胞樣樹突狀細(xì)胞(pDCs)與TLRs及RIG-I的共表達(dá)。結(jié)果免疫熒光染色顯示TLR-3和RIG-I主要表達(dá)在DM組的束周萎縮處,而在DM和PM組的炎性浸潤處和壞死再生纖維中,可見少量非特異性表達(dá),在FSHD組和正常對照組未見其表達(dá)；TLR-4和TLR-9在DM、PM和FSHD組的炎性浸潤處均有明顯的表達(dá),而在正常對照組未見其表達(dá)；TLR-7僅在7例DM患者及少數(shù)PM患者的炎性浸潤處可見的陽性表達(dá),而在其他DM/PM中,以及FSHD的炎性浸潤處未見表達(dá),TLR-7在所有患者肌肉組織中的神經(jīng)纖維上可見強(qiáng)陽性表達(dá)；RIG-I和TLR-9在DM組筋膜中的炎性浸潤處可見陽性表達(dá)。DM組的筋膜、肌內(nèi)膜和肌束膜內(nèi)可見大量pDCs與TLR-9的共表達(dá)細(xì)胞；在肌內(nèi)膜中可見部分pDCs同時(shí)表達(dá)TLR-7。RIG-I和TLR-3雖然明顯的表達(dá)在束周萎縮處,但與TLR.-4一樣,均未發(fā)現(xiàn)與pDCs的共表達(dá)。結(jié)論TLR-9在DM肌肉組織中pDCs作用下的內(nèi)源性IFN-I的生成中發(fā)揮主要途徑作用,次要途經(jīng)為TLR-7所介導(dǎo)。TLR-3和RIG-I選擇性高表達(dá)在DM束周肌纖維上,提示其可能在一定程度上參與DM特征性病理特征——束周萎縮的形成。
[Abstract]:Background dermatomyositis (DM) is a recognized acquired autoimmune disease of skeletal muscle, a subtype of idiopathic inflammatory myopathy (idiopathic inflammatory myopathies, IIMs), clinically with subacute progression of proximal myasthenia, characteristic rash, and pathological muscle tissue inflammatory cell infiltration and weeks. Muscle fiber atrophy is the main feature, so far, its immune pathological mechanism has not been fully elucidated. Type I interferon (type I interferon, IFN-I) plays an important role in autoimmune diseases such as lupus erythematosus, Sjogren syndrome and so on. More and more attention has been paid to the plasmacytoid dendritic cells (pDCs) that secretes and produces a large number of type I interferons. Previous studies have proved that it is widely distributed in the myomintima and the membrane of the muscle tissue of patients with dermatomyositis, and the production of type I interferon is dependent on various receptors and signal factors. Exogenous and endogenous two pathways are used to induce activation. Exogenous inducement pathway is mainly found in virus infection. The Toll like receptor (Toll-like receptors, TLRs) identifies the corresponding viral nucleic acid components and induces the production of type I interferon, and the endogenous activation pathway is mainly induced by retinoic acid (retinoic acidnducible gene I, RI). G-I) mediated, through nucleic acid and protein complex (endogenous autoimmunity complex), induced generation I interferon.TLRs and RIG-I as an important receptor in the IFN-I pathway, whether it is expressed at the same time in the DM muscle tissue, and which TLR expression is the dominant factor, and pDCs can produce a large number of type I interferon through the mechanism of pDCs, which is not yet available at home and abroad. In this study, the role of TLRs and RIG-I in the formation of endogenous interferon I in the muscle tissue of patients with dermatomyositis was investigated by immunohistochemistry, double immunofluorescence and immunoblotting. The distribution characteristics of dendritic cells in idiopathic inflammatory myopathy in part 1 were analyzed in order to analyze dendritic cells The distribution of muscle tissue in DM, polymyositis (PM) and inclusion body myositis (IBM), in order to preliminarily discuss the immune mechanism of myeloid dendritic cells (myeloid dendritic cell, mDCs) and pDCs in the pathogenesis of the disease. Methods 27 cases of muscle biopsy were summarized and analyzed. Cases, PM10 cases, IBM4 cases and 3 normal controls. The clinical data and pathological features of IIM patients were summarized. All the biopsy muscle tissues were treated with hematoxylin eosin staining (hematoxylin-eosin, HE) and blood dendritic cell antigen 1 (blood dendritic cell antigen 1, BDCA-1) and BDCA-2 immunohistochemical staining. The positive expression of.PDCs in DM was obviously expressed in the perivascular and inflammatory infiltration of the muscle tissue, but in PM and IBM, there were 8 cases of DM patients with no or only weak non specific expression of.10, which could see significant infiltration of pDCs, mainly in the perivascular and perivascular of the broad myofascial membrane and the broad myoplastic. There was no positive expression of mDCs and pDCs in the normal control group. Conclusion dendritic cells may participate in the infiltration of inflammatory cells and the damage of muscle fibers in IIM, and play an important role in the immuno pathological mechanism of IIM, especially the specific expression of pDCs in DM, suggesting that pDCs is closely related to the characteristic immune pathology of DM. Second parts are closely related to the immune pathology of DM. The role of Toll like receptor and retinol induced gene - I in the immuno pathological mechanism of dermatomyositis, the purpose of this study is to clarify the expression of TLRs and RIG-I in dermatomyositis, including TLR-3, TLR-4, TLR-7 and TLR-9, and to explore the role of TLRs and RIG-I in dermatomyositis. There were 31 cases, of which 20 cases in group DM and 11 cases in control group, including PM4, 4 cases of facioscapulohumeral muscular dystrophy, FSHD, and 3 cases of normal control group. All biopsy specimens were stained with HE staining and TLR-3, TLR-4, TLR-7, TLR-9 and RIG-I immunity. Results the expression of -7, TLR-9 and RIG-I showed that TLR-3 and RIG-I were clearly expressed in the peripheral atrophy of group DM, but in the inflammatory infiltration and necrotic fibers of the DM and PM groups, only a slight nonspecific expression was found in the group of FSHD and the normal control group, and RIG-I was in the inflammatory infiltration of the DM fascia. The positive expression of TLR-4 and TLR-9 was found in the inflammatory infiltration of DM, PM and FSHD groups, but no expression in the normal control group. TLR-9 was positive in the inflammatory infiltration of the fascia of the DM group; TLR-7 was only positive in the inflammatory infiltration of 9 cases of DM and a few PM patients, while in other DM/PM, and FS. There was no expression in the inflammatory infiltration of HD, and the strong positive expression of.Western-blot was found on the nerve fibers in all the muscle tissues of all the patients. The expression of TLR-3 and RIG-I in DM was obviously up - regulated, compared with the control group (P0.05), and the expression of TLR-9 in DM was obviously up - up. Compared with the control group, the expression of TLR-9 was significantly higher than that of the control groups. Statistical significance (P0.05); there was no significant difference in the expression of protein in the muscles of each group of DM, PM and FSHD (P0.05). The protein expression of TLR-4 in the DM group was compared with the normal control group, and there was a statistical difference (P0.05); TLR-7 in the DM group was up up, and compared with the other control groups, there were statistical differences (P0.05). Conclusions The specific distribution of G-I and TLR-3 in the peripheral atrophy of DM suggests that they play an important role in the formation of DM's characteristic peripheral atrophy, and the expression of.TLR-9 in the muscle tissue of DM is obviously up-regulated, suggesting that it plays an important role in the immune pathological mechanism of DM. The third part of Toll like receptor and retinol The role of acid induced gene - I in the production of endogenous interferon type I in the muscle tissue of patients with dermatomyositis, objective by detecting the co expression of pDCs and TLR-3, TLR-4, TLR-7, TLR-9 and RIG-I, in order to explore the mechanism of endogenous IFN-I in muscle tissue of DM patients. Methods 31 patients with muscle biopsy were selected, including 20 cases in DM group and 11 in control group. There were 3 cases of PM4, FSHD4 and normal control. All the biopsy specimens were performed TLR-3, TLR-4, TLR-7, TLR-9 and RIG-I immunofluorescence. The co expression of plasma like dendritic cells (pDCs) in DM muscle specimens was detected by double immunofluorescence, and the immunofluorescence staining showed that TLR-3 and main expression were mainly expressed in the group of DM muscles. In the inflammatory infiltration and necrotic fibers of group DM and PM, a small amount of nonspecific expression was found in group FSHD and normal control. TLR-4 and TLR-9 were clearly expressed in the inflammatory infiltration of DM, PM and FSHD groups, but no expression in the normal control group; TLR-7 was only in 7 cases of DM patients and a few PM patients. The positive expression of the inflammatory infiltration was seen in the other DM/PM, and the inflammatory infiltration of FSHD was not expressed. The strong positive expression of TLR-7 was found on the nerve fibers in all the muscle tissues of the patients, and RIG-I and TLR-9 were found positive in the fascia of the.DM group in the inflammatory infiltration of the fascia of the DM group, and the intima and myocutaneous membrane of the muscle were visible. The co expression of pDCs and TLR-9; partial pDCs was found in the intima, while TLR-7.RIG-I and TLR-3 were expressed in the peripheral atrophy, but no co expression with pDCs was found as TLR.-4. Conclusion TLR-9 plays a major role in the endogenous IFN-I production of pDCs in DM muscle tissue, and the secondary pathway is secondary. The selective high expression of.TLR-3 and RIG-I mediated by TLR-7 on the DM peri muscle fibers suggests that it may be involved in the characteristic pathological features of DM to a certain extent, the formation of peripheral atrophy.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R593.26

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