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,可導致全身多個臟器、系統(tǒng)受累,臨床表現(xiàn)多樣化,個體差異性大。目前,人們對SLE的發(fā)病機制認識并不是十分清楚,一般認為自身免疫抗體的產(chǎn)生后,與相應自身免抗原形成免疫復合物,沉積在皮膚、關節(jié)、腎臟等靶器官,激活補體,引起急慢性炎癥反應及組織壞死所致。臨床上,SLE主要依靠臨床表現(xiàn)結合實驗室檢查來確診,另外,也常常通過檢測包括炎癥因子和自身抗體等血清生物標志物來評估SLE的疾病活動性及治療效果,但均不能理想地反映全部患者的病情進展及臨床分類/分型情況。因此,探索和研究新的血清標記物及其理論基礎,對于更好的評估SLE患者病情進展、指導患者的臨床治療及評估預后具有重要的意義。本研究首先通過Luminex高通量蛋白檢測技術,對SLE患者血清中20種自身免疫抗體進行了檢測,篩選出了SLE患者血清中特異性高表達的自身抗體、最佳聯(lián)合診斷SLE的自身免疫抗體組合、與SLE疾病活動性相關的自身免疫抗體及與ANA、抗dsDNA抗體表達水平具有顯著相關的自身免疫抗體。用層次聚類分析方法分析了這20種自身免疫抗體在SLE患者血清中的表達譜,發(fā)現(xiàn)同一種類的自身免疫抗體在SLE患者中的表達類型相似,常常聯(lián)合出現(xiàn)。隨后,通過血漿蛋白超濾濃縮凍干、Native-PAGE及免疫印跡等實驗檢測了SLE患者血液中自身免疫抗原抗體復合體的存在情況,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合物,由此,我們推測不同類型的SLE患者外周血中形成了不同的大分子免疫復合物,隨血液循環(huán)進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性,我們用免疫熒光實驗證實了免疫復合物沉積與其SLE患者在血清中表達水平、腎臟病理損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。另外,我們還發(fā)現(xiàn)在Ⅰ型IFN及Ⅰ型IFN誘導基因在SLE的發(fā)病中起重要作用,Ⅰ型IFN可作為評價SLE疾病活動性的生物學指標,IFI27、ISG15、SIGLEC1可作為LN的血清學指標。總之,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患者中的表達水平,篩選出了可以聯(lián)合診斷SLE的血清學指標,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合物存在于SLE患者的血液和組織,與特定靶器官病理損傷的關系。其中,鑒于抗UlsnRNP抗體與其抗原形成的免疫復合物沉積與狼瘡性腎炎(Lupus nephritis,LN)相關性,我們提出了抗UlsnRNP抗體可作為臨床SLE用來衡量LN腎臟損傷的血清學生物標志物,用于SLE的診斷及治療效果評價。另外,我們還發(fā)現(xiàn)Ⅰ型IFN及其誘導的ISG在SLE發(fā)病中起著重要作用。上述研究的完成,進一步豐富可用于SLE診斷及治療效果評價的生物標志物種類,也為我們認識和理解SLE發(fā)病機制提供了線索。
[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.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R593.241

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