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標題: | 葛瑞芙氏眼病變之眼表面及淚腺相關研究 Ocular Surface and Lacrimal Gland Study in Graves’ Ophthalmopathy |
作者: | Wei-Yi Hsuan 魏以宣 |
指導教授: | 廖述朗 |
關鍵字: | 葛瑞芙氏眼病變,甲狀腺眼疾,活體共軛焦顯微鏡,印壓細胞學,結膜上皮細胞,乾眼,眼瞼攣縮,淚腺, Graves’ophthalmopathy,thyroid eye disease,in vivo confocal microscopy,impression cytology,conjunctival epithelial cell,dry eye,lid retraction,lacrimal gland, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 研究背景及目的:
葛瑞芙氏眼病變Graves’ ophthalmopathy (簡稱GO) 是一種自體免疫的疾病,病變處位於眼窩脂肪、結締組織及眼外肌,臨床表現為突眼、眼周水腫、眼外肌活動受限、眼瞼攣縮,然而葛瑞芙氏眼病變的致病機轉至今尚未完全明瞭。 葛瑞芙氏眼病變患者常有眼睛乾澀或異物感的臨床症狀,但其機轉目前尚未定論,可能是因為眼瞼攣縮造成眼睛閉合不全而使眼淚容易蒸發,或是促進發炎的細胞激素造成淚腺及眼表面的發炎反應。淚腺細胞中已被證實有促甲狀腺素受體 (thyroid stimulating hormone receptor,簡稱TSHR),因此淚腺可能是自體免疫疾病的一個目標物。 本研究目的是針對葛瑞芙氏眼病變患者的眼表面及淚腺進行研究,以進一步了解葛瑞芙氏眼病變患者眼睛乾澀或異物感之作用機轉,以及治療的新方向。 研究方法: 葛瑞芙氏眼病變患者和正常自願者各十五名,比較兩組之突眼程度、眼瞼裂距離、兔眼程度,以及淚液分泌檢查 (Schirmer’s test)、淚膜破裂時間 (tear break-up time)、和眼表面螢光染色結果。利用活體共軛焦顯微鏡 (in vivo confocal microscopy) 分析兩組受試者右眼的上側及顳側結膜,觀察結膜上皮細胞型態、結膜厚度、及細胞密度,並利用印壓細胞學 (impression cytology) 分析比較兩組結膜上皮細胞之形態變化。 另蒐集十名葛瑞芙氏眼病變患者以及十名正常人的淚腺組織,利用即時反轉錄聚合酶鏈鎖反應 (real time RT-PCR),比較兩組中細胞激素 (cytokine)、趨化素 (chemokine)、自體免疫抗原、及和脂肪生成有關的PPAR-γ、COX-2等的基因表現量。統計方式為Mann-Whitney U test。 研究結果: 葛瑞芙氏眼病變組的突眼程度、眼瞼裂距離、兔眼程度均顯著大於正常組,淚液分泌及淚膜破裂時間減少,眼表面螢光染色顯示眼表面上皮破損較為嚴重。In vivo confocal microscopy發現葛瑞芙氏眼病變組的上側結膜的superficial epithelial cell密度較正常組顯著減少,在顳側結膜則無此差異。位於上側或顳側結膜的basal epithelial cell密度及結膜厚度,在兩組並無顯著差異。葛瑞芙氏眼病變組的結膜中的蘭格罕細胞 (Langerhans cell) 密度較正常組顯著增加,杯狀細胞 (goblet cell) 密度則減少。Impression cytology的結果發現葛瑞芙氏眼病變組的結膜上皮細胞有顯著的鱗狀上皮化生 (squamous metaplasia) 變化,以及杯狀細胞減少現象。 GO組上側結膜表面上皮細胞密度與角膜中心光反射至上眼瞼緣的距離 (marginal reflex distance,簡稱MRD1) 有顯著之負相關,與淚膜破裂時間有顯著之正相關;然而,上側結膜表面上皮細胞密度和突眼程度、淚液分泌檢查結果、以及眼表面螢光染色結果並無顯著之相關性。 以real time RT-PCR分析兩組淚腺組織的基因表現量,發現和脂肪生成相關之PPAR-γ、COX-2在GO組的基因表現量顯著高於control組;自體免疫抗原IGF-1α、IGF-1R、及TSH-R在兩組間無顯著差異;細胞激素TGF-β、IL-1β、IL-6和趨化素CXCL-10在兩組並無顯著差異。 結論: 葛瑞芙氏眼病變會造成結膜上皮細胞變化、眼表面發炎反應,以及相關之乾眼症狀,其致病機轉與上眼瞼攣縮有關。淚腺中與脂肪增生相關的基因表現量增加,可能也會造成淚腺功能失調而導致乾眼。 Purpose: Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disorder of the orbital adipose, connective tissues and the extraocular muscles. The characteristic clinical manifestations of GO include proptosis, periorbital edema, extraocular muscle dysfunction, eyelid retraction and dry eye. However, the pathogenesis of Graves’ ophthalmopathy is still not clear. Just like many autoimmune diseases, dry eye is an important clinical manifestation in GO. Lacrimal dysfunction can result from many autoimmune diseases, such as Sjögren's syndrome, sarcoidosis, and thyroid disease. The pathogenesis of dry eye in GO is still uncelar. Increased palpebral fissure width in GO can accelerate tear film evaporation and result in increasing tear film osmolarity and ocular surface damage. Many inflammatory cytokines have been implicated in dry eye syndrome either on the ocular surface or in the lacrimal gland. Inflammatory cytokines alone have been reported to cause damages to the lacrimal gland. It has been demonstrated that lacrimal acinar cells physiologically express thyroid stimulating hormone receptor (TSHR). The lacrimal gland can become a target of the immune system and show signs of inflammation. The purpose of this study is to investigate the ocualr surface changes and gene expressions in the lacrimal gland of GO patients. It may give a new insight for the understanding of dry eye in GO and may offer a new strategy for the management of dry eye in GO. Methods: In ocular surface study, we recruited 15 GO patients and 15 normal volenteers in control group. We collected clinical data from the two groups, including Ocular Surface Disease Index (OSDI), marginal reflex distance (MRD1 and MRD2), severity of exophthalmos, palpebral fissure length, severity of lagophthalmos, Schirmer’s test, tear break-up time (TBUT), and ocular surface fluorescein staining. We used in vivo confocal microscopy and impression cytology to examine the upper and temporal bulbar conjunctiva in the two groups. We analyzed the conjunctival thickness, and the density of superficial epithelial cells, basal epithelial cells, Langerhans cells, and goblet cells. The grading of squamous metaplasia of conjunctival epithelum was also recorded. In lacrimal gland study, we collected the specimens of lacrimal gland from 10 GO patients and 10 normal cases. We used real time RT-PCR to compare the gene expression between the two groups, including genes of cytokines, chemokine, autoantigens, PPAR-γ, and COX-2. The results were analyzed by Mann-Whitney U test. Results: The severity of exophthalmos, palpebral fissure length, and severity of lagophthalmos were significantly increased in the GO group. The results of Schirmer’s test and tear break-up time were significantly decreased in the GO group. The grading of ocular surface fluorescein staining was significantly increased in the GO group. In vivo confocal microscopy study showed decreased superficial epithelial cell density of upper bulbar conjunctiva in the GO group. This difference was noted in the temporal bulbar conjunctiva. The conjunctival thickness and basal epithelial cell density were not significantly different between the two groups. The density of Langerhans cells was increased, and the density of goblet cell was decreased in the GO group. The impression cytology of conjunctival epithelium showed squamous metaplasia change in the GO group. The superficial epithelial cell density of upper bulbar conjunctiva showed negative correlation to MRD1, and positive correlation to TBUT in the GO group. However, no significant correlration was noted between superficial epithelial cell density and the severity of exophthalmos, the result of Schirmer’s test, or the grading of ocular surface fluorescein staining. The gene expression of PPAR-γ and COX-2 were significantly upregulated in the lacrimal gland of GO patients. The gene expressions of cytokines or autoantigenes have no statistical difference between the two groups. Conclusions: The changes of conjuncitval epithelium were demostrated in GO patients using in vivo confocal microscopy and impression cytology. The change was correlated to lid retraction, which maybe the important factor causing dry eye in GO patients. The gene associated with adipogenesis showed increased expression in the lacrimal gland of GO patients. The lacrimal dysfunction may play a role in the pathogenesis of GO-associated dry eye. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/32096 |
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