以新生兒臍帶血中誘餌接受體3濃度之變化作為預測嬰幼兒罹患過敏性疾病之生物指標

Cord Blood Decoy Receptor 3 as a New Biomarker in Predicting Neonates at Risk of Atopic Disease

胡逸然(I-Jan Hu)

指導教授 ： 謝武勳

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.10007

摘要

研究背景:
在台灣，兒童過敏性疾病的發生率高達三分之一。過敏性疾病包括異位性皮膚炎、過敏性鼻炎、氣喘等等，因為其症狀反覆發作或持續存在，為影響台灣兒童日常生活層面最廣泛與課業學習最重要的慢性疾病。過敏疾病的發生，來自於遺傳體質加上接觸到環境中之誘發因素，所以要預防幼童發生過敏疾病之症狀，就須儘早從改善體質以及避免環境中之誘發因素著手。在嬰兒出生後，如果有良好的生物性指標提供高危險群嬰兒的辨認，可能給予臨床醫師評估嬰兒發生過敏性疾病風險的客觀標準，並提供家屬考慮該及早採取預防措施的依據。
目前較安全、易取得的新生兒之生物性檢體為臍帶血，文獻上較廣為使用於預測嬰幼兒過敏性疾病的指標為免疫球蛋白E (Immunoglobulin E ， IgE)，然而因為其敏感度 (sensitivity) 與特異度 (specificity) 不高，所以並不是很好的預測指標。
過敏疾病之症狀是源自幫助型T 細胞 (Helper T Cell)的免疫反應，過度的傾向第二型幫助型T 細胞 (Th2) 免疫反應，而在不同器官引起之慢性發炎所導致，故檢測血液中Th2 細胞介質可能會呈現上升的情況。近年來，文獻報告的誘餌接受體3 (Decoy receptor 3， DcR3) 被視為具有調節人體內幫助型T 細胞的免疫反應之功能，會使其更容易走向Th2免疫反應的方向；臨床研究也發現罹患過敏性疾病的兒童與青年，其血清中的誘餌接受體3濃度相較於同年齡層沒有過敏性疾病的人為高。本研究之目的在探討臍帶血中誘餌接受體3濃度值之變化與嬰幼兒早期罹患過敏性疾病之相關性，並且探討以臍帶血誘餌接受體3作為預測過敏性疾病發生的生物指標之可行性；本研究的假說為早期罹患過敏性疾病症狀之嬰幼兒，其臍帶血中誘餌接受體3濃度值，較無過敏性疾病之嬰幼兒為高，而新生兒臍帶血誘餌接受體3濃度值可以作為比免疫球蛋白E更好的過敏性疾病之生物預測指標。
研究方法與程序:
本研究為一前瞻性出生世代研究，為台灣出生世代追蹤調查計劃之前驅研究，自2004年4月至2006年1月在北台灣收集430對母親與其足月活產之新生兒為研究對象，進行個案收集與臨床資料整理，針對納入的孕婦，紀錄其健康情況、妊娠併發症、疾病家族史，包括過敏性疾病、感染症、新生兒生產週數、出生體重、出生後餵食狀況等等，每對個案均收集其母親血液與臍帶血檢體。本研究依序分析並檢測健康的懷孕母親之血清樣本，與其所生產的健康之足月新生兒臍帶血樣本中的免疫球蛋白E以及誘餌接受體3濃度，並追蹤此出生世代之足月新生兒於出生後至滿二歲期間，發生過敏性疾病症狀 (包括異位性皮膚炎、過敏性鼻炎、反覆性喘鳴與氣喘)的嬰幼兒所佔比例。針對有無發生過敏性疾病之不同族群，分析其母親生產前與新生兒本身臍帶血之免疫球蛋白E以及誘餌接受體3濃度值之差異；同時也於臨床追蹤時，收集滿二歲個案之血液樣本檢測、並且探討有無發生過敏性疾病之不同族群嬰幼兒，於二歲時血清中免疫球蛋白E與誘餌接受體3濃度值之變化情況。
研究結果:
此研究有 231對母親同意提供本身之血清樣本與其配對新生兒之臍帶血樣本，並且參與過敏性疾病之追蹤，其中有 174對 (75.3%)之母親與其配對新生兒完成出生後二年的調查追蹤，並且同意提供幼兒二歲時之血液樣本。此研究分析顯示，出生後二年的追蹤期間，於174位新生兒中共有 48位嬰幼兒發生過敏性疾病的症狀，佔 27.6%；在本研究族群中，滿二歲嬰幼兒之異位性皮膚炎、過敏性鼻炎、反覆性喘鳴與氣喘之累積發生率分別為18.4%，10.3%，與7.5%。分析研究個案發現，於母親血清、新生兒臍帶血、與二歲幼兒血清中檢測之誘餌接受體3平均濃度分別為 0.49 ng/mL、0.64 ng/mL、以及 0.56 ng/mL；母親、臍帶血、與二歲血清中免疫球蛋白E平均濃度分別為 76.31 kU/L、0.64 kU/L、以及47.83 kU/L。相較於出生後二年內未曾發生過敏性疾病之嬰幼兒而言，有發生過敏性疾病的族群，其新生兒臍帶血與二歲血清中誘餌接受體3 的濃度呈現顯著升高的情況 ( P值< 0.05)，母親血清中誘餌接受體3的濃度則無此變化。新生兒臍帶血中之誘餌接受體3的濃度值每升高 1 ng/mL的時候，嬰幼兒於早期發生過敏性疾病症狀之風險增加 2.44倍（ P值= 0.002），此外，父母雙親有一位以上有過敏性疾病史的新生兒，其發生早期過敏性疾病症狀之風險增加 2.75倍（ P值= 0.038）。此研究結果發現，母親與新生兒臍帶血中免疫球蛋白E濃度值高低，在有無發生過敏性疾病之族群間，並沒有明顯的差異；罹患反覆性喘鳴與氣喘之嬰幼兒個案，其二歲血清中免疫球蛋白E濃度顯著的高於無過敏組個案。分析分別以臍帶血中誘餌接受體3或免疫球蛋白E的濃度做為預測嬰幼兒發生過敏性疾病之生物指標時，結果顯示使用誘餌接受體3是較好的生物預測指標，以臍帶血誘餌接受體3濃度大於0.66 ng/mL 為發生過敏性疾病之預測值時，陽性預測率為66.9%，敏感度為 48%，特異度為 75%。
討論與展望:
在本研究族群中，滿二歲嬰幼兒發生過敏性疾病的累積發生率為27.6%，與以往文獻報告之結果相接近。本研究是第一篇在臨床生物樣本的分析發現，於足月健康新生兒臍帶血與嬰幼兒二歲之血清中，誘餌接受體3濃度值均可以被檢測出來，而且在新生兒與二歲幼兒之誘餌接受體3檢測值比母親來得高，此現象在有過敏性疾病之嬰幼兒更為顯著；同時在研究族群中，母親血清樣本所檢測之生物指標濃度，與文獻之報告相類似。此研究分析發現，在校正過敏性疾病的各個潛在影響因子後，臍帶血中誘餌接受體3濃度值的上升，以及有過敏性疾病家族史，為與嬰幼兒早期發生過敏性疾病之症狀有顯著相關性的危險因子。本研究結果也發現，相較於臍帶血中免疫球蛋白E濃度，檢測新生兒臍帶血中誘餌接受體3的濃度值，可能可以做為預測足月健康的嬰幼兒早期罹患過敏性疾病，一較好之臨床生物指標。
本前瞻性出生世代研究的優點為時間先後關係性較為明確，而且較少因個案需要倚賴回憶以往健康情況所導致的誤差。然而本研究的限制包括追蹤完成比率不夠高，以及在嬰幼兒族群診斷早期發生過敏性疾病的困難，所以需在研究執行與資料分析時加以考量。
根據研究的結果，未來將可能可以進一步探討，誘餌接受體3對免疫系統發展與成熟過程之中所具有的生理作用，並可能應用在過敏性疾病之動物模型研究上，以了解誘餌接受體3對過敏性疾病之發生所扮演的角色，未來亦或可能據此發展出對於高危險群嬰幼兒早期發生過敏性疾病之症狀，有效而且安全的預防或是臨床治療的方式。
結論:
總結而言，本研究結果顯示，早期罹患過敏性疾病症狀之嬰幼兒，其臍帶血中誘餌接受體3濃度值，較無過敏性疾病之嬰幼兒為高，而新生兒之臍帶血誘餌接受體3濃度值，可能可以做為預測嬰幼兒是否早期發生過敏性疾病另一良好生物預測指標。

關鍵字

誘餌接受體3 ； 免疫球蛋白E ； 臍帶血 ； 嬰幼兒 ； 過敏性疾病 ； 出生世代

並列摘要

Introduction:
The incidence of atopic diseases has increased in Taiwan during recent decade. Early identification of infants at risk may help in prevention of atopic symptoms, including atopic dermatitis (AD), allergic rhinitis (AR), or asthma. Previous researches revealed that cord blood immunoglobulin E (IgE) could be used to predict infants at risk of atopy for many years but the predictive ability was questionable due to low sensitivity and specificity reported in recent studies. Identifying high-risk infants at an early age remains major task for pediatricians and immunologists.
The development of atopic disease is associated with overwhelmed T-helper 2 cell (Th2) - dependent immune response. Decoy receptor 3 (DcR3) is a soluble receptor that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 was found to be able to modulate human immune system via suppressing CD4+ T cell proliferation. DcR3-treated dendritic cells up-regulate IL-4 secretion of T cells suggests that DcR3 may act as an effector molecule to skew T cell response to the Th2 phenotype.
Serum DcR3 level had been found to be elevated among atopic children and adolescences in clinical study. The application of cord blood DcR3 level at birth in predicting infants at risk has not been explored. We hypothesized that cord blood DcR3 concentrations were higher in infants with early onset atopic diseases and cord blood DcR3 could serve as a new biomarker in predicting neonates at risk of atopic disease. The role of DcR3 in modulating immune system responsiveness can be explored in animal models of atopic disease according to the finding of this study. Further prevention or treatment strategy for the management of high risk infants may be developed based on the pathogenesis of DcR3.
Materials and methods:
This is a prospective study in the Taiwan birth panel cohort study (TBPS). 430 paired maternal serum and cord blood from full-term healthy neonates born in northern Taiwan from April 2004 to January 2006 were collected after informed consent was obtained from the parents. 231 mothers and newborns pairs were recruited for DcR3 and IgE levels measurement. Maternal health status, pregnancy conditions, and neonates’ birth conditions, feeding conditions, parental atopic history, environmental tobacco smoke exposure, and family income per year were recorded. The enrolled infants received regular follow up during their health check-up clinics until 2 year of age. The diagnosis of atopic disease was based on doctor diagnosis and physical examinations, International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, and objective measurement.
Results:
174 Mother – infant pairs completed two years follow-up were enrolled for analysis. 48 (27.6%) infants developed atopic diseases during the study period. The cumulative incidence for AD, AR, and recurrent wheezing/asthma of 2-year olds was 18.4%, 10.3%, and 7.5% in the study cohort. The DcR3 levels of the maternal, cord blood, and 2-year serum samples were 0.49 ng/mL, 0.64 ng/mL, and 0.56 ng/mL (mean). The maternal, cord blood, and 2-year serum IgE levels were 76.31 kU/L, 0.64 kU/L, and 47.83 kU/L (mean), respectively. The cord blood and 2-year serum DcR3 levels were significant higher in infants with atopic disease than in non-atopic group (p< 0.05). The risks of atopic disease for infants with elevated cord DcR3 and for infants with parental atopy history were 2.44 and 2.75 compared to those without these risk factors (p=0.002, p= 0.038, respectively). The maternal DcR3 level, maternal, cord blood, and 2-year serum IgE levels were not statistically different between two groups. Cord blood DcR3 level was a potential biomarker in predicting early onset atopic diseases in the study population. The highest positive predictive value of 66.9% was achieved for cord DcR3 with a cut-off point of 0.66 ng/mL, sensitivity of 48%, and a specificity of 75%.
Discussions:
The overall cumulative incidence of 2-year olds atopic diseases in the study population was 27.6% and was similar with previous studies. Our report showed that serum DcR3 was measurable among healthy pregnant women and paired term newborns at birth and at 2-year-old. We observed that serum DcR3 level was significantly higher in neonates and in young children than in mothers, especially of infants with early onset atopic diseases. This study showed that both parental atopic disease history and elevated cord blood DcR3 were predictors for early childhood atopic diseases.
The strength of this prospective cohort study included less recall bias and better temporal analysis. The limitations of the study included, first, 75.3% subjects completed follow-up and 24.7% did not. We performed data analysis and found no significant differences of demographic characteristics between those completed study and those who dropped out, therefore the representative of study population was acceptable. Second, the diagnosis for atopic diseases is difficult in young infants. We used ISAAC questionnaires, physical examination at check-up clinics, and parental reports of doctor diagnosis or medical records of atopic diseases to assist in subject identification. The method we applied to identified atopic infants had been used in previous studies and was applicable in our study cohort. Our results found that cord blood DcR3 concentration was higher in infants with early onset atopiic disease and that cord DcR3may serve as a substitute biomarker for the IgE in predicting the occurrence of early childhood atopic diseases.
Conclusion:
In conclusion, our study results suggest that cord blood DcR3 concentration may serve as a potential alternative biomarker in predicting high risk infants of atopic disease.

並列關鍵字

Decoy receptor 3 ； immunoglobulin E ； cord blood ； infant ； allergic disease ； cohort study

參考文獻

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