史云暉　柳　洋　韋　尼　劉小平　朱躍蘭

活血解毒方對(duì)干燥綜合征小鼠干擾素-γ、B細(xì)胞活化因子及其受體的干預(yù)作用研究

史云暉柳洋韋尼劉小平朱躍蘭

目的 探索活血解毒方對(duì)干燥綜合征小鼠干擾素(interferon,IFN)-γ、B細(xì)胞活化因子(B cell activating factor belonging to the TNF family,BAFF)及其受體BAFF-R的影響及其機(jī)制.方法以C57BL/6j小鼠及NOD/Ltj小鼠為實(shí)驗(yàn)動(dòng)物,分別以蒸餾水、白芍總苷混懸液、活血解毒方湯劑灌胃干預(yù),干預(yù)過程中觀察小鼠一般狀態(tài),于干預(yù)60天后測(cè)量小鼠唾液流率,并取小鼠頜下腺及血清,測(cè)量頜下腺指數(shù)及血清中BAFF、BAFF-R、IFN-γ及頜下腺BAFF、BAFF-R水平.結(jié)果 正常組唾液流率均較其他各組高(P<0.05),實(shí)驗(yàn)第40天開始,對(duì)照組及治療組的唾液流率開始較模型組升高(P<0.05),而對(duì)照組與治療組之間差異不明顯(P>0.05);第60天對(duì)照組與治療組之間差異明顯(P<0.05).頜下腺指數(shù),正常組較模型組、對(duì)照組、治療組高(P<0.05).模型組較對(duì)照組、治療組低(P<0.05),對(duì)照組與治療組之間差異不明顯(P>0.05).血清BAFF、BAFF-R、IFN-γ及頜下腺BAFF、BAFF-R水平,正常組均較模型組、對(duì)照組、治療組低(P<0.05),模型組較對(duì)照組、治療組高(P<0.05),其中對(duì)照組水平高于治療組(P<0.05),各組之間比較,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05).結(jié)論 活血解毒方可減輕NOD小鼠頜下腺炎癥,增加唾液分泌量,降低血清中BAFF、BAFF-R、IFN-γ及頜下腺BAFF、BAFF-R的水平,從而達(dá)到治療干燥綜合征的作用.

干燥綜合征; B細(xì)胞活化因子; 干擾素; 中醫(yī); 活血解毒

干燥綜合征是一種以侵犯淚腺、唾液腺等外分泌腺體為主,以口腔或眼干燥為主要表現(xiàn)的慢性自身免疫性疾病.其主要病理表現(xiàn)是外分泌腺體的灶性淋巴浸潤(rùn).各種細(xì)胞因子和炎癥遞質(zhì)造成組織損傷,其中在T輔助細(xì)胞的作用下,B淋巴細(xì)胞功能異常,產(chǎn)生多種自身抗體、多克隆免疫球蛋白以及免疫復(fù)合物,致使唾液腺和淚腺等組織發(fā)生炎癥和破壞性病變.近年來應(yīng)用利妥昔單抗進(jìn)行B細(xì)胞損耗治療取得良好療效[1-2].這使得B細(xì)胞在干燥綜合征發(fā)病中的重要地位越來越受到關(guān)注.研究發(fā)現(xiàn)干燥綜合征患者的血清及靶器官中的B細(xì)胞活化因子(B cell activating factor belonging to the TNF family,BAFF)水平升高[3-4].BAFF/BAFF-R在干燥綜合征發(fā)病中有著關(guān)鍵的作用.BAFF的表達(dá)受到干擾素(interferon,IFN)-γ、白細(xì)胞介素(interleukin,IL)-10、IL-4等細(xì)胞因子的調(diào)控,有研究表明IFN-γ處理單核細(xì)胞可增加BAFF表達(dá).同時(shí),IFN-γ又受到Toll樣受體等調(diào)節(jié).

干燥綜合征的中醫(yī)病機(jī)離不開瘀毒,臨床應(yīng)用活血解毒方治療干燥綜合征療效確切[5],但其作用機(jī)制尚不明確,目前相關(guān)基礎(chǔ)研究較少.本課題組前期發(fā)現(xiàn),活血解毒方對(duì)NOD小鼠的血清及頜下腺的Toll樣受體有一定的干預(yù)作用[6].本研究擬用活血解毒方干預(yù)干燥綜合征模型小鼠,測(cè)量其唾液流率、頜下腺指數(shù),測(cè)定其血清及頜下腺BAFF/BAFF-R水平、血清IFN-γ水平,從IFN-γ/BAFF/BAFF-R信號(hào)通路的角度分析干燥綜合征的作用機(jī)理及活血解毒方的作用途徑,為干燥綜合征的中醫(yī)藥治療提供基礎(chǔ)研究依據(jù).

1　材料與方法

1.1實(shí)驗(yàn)動(dòng)物

C57BL/6j小鼠10只,雌性,體質(zhì)量16～18 g; NOD/Ltj小鼠30只,雌性,體質(zhì)量16～18 g.均由北京華阜康生物科技股份有限公司提供,許可證號(hào):SCSY(京)2014-004.飼養(yǎng)于中國(guó)中醫(yī)科學(xué)院中藥研究所的屏障環(huán)境中,恒溫恒濕,水瓶給水,自由進(jìn)食.

1.2材料及儀器

帕夫林膠囊(主要成分為白芍總甙,300 mg/粒,由寧波立華制藥有限公司生產(chǎn),生產(chǎn)批號(hào):121204 EXP2014-11);活血解毒方(丹參30 g、連翹15 g、川芎15 g、雞血藤20 g、玄參20 g、甘草10 g、生地黃30 g、麥門冬20 g、石斛20 g、南沙參15 g、北沙參15 g、炒白芍30 g,由北京中醫(yī)藥大學(xué)東方醫(yī)院中藥房提供)制成200 mL水煎劑.小鼠BAFF試劑盒(購(gòu)自普博欣生物有限公司);小鼠BAFF-R試劑盒(購(gòu)自普博欣生物有限公司);小鼠IFN-γ試劑盒(購(gòu)自普博欣生物有限公司);酶標(biāo)儀(Thermo公司生產(chǎn),型號(hào)MK3).

表1　各組小鼠唾液流量比較(±s,mg/min)

表1　各組小鼠唾液流量比較(±s,mg/min)

注:與正常組相比,aP<0.05;與模型組相比,bP<0.05;與對(duì)照組相比,cP<0.05.

組別n第0天第20天第40天第60天正常組915.53±1.3716.07±1.2216.62±1.3417.17±1.56模型組84.25±0.28a4.56±0.43a4.70±0.32a4.86±0.28a對(duì)照組84.56±0.35ab4.90±0.20ab6.07±0.25ab7.56±0.47ab治療組84.53±0.31ab4.78±0.24ab6.60±0.38ab8.37±0.29abc

1.3實(shí)驗(yàn)動(dòng)物分組及給藥

C57BL/6j小鼠10只,作為正常組,NOD小鼠30只,隨機(jī)分為模型組、對(duì)照組、治療組,每組各10只.正常組及模型組小鼠給予蒸餾水灌胃10 mL/kg;對(duì)照組小鼠給予帕夫林膠囊制成的混懸液灌胃,根據(jù)小鼠與人的體表面積比值換算,予234 mg/kg;中藥組與活血解毒方中藥煎劑灌胃,根據(jù)小鼠與人的體表面積比值換算將中藥煎劑進(jìn)行相應(yīng)比例的濃縮,予31.2 g/kg.每天給藥1次,連續(xù)60天.

1.4一般狀態(tài)觀察

觀察小鼠精神狀態(tài)、活動(dòng)、飲水、攝食、睡眠狀態(tài).

1.5唾液流量及頜下腺指數(shù)測(cè)定

唾液分泌量:于給藥后動(dòng)態(tài)測(cè)定小鼠唾液分泌量.測(cè)量前做好棉球稱干重(5.5±1.0)mg.測(cè)唾液分泌時(shí)將干棉球放入實(shí)驗(yàn)用動(dòng)物口頰內(nèi),3分鐘后取出稱濕重.唾液分泌量(mg)=濕重(mg)-干重(mg).

頜下腺指數(shù):將小鼠摘眼球放血處死,取一側(cè)頜下腺稱重.頜下腺指數(shù)=頜下腺重量(mg)/小鼠體質(zhì)量(g).

1.6BAFF、BAFF-R及IFN-γ水平測(cè)定

血清BAFF及BAFF-R水平測(cè)定:眼眶取血,靜置1小時(shí)后,以3000 rpm轉(zhuǎn)速離心10分鐘,分離血清,用酶聯(lián)免疫吸附法測(cè)定BAFF、BAFF-R、IFN-γ水平;取小鼠一側(cè)頜下腺,勻漿后用酶聯(lián)免疫吸附法測(cè)定BAFF及BAFF-R水平;按試劑盒提供的操作流程進(jìn)行.

1.7統(tǒng)計(jì)學(xué)處理

使用統(tǒng)計(jì)軟件SPSS 12.0進(jìn)行統(tǒng)計(jì)分析,所得數(shù)據(jù)以均數(shù)±標(biāo)準(zhǔn)差表示.經(jīng)檢驗(yàn)數(shù)據(jù)符合正態(tài)分布,方差齊.組間比較采用單因素方差分析(one-way ANOVA),兩兩比較采用LSD法,以P<0.05為差異有統(tǒng)計(jì)學(xué)意義.

2　結(jié)果

2.1唾液流量

各時(shí)間點(diǎn)正常組與模型組、對(duì)照組、治療組相比均有明顯差異(P<0.05);實(shí)驗(yàn)開始時(shí)及第20天時(shí),模型組、對(duì)照組、治療組之間無明顯差異(P>0.05);第40天模型組開始與對(duì)照組、治療組出現(xiàn)明顯差異(P<0.05),而對(duì)照組與治療組之間差異不明顯(P>0.05);第60天對(duì)照組與治療組之間差異明顯(P<0.05).具體數(shù)值見表1.

2.2頜下腺指數(shù)

正常組與模型組、對(duì)照組、治療組相比,差異顯著(P<0.05).模型組與對(duì)照組、治療組相比,差異顯著(P<0.05).但對(duì)照組與治療組之間差異不明顯(P>0.05).具體數(shù)值見表2.

表2　各組小鼠頜下腺指數(shù)比較(±s,mg/g)

表2　各組小鼠頜下腺指數(shù)比較(±s,mg/g)

注:與正常組相比,aP<0.05;與模型組相比,bP<0.05.

頜下腺指數(shù)正常組組別n 5.53±0.74模型組84.06±0.53a對(duì)照組84.81±0.25ab治療組84.89±0.66 9 a b

2.3血清BAFF及BAFF-R水平

正常組血清BAFF及BAFF-R含量較低,模型組血清BAFF及BAFF-R含量較高,對(duì)照組與治療組血清BAFF及BAFF-R含量均低于模型組,其中治療組的血清BAFF及BAFF-R含量又較對(duì)照組低,各組之間比較,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05).具體數(shù)值見表3.

表3　各組小鼠血清BAFF及BAFF-R水平測(cè)定(±s,ng/L)

表3　各組小鼠血清BAFF及BAFF-R水平測(cè)定(±s,ng/L)

注:與正常組相比,aP<0.05;與模型組相比,bP<0.05;與對(duì)照組相比,cP<0.05.

水平正常組組別n血清BAFF水平血清BAFF-R 91515.35±50.13350.74±15.91模型組82474.32±98.77a611.02±26.69a對(duì)照組82184.11±31.12ab545.08±18.70ab治療組81905.25±46.09abc434.96±36.70abc

2.4頜下腺BAFF及BAFF-R水平

正常組頜下腺BAFF及BAFF-R含量較低,模型組頜下腺BAFF及BAFF-R含量較高,對(duì)照組與治療組頜下腺BAFF及BAFF-R含量均低于模型組,其中治療組的頜下腺BAFF及BAFF-R含量又較對(duì)照組低,各組之間比較,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05).具體數(shù)值見表4.

表4　各組小鼠頜下腺BAFF及BAFF-R水平測(cè)定(±s,ng/mL)

表4　各組小鼠頜下腺BAFF及BAFF-R水平測(cè)定(±s,ng/mL)

注:與正常組相比,aP<0.05;與模型組相比,bP<0.05;與對(duì)照組相比,cP<0.05.

組別nBAFF水平BAFF-R 水平正常組932.03±8.2070.99±10.15模型組873.16±9.71a112.40±10.89a對(duì)照組863.84±9.38ab92.98±12.24ab治療組847.53±8.16abc81.87±9.97abc

2.5血清IFN-γ水平

正常組血清IFN-γ含量較低,模型組血清IFN-γ含量較高,對(duì)照組與治療組血清IFN-γ含量均低于模型組,其中治療組的血清IFN-γ含量又較對(duì)照組低,各組之間比較,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05).見表5.

表5　各組小鼠血清IFN-γ水平測(cè)定(±s,ng/L)

表5　各組小鼠血清IFN-γ水平測(cè)定(±s,ng/L)

注:與正常組相比,aP<0.05;與模型組相比,bP<0.05;與對(duì)照組相比,cP<0.05.

組別nIFN-γ正常組33.56±11.11模型組893.22±14.01a對(duì)照組862.85±14.53ab治療組850.23±13.94 9 a bc

3　討論

BAFF又叫B淋巴細(xì)胞激活因子(B-lymphacyte stimulator,BLyS),主要由單核細(xì)胞、樹突狀細(xì)胞、T細(xì)胞、B細(xì)胞和唾液腺上皮細(xì)胞分泌產(chǎn)生[7-8],是腫瘤壞死因子(tumor necrosis factor,TNF)家族中的一員,它能與B淋巴細(xì)胞特異性結(jié)合并誘導(dǎo)期增值、分化并分泌免疫球蛋白(immunoglobulin,Ig)G、IgA和IgM等,在體液免疫中發(fā)揮著重要的作用.包括干燥綜合征在內(nèi)的許多自身免疫性疾病患者體內(nèi)都有BAFF過表達(dá)的現(xiàn)象[4-5].BAFF有很強(qiáng)的B細(xì)胞趨向性,BAFF可促進(jìn)B細(xì)胞的增殖和分化,如果BAFF缺失,B細(xì)胞將停留在T1階段.BAFF還能抑制B細(xì)胞的凋亡.如果不考慮受體的表達(dá)水平,BAFF是B細(xì)胞T2階段凋亡的主要阻力因素. BAFF轉(zhuǎn)基因小鼠的外分泌腺可以表達(dá)T2細(xì)胞,這同干燥綜合征患者唾液腺中B細(xì)胞聚集相同[9].由于新形成的B細(xì)胞依賴于BAFF,研究人員推測(cè),在細(xì)胞聚集區(qū)及其周圍細(xì)胞可產(chǎn)生大量的BAFF.有研究證明,BAFF的異常表達(dá)不僅存在于上皮細(xì)胞及活化的T淋巴細(xì)胞,還存在于正常唾液腺分離出來的細(xì)胞及從干燥綜合征患者唾液腺中分離出來的受B細(xì)胞浸潤(rùn)的唾液腺細(xì)胞[10].體外研究顯示,用病毒或拮抗劑刺激Toll樣受體可誘導(dǎo)干燥綜合征唾液腺上皮細(xì)胞BAFF mRNA高表達(dá),抑制IFN可抑制BAFF表達(dá)[11].雙鏈RNA病毒和單鏈RNA病毒感染都可促進(jìn)BAFF的表達(dá),雙鏈RNA主要促進(jìn)樹突樣細(xì)胞的BAFF表達(dá),單鏈RNA促進(jìn)單核細(xì)胞和唾液腺上皮細(xì)胞的BAFF表達(dá),而阻斷單核細(xì)胞的IFN受體,可抑制BAFF表達(dá)[12].臨床研究也發(fā)現(xiàn),單核細(xì)胞表達(dá)IFN信號(hào)的患者亞群都具有較高的疾病活動(dòng)指數(shù)及BAFF mRNA表達(dá),阻礙IFN的表達(dá)或活性有望能使這類患者的病情得到改善[13],干燥綜合征患者的單核細(xì)胞比健康對(duì)照者的單核細(xì)胞在受到IFN刺激后更容易促進(jìn)BAFF的表達(dá)和分泌增加[4,14].

干燥綜合征在中醫(yī)古籍中并沒有對(duì)應(yīng)的病名,有醫(yī)家認(rèn)為按癥、證當(dāng)屬"燥證"范疇,亦有醫(yī)家認(rèn)為其累及周身關(guān)節(jié)肌肉、關(guān)節(jié)疼痛、臟腑損害等而稱為"周痹""痹證""臟腑痹"等.多數(shù)醫(yī)家多遵從"燥盛則干"的病機(jī)理論,認(rèn)為本病多因先天稟賦不足,陰津虧虛而發(fā)病,基本病機(jī)是血虛津虧.綜合文獻(xiàn)檢索及臨證經(jīng)驗(yàn),本研究認(rèn)為燥痹初起即有燥毒存在,津傷日久,燥毒日盛,邪毒局部聚集,亦可成血瘀之弊,成燥瘀毒交雜之勢(shì),三者之間存在有機(jī)聯(lián)系[15].活血解毒方以丹參為君,涼血活血,川芎助君活血之功;玄參解毒涼血清熱,連翹清熱解毒,生地、麥門冬、石斛、沙參生津;雞血藤活血養(yǎng)血通絡(luò),生甘草調(diào)和諸藥,諸藥共奏活血解毒,養(yǎng)血生津之功能.本研究發(fā)現(xiàn),經(jīng)活血解毒方干預(yù)后,NOD小鼠血清及頜下腺中BAFF、BAFF-R水平及血清IFN-γ水平都有不同程度的降低.

由此可見,IFN-γ、BAFF、BAFF-R在干燥綜合征的發(fā)病中起著重要的作用,IFN/BAFF/BAFF-R信號(hào)通路在調(diào)節(jié)B細(xì)胞穩(wěn)態(tài)中起著重要的作用,以B細(xì)胞為靶點(diǎn)的治療,也將成為治療干燥綜合征的一大突破點(diǎn).目前中醫(yī)藥治療干燥綜合征的基礎(chǔ)研究相對(duì)缺乏,IFN/BAFF/BAFF-R在干燥綜合征發(fā)病及治療中的作用也屬于該領(lǐng)域近年來興起的新方向,這是本研究的創(chuàng)新點(diǎn)所在.本研究的結(jié)果顯示活血解毒方可減輕NOD小鼠頜下腺炎癥,增加唾液分泌量,這一作用機(jī)制可能是通過干預(yù)IFN/BAFF/BAF-R信號(hào)通路而實(shí)現(xiàn)的,本研究的結(jié)果可為活血解毒方的作用機(jī)制提供一部分理論依據(jù).

本研究仍有不足之處,本研究以NOD小鼠作為模型,有關(guān)研究發(fā)現(xiàn),NOD小鼠的頜下腺浸潤(rùn)灶的淋巴細(xì)胞以T細(xì)胞為主,并且頜下腺組織表達(dá)的多種促炎性因子,可模擬臨床干燥綜合征表現(xiàn).但因體積較小,血清及頜下腺標(biāo)本取材較少,對(duì)進(jìn)行更深入的研究造成一定困難,IFN/BAFF/BAFF-R上、下游的信號(hào)通路的影響以及活血解毒方對(duì)干燥綜合征病灶中B細(xì)胞的作用還有待更進(jìn)一步研究.

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(本文編輯:蒲曉田)

Effect of Huoxue Jiedu formula on IFN-γ and BAFF/BAFF-R in NOD mice with Sj?gren's syndrome

SHI Yun-hui,LIU Yang,WEI Ni,et al. Graduate School of Beijing University of Chinese Medicine,Beijing 100029,China
Corresponding author:ZHU Yue-lan,E-mail:zhuyuelanting@163.com

Objective To observe the effect of Huoxue Jiedu formula on BAFF/BAFF-R in NOD mice and explore the mechanism of Huoxue Jiedu formula to Sj?gren's syndrome.Methods C57BL/6j mice and NOD/Ltj mice were used for research.The mice were intervened with water,total glucosides of peaony and Huoxue Jiedu formula respectively.The general status was observed.After 60 days of intervenation,the flow rate of saliva,index of submandibular gland,BAFF,BAFF-R and IFN-γ in serum and BAFF,BAFF-R in salivary gland were tested.Results One-way ANOVA was used for statistical analysis.When compared between two groups,LSD was used.The flow rate of saliva of the normal group was higher than other groups in every time point(P<0.05).Since the 40thday,the flow rates of saliva of control group and treatment group was higher than that in model group.There was no significant difference between control group and treatment group at that time(P>0.05).At the 60thday,the flow rate in treatment group was significantly higher than that in control group(P<0.05).The index of submandibular gland of the normal group was the highest(P<0.05)while that was the lowest of the model group (P<0.05).There was no significantly difference between the treatment group and control group (P>0.05).As for BAFF,BAFF-R and IFN-γ in serum and BAFF,BAFF-R in salivary gland,the normal group was the lowest(P<0.05),the model group was the highest(P<0.05),the treatment group was significantly lower than the control group(P<0.05).Conclusions Huoxue Jiedu formula can alleviate the inflammation of salivary gland,increase saliva and reduce BAFF,BAFF-R and IFN-γ in serum and BAFF, BAFF-R in salivary gland.

Sj?gren's syndrome; B cell activating factor belonging to the TNF family; Interferon; Traditional Chinese medicine; Huoxue Jiedu

R285.5

A

10.3969/j.issn.1674-1749.2016.01.005

北京中醫(yī)藥大學(xué)校級(jí)自主課題(2014-JYBZZ-XS-147)

100029 北京中醫(yī)藥大學(xué)研究生院[史云暉(博士研究生)、柳洋(碩士研究生)];北京中醫(yī)藥大學(xué)東方醫(yī)院風(fēng)濕病科(韋尼、劉小平、朱躍蘭)

史云暉(1989-),女,2013級(jí)在讀博士研究生.研究方向:中醫(yī)藥治療風(fēng)濕免疫病.E-mail: syh890501@163.com

朱躍蘭(1959-),女,博士,主任醫(yī)師,博士生導(dǎo)師.研究方向:中醫(yī)藥治療風(fēng)濕免疫病.E-mail: zhuyuelanting@163.com

2015-06-22)