本文選題：POEMS綜合征 + VEGF�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：背景和目的POEMS綜合征是一種少見(jiàn)的單克隆漿細(xì)胞增殖性疾病,主要臨床特點(diǎn)包括多發(fā)周?chē)窠?jīng)病、硬化性骨病和水負(fù)荷異常等。血管內(nèi)皮生長(zhǎng)因子(VEGF),作為一種調(diào)控血管新生和增強(qiáng)血管通透性的重要細(xì)胞因子,是該病診斷、病情監(jiān)測(cè)和療效評(píng)價(jià)的核心分子標(biāo)志物。但是,目前關(guān)于POEMS綜合征患者高水平血清VEGF的具體細(xì)胞來(lái)源,及其產(chǎn)生調(diào)控機(jī)制還缺乏系統(tǒng)的研究。材料與方法收集2014年2月至2015年4月就診于北京協(xié)和醫(yī)院的62例初治及46例其間完成治療的POEMS綜合征患者臨床資料、血清和骨髓標(biāo)本。采用ELISA法測(cè)定血清VEGF水平。通過(guò)實(shí)時(shí)熒光定量PCR和流式細(xì)胞學(xué),分別在mRNA和蛋白水平測(cè)定骨髓內(nèi)漿細(xì)胞表達(dá)VEGF的相對(duì)水平,并和血清VEGF水平進(jìn)行相關(guān)性分析。利用流式細(xì)胞學(xué),對(duì)骨髓內(nèi)漿細(xì)胞亞群進(jìn)行分析,并測(cè)定不同亞群細(xì)胞表達(dá)VEGF和白介素-6(IL-6)的水平。應(yīng)用免疫組織化學(xué)法,檢測(cè)患者骨髓活檢組織中漿細(xì)胞分布、克隆性和VEGF及相關(guān)調(diào)控分子,包括IL-6和缺氧誘導(dǎo)因子1-α(HIF-1α)的表達(dá)情況。采用SPSS 22軟件進(jìn)行統(tǒng)計(jì)分析,當(dāng)p0.05時(shí)認(rèn)為存在統(tǒng)計(jì)學(xué)差異。結(jié)果初治POEMS綜合征患者血清VEGF水平(中位值5958 pg/mL),顯著高于其他疾病和健康對(duì)照(p0.001),具有明確的診斷價(jià)值(受試者工作曲線下面積0.988,p0.001),當(dāng)選取2000 pg/mL作為臨界值時(shí),其診斷的特異性和敏感性分別為97.7%和91.9%。隨治療進(jìn)行,血清VEGF水平逐漸下降(6程治療后,中位值1184pg/mL, p 0.001;12程治療后,中位值832 pg/mL, p 0.001). POEMS綜合征患者骨髓內(nèi)漿細(xì)胞VEGF在mRNA和蛋白水平上均高于對(duì)照,且隨治療逐步下降。重要的是,骨髓內(nèi)漿細(xì)胞VEGF水平和血清VEGF水平有顯著相關(guān)性(初治,rho= 0.33,p=0.01;治療后,rho=0.53, p0.001)。在62例初治POEMS綜合征患者中,51例經(jīng)骨髓流式細(xì)胞學(xué)未檢測(cè)到單克隆漿細(xì)胞,僅存在多克隆漿細(xì)胞。另11例患者(18%),骨髓中同時(shí)檢測(cè)到單克隆和多克隆漿細(xì)胞,數(shù)量上以后者較多(41%vs.59%)。單克隆漿細(xì)胞VEGF水平與多克隆漿細(xì)胞類似(平均熒光強(qiáng)度2009 vs.2367,p=0.594),但I(xiàn)L-6水平顯著高于后者(平均熒光強(qiáng)度1635 vs.865,p=0.006)。在46例骨髓活檢組織中,POEMS綜合征患者漿細(xì)胞呈現(xiàn)散在分布(25例,54%)或散在伴灶性分布(21例,46%)兩種形式。其中散在漿細(xì)胞為多克隆,而灶性區(qū)域內(nèi)同時(shí)存在單克隆和多克隆漿細(xì)胞,兩者均表達(dá)VEGF和HIF-1α,而IL-6則主要為單克隆漿細(xì)胞表達(dá)。結(jié)論P(yáng)OEMS綜合征患者骨髓內(nèi)漿細(xì)胞是VEGF的主要來(lái)源。其中,單克隆漿細(xì)胞可能通過(guò)旁分泌IL-6,刺激多克隆漿細(xì)胞增生、產(chǎn)生VEGF。
[Abstract]:Background and objective POEMS syndrome is a rare monoclonal plasmacyte proliferative disease. The main clinical features include multiple peripheral neuropathy sclerosing osteopathy and abnormal water load. Vascular endothelial growth factor (VEGF), as an important cytokine to regulate angiogenesis and enhance vascular permeability, is the core molecular marker for diagnosis, disease monitoring and curative effect evaluation. However, there is no systematic study on the specific cell source and its production regulation mechanism of high level serum VEGF in patients with POEMS syndrome. Materials and methods Clinical data, serum and bone marrow samples of 62 patients with POEMS syndrome and 46 patients with POEMS syndrome who were admitted to Beijing Union Hospital from February 2014 to April 2015 were collected. Serum VEGF level was measured by ELISA method. The relative levels of VEGF expression in plasma cells of bone marrow were measured by real-time fluorescence quantitative PCR and flow cytometry, respectively, at the level of mRNA and protein, and the correlation between VEGF expression and serum VEGF level was analyzed. The plasma cell subsets in bone marrow were analyzed by flow cytometry, and the expression levels of VEGF and interleukin-6 (IL-6) in different subgroups were measured. The plasma cell distribution, clonality and the expression of VEGF and related regulatory molecules, including IL-6 and hypoxia inducible factor 1- 偽 (HIF-1 偽), in bone marrow biopsy tissues were detected by immunohistochemical method. SPSS 22 software was used for statistical analysis, when p0.05 there was a statistical difference. Results the serum VEGF level (median value 5958 PG / mL) in patients with newly diagnosed POEMS syndrome was significantly higher than that in other disease and healthy controls (P 0.001), and had a definite diagnostic value (the area under the operating curve of the subjects was 0.988g / ml). When 2000 pg/mL was selected as the critical value, The specificity and sensitivity of its diagnosis were 97.7% and 91.9%, respectively. With the treatment, the serum VEGF level decreased gradually after 6 weeks treatment, the median value was 1184pg / mL, p 0.001g / mL, the median value was 832pg / mL, p 0.001g / mL. Plasma cell VEGF in bone marrow of POEMS syndrome patients was higher than that of control group in mRNA and protein levels, and decreased gradually with treatment. Importantly, there was a significant correlation between plasma cell VEGF level in bone marrow and serum VEGF level (initial rhodia = 0.33 p0. 01, P 0. 001, P 0. 001, P 0. 001). In 62 cases of newly treated POEMS syndrome, 51 cases were not detected by bone marrow flow cytology, only polyclonal plasmacytes were found. In the other 11 patients, both monoclonal and polyclonal plasmacytes were detected in bone marrow. The VEGF level of monoclonal plasma cells was similar to that of polyclonal plasmacytes (mean fluorescence intensity was 2009 vs.2367, P < 0.05), but the IL-6 level was significantly higher than that of the latter (mean fluorescence intensity 1635 vs.865P0. 006). In 46 cases of bone marrow biopsy tissues, the plasma cells of patients with poems syndrome were in the form of scattered distribution (25 cases) or scattered with focal distribution (21 cases). The scattered plasmacytes were polyclonal, while in the focal region there were both monoclonal and polyclonal plasmacytes. Both expressed VEGF and HIF-1 偽, while IL-6 was mainly expressed by monoclonal plasmacytes. Conclusion Plasma cells in bone marrow of patients with POEMS syndrome are the main source of VEGF. Monoclonal plasma cells may stimulate the proliferation of polyclonal plasma cells by paracrine of IL-6 and produce VEGF.
【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】：2015
【分類號(hào)】：R55

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