本文選題：系統(tǒng)性紅斑狼瘡 + 自身免疫抗體　； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：系統(tǒng)性紅斑狼瘡(Systemic lupus erythematosus,SLE)是一種經(jīng)典的炎癥性自身免疫性疾病,可導(dǎo)致全身多個(gè)臟器、系統(tǒng)受累,臨床表現(xiàn)多樣化,個(gè)體差異性大。目前,人們對(duì)SLE的發(fā)病機(jī)制認(rèn)識(shí)并不是十分清楚,一般認(rèn)為自身免疫抗體的產(chǎn)生后,與相應(yīng)自身免抗原形成免疫復(fù)合物,沉積在皮膚、關(guān)節(jié)、腎臟等靶器官,激活補(bǔ)體,引起急慢性炎癥反應(yīng)及組織壞死所致。臨床上,SLE主要依靠臨床表現(xiàn)結(jié)合實(shí)驗(yàn)室檢查來(lái)確診,另外,也常常通過(guò)檢測(cè)包括炎癥因子和自身抗體等血清生物標(biāo)志物來(lái)評(píng)估SLE的疾病活動(dòng)性及治療效果,但均不能理想地反映全部患者的病情進(jìn)展及臨床分類/分型情況。因此,探索和研究新的血清標(biāo)記物及其理論基礎(chǔ),對(duì)于更好的評(píng)估SLE患者病情進(jìn)展、指導(dǎo)患者的臨床治療及評(píng)估預(yù)后具有重要的意義。本研究首先通過(guò)Luminex高通量蛋白檢測(cè)技術(shù),對(duì)SLE患者血清中20種自身免疫抗體進(jìn)行了檢測(cè),篩選出了SLE患者血清中特異性高表達(dá)的自身抗體、最佳聯(lián)合診斷SLE的自身免疫抗體組合、與SLE疾病活動(dòng)性相關(guān)的自身免疫抗體及與ANA、抗dsDNA抗體表達(dá)水平具有顯著相關(guān)的自身免疫抗體。用層次聚類分析方法分析了這20種自身免疫抗體在SLE患者血清中的表達(dá)譜,發(fā)現(xiàn)同一種類的自身免疫抗體在SLE患者中的表達(dá)類型相似,常常聯(lián)合出現(xiàn)。隨后,通過(guò)血漿蛋白超濾濃縮凍干、Native-PAGE及免疫印跡等實(shí)驗(yàn)檢測(cè)了SLE患者血液中自身免疫抗原抗體復(fù)合體的存在情況,證據(jù)支持在SLE患者血液中存在有大量的各種自身抗原及其抗體形成的抗原抗體復(fù)合物,由此,我們推測(cè)不同類型的SLE患者外周血中形成了不同的大分子免疫復(fù)合物,隨血液循環(huán)進(jìn)入到不同靶器官沉積致病。其中,抗U1小核糖核蛋白(1-small nuclear ribonucleoprotein,UlsnRNP)抗體與SLE腎臟受累具有顯著相關(guān)性,我們用免疫熒光實(shí)驗(yàn)證實(shí)了免疫復(fù)合物沉積與其SLE患者在血清中表達(dá)水平、腎臟病理?yè)p害及腎臟功能損害一致,提示抗UlsnRNP抗體可作為SLE腎臟損傷的生物指標(biāo)。另外,我們還發(fā)現(xiàn)在Ⅰ型IFN及Ⅰ型IFN誘導(dǎo)基因在SLE的發(fā)病中起重要作用,Ⅰ型IFN可作為評(píng)價(jià)SLE疾病活動(dòng)性的生物學(xué)指標(biāo),IFI27、ISG15、SIGLEC1可作為L(zhǎng)N的血清學(xué)指標(biāo)�？傊�,本研究首次同步系統(tǒng)地分析了多種不同自身免疫抗體在SLE患者中的表達(dá)水平,篩選出了可以聯(lián)合診斷SLE的血清學(xué)指標(biāo),并初步揭示了特異性自身免疫抗體以大分子抗原抗體免疫復(fù)合物存在于SLE患者的血液和組織,與特定靶器官病理?yè)p傷的關(guān)系。其中,鑒于抗UlsnRNP抗體與其抗原形成的免疫復(fù)合物沉積與狼瘡性腎炎(Lupus nephritis,LN)相關(guān)性,我們提出了抗UlsnRNP抗體可作為臨床SLE用來(lái)衡量LN腎臟損傷的血清學(xué)生物標(biāo)志物,用于SLE的診斷及治療效果評(píng)價(jià)。另外,我們還發(fā)現(xiàn)Ⅰ型IFN及其誘導(dǎo)的ISG在SLE發(fā)病中起著重要作用。上述研究的完成,進(jìn)一步豐富可用于SLE診斷及治療效果評(píng)價(jià)的生物標(biāo)志物種類,也為我們認(rèn)識(shí)和理解SLE發(fā)病機(jī)制提供了線索。
[Abstract]:Systemic lupus erythematosus (Systemic lupus erythematosus, SLE) is a classic inflammatory autoimmune disease, which can cause multiple organs in the whole body. The system is involved, the clinical manifestations are diverse and the individual difference is large. At present, people are not ten distinct in understanding the pathogenesis of SLE. Immune complexes are formed by self antigen free antigen, which are deposited in target organs such as skin, joints and kidneys, activating complement, causing acute and chronic inflammatory reactions and tissue necrosis. Clinically, SLE is mainly confirmed by clinical manifestations combined with laboratory tests. In addition, serum biomarkers, including inflammatory factors and autoantibodies, are often detected. To evaluate the disease activity and therapeutic effect of SLE, it is not ideal to reflect the progress of the patients and the clinical classification / classification. Therefore, it is important to explore and study the new serum markers and their theoretical basis for the better evaluation of the progression of SLE patients, the clinical treatment and the prognosis of the patients. In this study, 20 kinds of autoantibodies in serum of SLE patients were detected by Luminex high throughput protein detection technology, and the specific high expression of autoantibodies in serum of SLE patients was screened. The best combination of the autoimmune antibody combination of the diagnostic SLE, the autoimmune antibody related to the activity of SLE and the anti dsDNA resistance to the ANA, and the anti dsDNA resistance were found. A hierarchical cluster analysis method was used to analyze the expression profiles of these 20 autoimmune antibodies in the serum of SLE patients. It was found that the same type of autoimmune antibody in SLE patients was similar and often appeared together. Then, the plasma protein ultrafiltration was used to concentrate the freeze-dried, Native-PA GE and immunoblotting were used to detect the presence of autoantigen antibody complexes in the blood of SLE patients. The evidence supports the presence of a large number of various antigens and antibodies in the blood of SLE patients. Therefore, we speculate that different types of SLE patients have different macromolecules in the peripheral blood. The Phytophthora complex, with the circulation of blood circulation into different target organs, is deposited and pathogenic. Among them, the anti U1 1-small nuclear ribonucleoprotein (UlsnRNP) antibody and the SLE renal involvement have significant correlation. We confirmed the expression level of the immune complex in the serum of the SLE patients and the renal pathological damage by the immunofluorescence test. It is consistent with renal function damage, suggesting that anti UlsnRNP antibody can be used as a biomarker for SLE renal injury. In addition, we also found that type I IFN and type I IFN induced genes play an important role in the pathogenesis of SLE. Type I can be used as a biological indicator for evaluating the activity of SLE disease. IFI27, ISG15, SIGLEC1 can be used as a LN serological index. Anyway, In this study, the expression level of various autoimmune antibodies in SLE patients was analyzed synchronously for the first time. The serological indexes that could be combined with the diagnosis of SLE were screened, and the specific autoimmune antibodies were found in the blood and tissue of the SLE patients with the large molecular antigen antibody immune complex and the specific target organ pathology. In addition, in view of the correlation between the immune complex deposition of anti UlsnRNP antibody and its antigen formation and the Lupus nephritis (LN), we suggest that anti UlsnRNP antibody can be used as a serological biomarker for the clinical SLE used to measure the renal injury of LN, used in the diagnosis and evaluation of the therapeutic effect of SLE. In addition, we also send it. The present type I IFN and its induced ISG play an important role in the pathogenesis of SLE. The completion of these studies further enriches the species of biomarkers which can be used to evaluate the diagnostic and therapeutic effects of SLE, and also provides a clue to our understanding and understanding of the pathogenesis of SLE.

【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】：2017
【分類號(hào)】：R593.241

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