發(fā)布時(shí)間：2017-12-27 17:00

  本文關(guān)鍵詞：中國成人自身炎癥性疾病臨床和基因表型譜及自噬的作用初探　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 自身炎癥性疾病 家族性地中海熱 冷炎素相關(guān)周期性綜合征 NLRP12自身炎癥性疾病 成人Still病 周期性發(fā)熱-阿弗它口炎-咽炎-淋巴結(jié)炎 自噬

【摘要】：背景:自身炎癥性疾病(Autoinflammatory diseases,AUIDs)是由固有免疫失調(diào)導(dǎo)致全身炎癥反應(yīng)的疾病,包括單基因AUIDs和多基因AUIDs。我國漢族與國外其他種族、成人與兒童AUIDs在疾病譜、臨床表型譜和基因表型譜方面很可能存在不同,目前關(guān)于我國成人AUIDs的臨床和基礎(chǔ)研究極為缺乏。目的:建立我國漢族成人AUIDs的前瞻性隊(duì)列,并與國外AUIDs、兒童AUIDs的疾病譜、臨床表型譜和基因表型譜對(duì)比。對(duì)確診成人單基因和多基因AUIDs患者進(jìn)行隨訪,建立應(yīng)用客觀指標(biāo)評(píng)價(jià)疾病嚴(yán)重程度的模型,觀察AUIDs治療前后疾病嚴(yán)重程度的變化,尋找導(dǎo)致療效不佳的獨(dú)立危險(xiǎn)因素,并通過血清學(xué)指標(biāo)檢測(cè)探尋新的反映疾病嚴(yán)重程度的指標(biāo)。初步探究自噬在成人AUIDs發(fā)病機(jī)制中的可能作用,探索適合在臨床患者中檢測(cè)細(xì)胞自噬功能的實(shí)驗(yàn)方法。方法:就診時(shí)年齡≥16歲,符合2010年Kastner教授定義擬診AUIDs的患者納入前瞻性觀察隊(duì)列。收集患者入組及隨訪的人口學(xué)信息、臨床資料、實(shí)驗(yàn)室檢查及生物學(xué)標(biāo)本,描述成人AUIDs患者臨床特點(diǎn),并與國外AUIDs和兒童AUIDs進(jìn)行疾病譜、臨床表型和基因表型的比較。采用Mann Whitney檢驗(yàn)分析各炎癥指標(biāo)與疾病活動(dòng)性的關(guān)系。采用逐步回歸法進(jìn)行多重線性回歸分析,建立由臨床癥狀、炎性指標(biāo)及SF-36評(píng)分組成的評(píng)估疾病嚴(yán)重程度的模型。利用新建模型對(duì)AUIDs療效進(jìn)行評(píng)估,采用二分類Logistic回歸分析尋找成人Still病(AOSD)傳統(tǒng)免疫抑制劑治療效果欠佳的獨(dú)立危險(xiǎn)因素。使用BD流式液相多重蛋白定量檢測(cè)技術(shù)進(jìn)行血清多因子檢測(cè)。使用Western blotting方法對(duì)AUIDs患者WBC或外周血單個(gè)核細(xì)胞(PBMC)進(jìn)行細(xì)胞自噬功能檢測(cè)。結(jié)果:自2015年4月至2017年4月,北京協(xié)和醫(yī)院(PUMCH)風(fēng)濕免疫科成人AUIDs中心共納入103例擬診AUIDs患者,26例(25.2%)診斷單基因AUIDs,61例(59.2%)診斷多基因AUIDs。單基因AUIDs中,中國成人NLRP12自身炎癥性疾病(NLRP12-AD)、Blau綜合征(BS)比例較國外成人高,而腫瘤壞死因子受體相關(guān)周期性綜合征(TRAPS)的比例較低。與兒童相比,家族性地中海熱(FMF)、高IgD綜合征(HIDS)所占比例較低,而NLRP12-AD在兒童中則尚未被發(fā)現(xiàn)。中國成人FMF的基因表型譜與日本相近,而與其他種族差異較大。與兒童相比,成人FMF乏力、結(jié)膜炎的發(fā)生率更高,而關(guān)節(jié)癥狀的發(fā)生率更低,且成人FMF無一例出現(xiàn)皮疹;成人冷炎素相關(guān)周期性綜合征(CAPS)皮膚癥狀的發(fā)生率更低;成人周期性發(fā)熱-阿弗它口炎-咽炎-淋巴結(jié)炎(PFAPA)綜合征乏力、肌痛發(fā)生率更高,咽痛、腹痛的發(fā)生率更低。87例單基因或多基因AUIDs中,大部分使用傳統(tǒng)免疫抑制劑治療,少部分應(yīng)用生物制劑。使用活動(dòng)性評(píng)分作為疾病緩解程度的指標(biāo),發(fā)現(xiàn)隊(duì)列中的患者經(jīng)過治療后疾病有明顯緩解。為更加精確的評(píng)估疾病嚴(yán)重程度,利用臨床癥狀個(gè)數(shù)、CRP和SF-36健康問卷總分3個(gè)客觀指標(biāo)建立評(píng)估疾病嚴(yán)重程度的模型,將利用該模型計(jì)算的結(jié)果命名為疾病嚴(yán)重程度指數(shù)(disease severity index,DSI)。利用DSI評(píng)價(jià)單基因和多基因AUIDs的療效,結(jié)果表明應(yīng)用秋水仙堿和/或激素治療FMF可以使疾病得到有效緩解;傳統(tǒng)免疫抑制劑治療可以使大部分AOSD患者的病情得到有效緩解,仍有小部分患者效果不佳。通過探究導(dǎo)致療效差異的危險(xiǎn)因素,發(fā)現(xiàn)女性、有關(guān)節(jié)癥狀、皮疹及淋巴結(jié)腫大者,對(duì)傳統(tǒng)治療的反應(yīng)較好,男性、Hgb或RBC水平較高的患者對(duì)傳統(tǒng)治療反應(yīng)較差。使用Logistic回歸分析得到傳統(tǒng)治療療效欠佳的獨(dú)立危險(xiǎn)因素為高RBC水平。檢測(cè)患者血清學(xué)標(biāo)本的多種炎癥細(xì)胞因子,發(fā)現(xiàn)血清CD54水平和疾病嚴(yán)重程度具有良好的相關(guān)性。建立適合在AUIDs患者中檢測(cè)細(xì)胞自噬功能的實(shí)驗(yàn)方法,發(fā)現(xiàn)盡管差異無統(tǒng)計(jì)學(xué)意義,活動(dòng)期AOSD患者PBMC的MDP誘導(dǎo)后自噬活化低于緩解期AOSD和健康對(duì)照。利用痛風(fēng)患者新鮮提取的WBC,可以有效地檢測(cè)自噬功能。結(jié)論:本研究建立了我國漢族成人AUIDs的前瞻性隊(duì)列,并獲得了入組患者人口學(xué)基本信息、臨床資料及生物學(xué)標(biāo)本。中國成人AUIDs與國外成人AUIDs或兒童AUIDs的疾病譜、基因表型譜和臨床表型譜均有不同。建立了利用臨床癥狀個(gè)數(shù)、CRP和SF-36健康問卷總分3個(gè)客觀指標(biāo)評(píng)估疾病嚴(yán)重程度的模型。利用該模型評(píng)估抗炎和傳統(tǒng)非生物免疫抑制劑治療可以使大部分AUIDs患者病情得到緩解,并進(jìn)一步找到導(dǎo)致傳統(tǒng)治療效果不佳的AOSD的獨(dú)立危險(xiǎn)因素為高RBC水平。CD54可能成為新的評(píng)價(jià)疾病嚴(yán)重程度的指標(biāo)。建立適合在AUIDs患者中檢測(cè)細(xì)胞自噬功能的實(shí)驗(yàn)方法。
[Abstract]:Background: Autoinflammatory diseases (AUIDs) is a systemic inflammatory response disease caused by inherent immune dysfunction, including monogenic AUIDs and multiple gene AUIDs. The AUIDs of Han nationality in China is different from other races, adults and children in disease spectrum, clinical phenotype spectrum and gene phenotype spectrum. Currently, the clinical and basic research on adult AUIDs in China is extremely scarce. Objective: to establish a prospective cohort of Chinese Han adult AUIDs, and to compare the disease spectrum, clinical phenotypic spectrum and gene phenotypic spectrum of foreign AUIDs and children AUIDs. Follow up of the diagnosis of adult single gene and multi gene AUIDs were established using objective index to evaluate the severity of the disease model, observe the change of the severity of the disease before and after treatment of AUIDs, to find independent risk factors for poor outcomes, and the serological detection and find new reflect disease severity index. To explore the possible role of autophagy in the pathogenesis of adult AUIDs, and to explore an experimental method suitable for detecting autophagic function in clinical patients. Methods: age greater than 16 years, in line with the 2010 Kastner definition of professor suspected of AUIDs were included in the prospective observational cohort. We collected demographic information, clinical data, laboratory tests and biological specimens from patients in group and follow-up. We described the clinical characteristics of adult AUIDs patients, and compared their disease profiles, clinical phenotypes and gene phenotypes with foreign AUIDs and children AUIDs. The relationship between the inflammatory markers and the activity of the disease was analyzed by Mann Whitney test. Multiple linear regression analysis was carried out by stepwise regression, and a model of evaluating the severity of the disease was established by the clinical symptoms, inflammatory indices and SF-36 scores. The efficacy of AUIDs was evaluated by the new model. Two classification Logistic regression analysis was used to find out the independent risk factors of adult Still disease (AOSD). BD flow multiprotein quantitative detection was used to detect multiple factors in serum. The Western blotting method was used to detect the autophagy function of WBC or peripheral blood mononuclear cells (PBMC) in AUIDs patients. Results: from April 2015 to April 2017, a total of 103 patients diagnosed with AUIDs were enrolled in the AUIDs center of the rheumatology and Immunology Department of Peking Union Medical College Hospital (PUMCH), 26 patients (25.2%) were diagnosed with single gene AUIDs, and 61 patients (59.2%) were diagnosed with multiple gene AUIDs. In single gene AUIDs, the proportion of NLRP12 inflammatory disease (NLRP12-AD) and Blau syndrome (BS) in Chinese adults is higher than that in foreign adults, while the proportion of tumor necrosis factor receptor related periodic syndrome (TRAPS) is low. Compared with children, the proportion of familial Mediterranean fever (FMF) and high IgD syndrome (HIDS) is low, while NLRP12-AD has not been found in children. The gene phenotypic spectrum of Chinese adult FMF is similar to that of Japan, but it is very different from other races. Compared with children, adult FMF fatigue, a higher incidence of conjunctivitis, and joint symptoms were lower, and the adult FMF there were no rash; adult cold Yansu associated periodic syndrome (CAPS) with lower incidence of skin symptoms in adults; periodic fever aphthous pharyngitis - mouth inflammation - - (lymphadenitis PFAPA) syndrome, fatigue, myalgia rate higher, lower incidence of sore throat, abdominal pain. In 87 cases of monogenic or polygenic AUIDs, most of them were treated with traditional immunosuppressive agents and a few biological agents were used. The activity score was used as an indicator of the degree of remission of the disease, and it was found that the patients in the cohort were significantly relieved after treatment. For a more accurate assessment of the severity of the disease, the clinical symptoms, CRP and SF-36 Health Questionnaire score of 3 indicators to establish an objective assessment of the severity of the disease model, using the calculation result from the model named the disease severity index (disease severity, index, DSI). Evaluation of the efficacy of single gene and multi gene AUIDs by DSI, the results show that the application of colchicine and / or hormone therapy can effectively alleviate the FMF disease; traditional immunosuppressive therapy can make the most of AOSD patients to effectively alleviate the effect of a small number of patients are still poor. Through exploring the risk factors that lead to differences in efficacy, it is found that women who have joint symptoms, rash and lymph node enlargement have a better response to traditional treatment. Patients with higher Hgb or RBC level are less responsive to traditional treatment. The independent risk factor of poor curative effect of traditional treatment was high RBC level using Logistic regression analysis. A variety of inflammatory cytokines were detected in the serological specimens of the patients, and there was a good correlation between the serum CD54 level and the severity of the disease. To establish an experimental method suitable for detecting autophagy function in AUIDs patients, it was found that although the difference was not statistically significant, the autophagy activation of PBMC after MDP induction in active AOSD patients was lower than that in the remission stage AOSD and healthy controls. The function of autophagy can be detected effectively by using the fresh WBC extracted from gout patients. Conclusion: the prospective cohort of Chinese Han adult AUIDs was established and the basic information, clinical data and biological specimens of the patients were obtained. The disease spectrum, gene phenotypic spectrum and clinical phenotypic spectrum of Chinese adult AUIDs and foreign adult AUIDs or child AUIDs are different. A model was established to evaluate the severity of the disease with 3 objective indicators, the number of clinical symptoms, the total score of the CRP and the SF-36 health questionnaire. Using this model to evaluate the effect of anti-inflammatory and traditional abiotic immunosuppressive therapy, most AUIDs patients can be relieved, and further find the independent risk factor of AOSD that leads to traditional treatment is high RBC level. CD54 may be a new indicator of the severity of the disease. To establish an experimental method suitable for the detection of autophagic function in AUIDs patients.
【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)】：R593.2

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