中国成人自身炎症性疾病临床和基因表型谱及自噬的作用初探

发布时间：2017-12-27 17:00

  本文关键词：中国成人自身炎症性疾病临床和基因表型谱及自噬的作用初探　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

  更多相关文章： 自身炎症性疾病 家族性地中海热 冷炎素相关周期性综合征 NLRP12自身炎症性疾病 成人Still病 周期性发热-阿弗它口炎-咽炎-淋巴结炎 自噬

【摘要】：背景:自身炎症性疾病(Autoinflammatory diseases,AUIDs)是由固有免疫失调导致全身炎症反应的疾病,包括单基因AUIDs和多基因AUIDs。我国汉族与国外其他种族、成人与儿童AUIDs在疾病谱、临床表型谱和基因表型谱方面很可能存在不同,目前关于我国成人AUIDs的临床和基础研究极为缺乏。目的:建立我国汉族成人AUIDs的前瞻性队列,并与国外AUIDs、儿童AUIDs的疾病谱、临床表型谱和基因表型谱对比。对确诊成人单基因和多基因AUIDs患者进行随访,建立应用客观指标评价疾病严重程度的模型,观察AUIDs治疗前后疾病严重程度的变化,寻找导致疗效不佳的独立危险因素,并通过血清学指标检测探寻新的反映疾病严重程度的指标。初步探究自噬在成人AUIDs发病机制中的可能作用,探索适合在临床患者中检测细胞自噬功能的实验方法。方法:就诊时年龄≥16岁,符合2010年Kastner教授定义拟诊AUIDs的患者纳入前瞻性观察队列。收集患者入组及随访的人口学信息、临床资料、实验室检查及生物学标本,描述成人AUIDs患者临床特点,并与国外AUIDs和儿童AUIDs进行疾病谱、临床表型和基因表型的比较。采用Mann Whitney检验分析各炎症指标与疾病活动性的关系。采用逐步回归法进行多重线性回归分析,建立由临床症状、炎性指标及SF-36评分组成的评估疾病严重程度的模型。利用新建模型对AUIDs疗效进行评估,采用二分类Logistic回归分析寻找成人Still病(AOSD)传统免疫抑制剂治疗效果欠佳的独立危险因素。使用BD流式液相多重蛋白定量检测技术进行血清多因子检测。使用Western blotting方法对AUIDs患者WBC或外周血单个核细胞(PBMC)进行细胞自噬功能检测。结果:自2015年4月至2017年4月,北京协和医院(PUMCH)风湿免疫科成人AUIDs中心共纳入103例拟诊AUIDs患者,26例(25.2%)诊断单基因AUIDs,61例(59.2%)诊断多基因AUIDs。单基因AUIDs中,中国成人NLRP12自身炎症性疾病(NLRP12-AD)、Blau综合征(BS)比例较国外成人高,而肿瘤坏死因子受体相关周期性综合征(TRAPS)的比例较低。与儿童相比,家族性地中海热(FMF)、高IgD综合征(HIDS)所占比例较低,而NLRP12-AD在儿童中则尚未被发现。中国成人FMF的基因表型谱与日本相近,而与其他种族差异较大。与儿童相比,成人FMF乏力、结膜炎的发生率更高,而关节症状的发生率更低,且成人FMF无一例出现皮疹;成人冷炎素相关周期性综合征(CAPS)皮肤症状的发生率更低;成人周期性发热-阿弗它口炎-咽炎-淋巴结炎(PFAPA)综合征乏力、肌痛发生率更高,咽痛、腹痛的发生率更低。87例单基因或多基因AUIDs中,大部分使用传统免疫抑制剂治疗,少部分应用生物制剂。使用活动性评分作为疾病缓解程度的指标,发现队列中的患者经过治疗后疾病有明显缓解。为更加精确的评估疾病严重程度,利用临床症状个数、CRP和SF-36健康问卷总分3个客观指标建立评估疾病严重程度的模型,将利用该模型计算的结果命名为疾病严重程度指数(disease severity index,DSI)。利用DSI评价单基因和多基因AUIDs的疗效,结果表明应用秋水仙碱和/或激素治疗FMF可以使疾病得到有效缓解;传统免疫抑制剂治疗可以使大部分AOSD患者的病情得到有效缓解,仍有小部分患者效果不佳。通过探究导致疗效差异的危险因素,发现女性、有关节症状、皮疹及淋巴结肿大者,对传统治疗的反应较好,男性、Hgb或RBC水平较高的患者对传统治疗反应较差。使用Logistic回归分析得到传统治疗疗效欠佳的独立危险因素为高RBC水平。检测患者血清学标本的多种炎症细胞因子,发现血清CD54水平和疾病严重程度具有良好的相关性。建立适合在AUIDs患者中检测细胞自噬功能的实验方法,发现尽管差异无统计学意义,活动期AOSD患者PBMC的MDP诱导后自噬活化低于缓解期AOSD和健康对照。利用痛风患者新鲜提取的WBC,可以有效地检测自噬功能。结论:本研究建立了我国汉族成人AUIDs的前瞻性队列,并获得了入组患者人口学基本信息、临床资料及生物学标本。中国成人AUIDs与国外成人AUIDs或儿童AUIDs的疾病谱、基因表型谱和临床表型谱均有不同。建立了利用临床症状个数、CRP和SF-36健康问卷总分3个客观指标评估疾病严重程度的模型。利用该模型评估抗炎和传统非生物免疫抑制剂治疗可以使大部分AUIDs患者病情得到缓解,并进一步找到导致传统治疗效果不佳的AOSD的独立危险因素为高RBC水平。CD54可能成为新的评价疾病严重程度的指标。建立适合在AUIDs患者中检测细胞自噬功能的实验方法。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R593.2

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