【摘要】：目的: 變應(yīng)性鼻炎(AR)是常見(jiàn)的耳鼻咽喉科疾病,也是常見(jiàn)的呼吸道變應(yīng)性疾病。變應(yīng)性鼻炎在全球范圍內(nèi)的患病率為10-25%,而在我國(guó)西部的部分地區(qū)其患病率高達(dá)34.31%,是嚴(yán)重危害人類(lèi)健康和生活質(zhì)量的常見(jiàn)疾病。以變應(yīng)性鼻炎為代表的變應(yīng)性疾病的發(fā)病機(jī)制研究一直都是國(guó)內(nèi)外專(zhuān)家關(guān)注的熱點(diǎn)。一般經(jīng)典的認(rèn)識(shí)是,變應(yīng)原橋聯(lián)IgE,介導(dǎo)肥大細(xì)胞脫顆粒釋放炎性介質(zhì),引起不同程度的鼻黏膜炎癥,即Ⅰ型超敏反應(yīng)是變應(yīng)性鼻炎發(fā)病的主要機(jī)制。但臨床上發(fā)現(xiàn),血清中特異性IgE水平與癥狀嚴(yán)重程度并非完全相關(guān),可能存在非經(jīng)典途徑。近年來(lái),細(xì)菌超抗原學(xué)說(shuō)越來(lái)越得到廣大學(xué)者的重視�，F(xiàn)有研究證實(shí),細(xì)菌超抗原影響免疫調(diào)節(jié)細(xì)胞(T淋巴細(xì)胞)和促炎細(xì)胞(樹(shù)突狀細(xì)胞、嗜酸性粒細(xì)胞、上皮細(xì)胞等)的活性,誘導(dǎo)或促進(jìn)變態(tài)反應(yīng)性疾病的發(fā)生和發(fā)展。 金黃色葡萄球菌腸毒素B(SEB)是由金黃色葡萄球菌產(chǎn)生的一種超抗原,能直接連接抗原提呈細(xì)胞的MHC II類(lèi)分子外側(cè)和T細(xì)胞受體Vβ區(qū),同時(shí)非特異性激活體內(nèi)將近30%的T細(xì)胞,而普通抗原僅能激活0.01%的T細(xì)胞。通過(guò)SEB超抗原的這種槽外連接,有利于被MHC呈遞的抗原肽更有效的與T細(xì)胞可變區(qū)結(jié)合,增強(qiáng)了變應(yīng)原的抗原性,促進(jìn)變態(tài)反應(yīng)性炎癥的發(fā)生、發(fā)展。另外,SEB可以作為變應(yīng)原活化特異性T細(xì)胞,繼而誘導(dǎo)抗原特異性IgE產(chǎn)生,發(fā)生經(jīng)典的變態(tài)反應(yīng)。金黃色葡萄球菌及其分泌的超抗原廣泛分布人類(lèi)的皮膚和鼻腔,人們?cè)谌粘Ｉ钪薪佑|金葡菌超抗原的頻率極高,這就增加了特應(yīng)性個(gè)體罹患變態(tài)反應(yīng)性疾病的風(fēng)險(xiǎn)。但尚無(wú)確切證據(jù)說(shuō)明SEB可作為變應(yīng)原誘導(dǎo)變應(yīng)性鼻炎的發(fā)生。 本研究應(yīng)用SEB反復(fù)鼻腔噴滴,觀(guān)察豚鼠打噴嚏、抓鼻等變應(yīng)性鼻炎典型癥狀,鼻黏膜中嗜酸性粒細(xì)胞的浸潤(rùn)情況,及血清SEB特異性IgE和IgG1的表達(dá),從而證明SEB作為變應(yīng)原,能夠誘導(dǎo)變應(yīng)性鼻炎的發(fā)生。 方法: 將20只健康Hartley系豚鼠隨機(jī)分為2組:模型組和對(duì)照組,每組10只。模型組鼻腔噴滴SEB,每天1次,連續(xù)14天。每次噴滴前,用4%利多卡因(每側(cè)鼻孔20μl)先噴滴鼻腔,以抑制鼻腔纖毛運(yùn)動(dòng),延長(zhǎng)變應(yīng)原在鼻腔停留時(shí)間。間隔7天后,以同樣劑量SEB噴滴鼻腔激發(fā),每周激發(fā)2次,連續(xù)激發(fā)3周。激發(fā)前,不再鼻腔應(yīng)用利多卡因。對(duì)照組以生理鹽水代替SEB進(jìn)行實(shí)驗(yàn)。在激發(fā)階段,對(duì)其噴嚏和抓鼻做動(dòng)態(tài)癥狀學(xué)觀(guān)察;間接ELISA法檢測(cè)血清SEB特異性IgE、IgG1和IgG2水平;HE染色觀(guān)察鼻腔組織的病理改變。 結(jié)果: ⑴模型組豚鼠出現(xiàn)典型的變應(yīng)性鼻炎癥狀,如頻繁噴嚏和抓鼻;模型組豚鼠血清SEB特異性IgE和IgG1滴度明顯升高;模型組豚鼠的鼻腔黏膜出現(xiàn)以嗜酸性粒細(xì)胞為主的炎癥細(xì)胞浸潤(rùn),黏膜下間質(zhì)明顯水腫,小血管擴(kuò)張。 ⑵對(duì)照組豚鼠未出現(xiàn)變應(yīng)性鼻炎的典型癥狀,血清中無(wú)可檢測(cè)水平的SEB特異性IgE和IgG1,鼻黏膜未見(jiàn)明顯改變。 ⑶與對(duì)照組比較,模型組豚鼠鼻黏膜相關(guān)淋巴組織中IL-23 mRNA表達(dá)下調(diào),鼻腔灌洗液中IL-17水平降低。 結(jié)論: ⑴采用反復(fù)鼻腔噴滴SEB的方法誘導(dǎo)出鼻腔黏膜變應(yīng)性炎癥,驗(yàn)證了SEB可以作為傳統(tǒng)的變應(yīng)原誘導(dǎo)變應(yīng)性鼻炎的發(fā)生。 ⑵采用反復(fù)鼻腔噴滴SEB致敏,鼻腔連續(xù)激發(fā)的方法誘導(dǎo)出鼻腔變應(yīng)性炎癥,從而成功地建立了具有雙相反應(yīng)的變應(yīng)性鼻炎動(dòng)物模型,為進(jìn)一步研究伴有金葡菌鼻腔攜帶的變應(yīng)性鼻炎的發(fā)病機(jī)制和遲發(fā)相反應(yīng)奠定了基礎(chǔ)。 ⑶模型組豚鼠Th17型細(xì)胞因子IL-23、IL-17的表達(dá)降低,而Th2細(xì)胞因子IL-4的表達(dá)升高,提示變應(yīng)性鼻炎存在Th2/Th17細(xì)胞因子網(wǎng)絡(luò)失衡,這可能在變應(yīng)性鼻炎的發(fā)病中起著關(guān)鍵的作用。
[Abstract]:Objective:
Allergic rhinitis (AR) is a common ear-nose-throat disease and a common respiratory allergic disease. The prevalence of allergic rhinitis is 10-25% in the world, while it is 34.31% in the western part of China. It is a common disease that seriously endangers human health and quality of life. The pathogenesis of allergic diseases has always been the focus of attention of experts at home and abroad.The classical understanding is that allergen bridging IgE mediates mast cell degranulation to release inflammatory mediators and induces varying degrees of nasal mucosal inflammation, i.e. type I hypersensitivity is the main pathogenesis of allergic rhinitis.But clinically, it is found that serum is specific. In recent years, the theory of bacterial superantigens has attracted more and more attention of scholars. It has been confirmed that bacterial superantigens affect the activity of immunoregulatory cells (T lymphocytes) and inflammatory cells (dendritic cells, eosinophils, epithelial cells, etc.). Inducing or promoting the occurrence and development of allergic diseases.
Staphylococcal enterotoxin B (SEB) is a superantigen produced by Staphylococcus aureus. It can directly connect the MHC class II molecule of antigen-presenting cells with the V beta region of T cell receptor. At the same time, it can nonspecifically activate nearly 30% of T cells in vivo, while common antigen can only activate 0.01% of T cells. In addition, SEB can be used as an allergen to activate specific T cells, and then induce the production of antigen-specific IgE, resulting in classical allergic reactions. Staphylococcus aureus and its components. The secreted superantigens are widely distributed in human skin and nasal cavity, and people are exposed to Staphylococcus aureus superantigens very frequently in daily life, which increases the risk of allergic diseases in atopic individuals.
The typical symptoms of allergic rhinitis, such as sneezing and scratching nose, the infiltration of eosinophils in nasal mucosa, and the expression of SEB-specific IgE and IgG1 in serum were observed by repeated nasal drops of SEB, which proved that SEB as an allergen could induce the occurrence of allergic rhinitis in guinea pigs.
Method:
20 healthy Hartley guinea pigs were randomly divided into two groups: model group and control group, 10 in each group. The model group was given SEB once a day for 14 consecutive days. Lidocaine was not used in nasal cavity before stimulation. The control group was treated with normal saline instead of SEB. The sneezing and scratching noses were observed by dynamic symptoms during stimulation. The serum levels of SEB-specific IgE, IgG1 and IgG2 were detected by indirect ELISA, and the pathological changes of nasal tissues were observed by HE staining. Change.
Result:
_The model group showed typical allergic rhinitis symptoms, such as frequent sneezing and scratching nose; the serum SEB-specific IgE and IgG1 titers of the model group increased significantly; the nasal mucosa of the model group showed eosinophil-based inflammatory cell infiltration, submucosal interstitial edema, and small vessel dilatation.
_There were no typical symptoms of allergic rhinitis in the control group, no detectable levels of SEB-specific IgE and IgG1 in serum, and no significant changes in nasal mucosa.
_Compared with the control group, the expression of IL-23 mRNA in the nasal mucosa-associated lymphoid tissue was down-regulated and the level of IL-17 in nasal lavage fluid was down-regulated in the model group.
Conclusion:
_Allergic inflammation of nasal mucosa was induced by repeated nasal Dropping of SEB, which proved that SEB could be used as a traditional allergen to induce allergic rhinitis.
_The allergic rhinitis animal model with biphasic reaction was successfully established by repeated nasal instillation of SEB and nasal continuous stimulation, which laid a foundation for further study on the pathogenesis and delayed phase reaction of allergic rhinitis with Staphylococcus aureus.
_In the model group, the expression of Th17 cytokines IL-23 and IL-17 was decreased, while the expression of Th2 cytokines IL-4 was increased, suggesting that there was an imbalance of Th2/Th17 cytokine network in allergic rhinitis, which may play a key role in the pathogenesis of allergic rhinitis.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類(lèi)號(hào)】：R765.21

【共引文獻(xiàn)】

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10 徐U，

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