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        B細胞刺激因子及其受體在干燥綜合征發(fā)病機制中的作用進展

        2017-03-21 23:20:34程曉靜張葵符向輝
        中國醫(yī)藥導報 2017年3期
        關鍵詞:干燥綜合征

        程曉靜 張葵 符向輝

        [摘要] 干燥綜合征(SS)是一種累及唾液腺、淚腺等外分泌腺體的慢性炎癥性自身免疫性疾病,好發(fā)于中年女性,其炎性反應常表現(xiàn)為受損腺體周圍淋巴細胞浸潤,除口干、眼干外,臨床還表現(xiàn)為其他外分泌腺體及腺體外器官受累的多器官損害癥狀。目前SS的發(fā)病機制并不清楚。B細胞高反應性是SS的一個重要的特點,在患者及動物模型中B細胞高反應性及升高的B細胞刺激因子(BAFF)水平可以由某些免疫細胞中BAFF/BAFF受體(BAFF-R)的表達變化引起。此外,BAFF的過表達促使B細胞增殖是SS相關淋巴細胞增殖的額外風險因素,因此掌握BAFF/BAFF-R在SS發(fā)病機制方面的作用,能促進新的治療策略的產(chǎn)生。

        [關鍵詞] 干燥綜合征;B細胞刺激因子;B細胞刺激因子受體;貝利單抗

        [中圖分類號] R593.2 [文獻標識碼] A [文章編號] 1673-7210(2017)01(c)-0047-05

        [Abstract] Sjgren syndrome (SS) is a chronic inflammatory autoimmune disease involving exocrine glands such as salivary glands and lacrimal glands. SS predominantly affects mid-aged females. Patients with SS have abnormal immune response with T and B cells activation and subsequent lymphocytic infiltration in target tissues leading to dry eye and dry mouth. Multiple organs may be affected, causing a broad spectrum of extraglandular manifestations. The pathogenesis of SS is unkown. While B cell hyperactivity is a dominant feature of SS patients. The B cell hyperactivity and elevated levels of B-cell activating factor (BAFF) may be induced by the abnormal expression of BAFF/BAFF receptors (BAFF-R) in certain immune cells in the SS patients and in animal models. The overproduction of serum BAFF, which is a known antiapoptotic cytokine driving B-cell autoreactive clonal expansion, may be an additional risk factor for SS-related lymphoproliferation. Therefore, understanding the role of BAFF/BAFF-R in the pathogenesis of SS may contribute to the generation of new therapeutic strategies.

        [Key words] Sjgren syndrome; B-cell activating factor; B-cell activating factor receptors; Belimumab

        干燥綜合征(sjgren syndrome,SS)是一種慢性器官特異性自身免疫性疾病,發(fā)病率為0.1%~0.4%,男女比例為9∶1,通常在40~50歲發(fā)病[1],主要引起唾液腺和淚腺組織中淋巴細胞和單核細胞的浸潤[2],臨床表現(xiàn)主要為眼干、口干等。SS可以分為兩類:原發(fā)性SS(primary SS,pSS)和繼發(fā)性SS(secondary SS,sSS),其中pSS不伴其他結(jié)締組織病,sSS伴有其他結(jié)締組織病,如類風濕關節(jié)炎(rheumatoid arthritis,RA)、系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus,SLE)等。SS患者常有唾液腺和淚腺組織中腺管周圍及血管周圍的淋巴細胞浸潤,且B細胞高反應性是SS的一個重要的特點,主要表現(xiàn)為高丙種球蛋白血癥、多種自身抗體的產(chǎn)生及冷球蛋白血癥等[1]。

        研究表明B細胞刺激因子(B cell activating factor,BAFF)在B淋巴細胞的生長、成熟和動態(tài)平衡中起著至關重要的作用[3]。在SS、RA、SLE等自身免疫病患者血清中BAFF的濃度明顯增加[4],且唾液腺組織中上皮細胞、B細胞、T細胞等均可以表達BAFF,因此研究BAFF/BAFF受體(BAFF receptors,BAFF-R)在SS發(fā)病機制中的作用,以及進一步探索新型治療方案以控制SS中BAFF的表達水平非常重要。基于以上目的,本文就SS與BAFF/BAFF-R的關系進行綜述。

        1 BAFF/BAFF-R的結(jié)構(gòu)

        BAFF是腫瘤壞死因子(tumor necrosis factor,TNF)亞家族的成員,它可以促進B細胞的生存和成熟,并調(diào)節(jié)機體免疫應答的發(fā)生,包括跨膜蛋白(mBAFF)和可溶性蛋白(sBAFF)兩種形式。mBAFF屬于Ⅱ型跨膜蛋白,可以經(jīng)蛋白酶水解從細胞膜上釋放成為sBAFF[5-6]。BAFF可以由很多細胞產(chǎn)生,包括抗原呈遞細胞(B細胞、單核/巨噬細胞、樹突狀細胞)、中性粒細胞、上皮細胞以及活化的T淋巴細胞等[5]。

        BAFF結(jié)合于3種受體,包括BAFF-R、跨膜激活劑及鈣調(diào)親環(huán)素配體相互作用分子和B細胞成熟抗原[5,7]。BAFF-R在B細胞(除漿細胞)及記憶T細胞中表達,在激活狀態(tài)下可以特異性地與BAFF結(jié)合[5]。BAFF與BAFF-R的結(jié)合分為膜結(jié)合形式和可溶性結(jié)合形式,從而以不同形式激活細胞。B細胞膜上mBAFF也可以通過T細胞表面的BAFF-R刺激T細胞,證明mBAFF在細胞與細胞間有重要作用[6]。另外,sBAFF與BAFF-R結(jié)合可以促進炎癥介質(zhì)的表達,同時抑制與巨噬細胞吞噬作用和細胞轉(zhuǎn)移作用等相關聯(lián)的細胞骨架的運動[8]。

        2 BAFF/BAFF-R的功能

        在細胞生物學方面,BAFF可誘導改變多種細胞的生物學功能。BAFF與B細胞膜上BAFF-R結(jié)合可促進自身反應性B細胞的生存和增殖,有研究表明BAFF可以通過胞外信號調(diào)節(jié)激酶1/2(extracellular signal-related kinases 1/2,Erk1/2)來調(diào)節(jié)多種Bcl-2家族成員的表達,且BAFF還可以通過抑制蛋白磷酸酶2A激活Erk1/2通路促進B細胞的生存和增殖[9]。在B細胞中BAFF-R與B細胞受體的相關信號通路有密切聯(lián)系,并且這兩種信號均參與外周血中B細胞的存活和分化、生發(fā)中心的形成、血漿細胞的存活和IgG、IgE的轉(zhuǎn)化等過程,并起關鍵作用[10-11]。然而只有少量特定形式的BAFF是上皮細胞存活所必需的,有研究表明自分泌的BAFF通過與BAFF-R結(jié)合參與上皮細胞的凋亡與存活過程,阻斷其BAFF-R以促進體外上皮細胞凋亡[12]。

        BAFF與BAFF-R結(jié)合后激活核因子κB(Nuclear Factor κB,NF-κB)信號通路,且胞內(nèi)TNF受體結(jié)合因子3與BAFF-R結(jié)合可以逆轉(zhuǎn)其對NF-κB信號通路的抑制作用,并且釋放NF-κB誘導激酶,其中磷酸化的NF-κB抑制子激酶1可以間接激活NF-κB[5],另外,有研究發(fā)現(xiàn)SS患者BAFF-R His159Tyr變異的發(fā)生率較正常人顯著增高,且該變異體也可介導NF-κB信號通路的激活,使NF-κB暴露核定位位點而誘導相關基因轉(zhuǎn)錄,從而誘發(fā)SS[13]。

        3 BAFF在SS動物模型中的作用

        目前尚無模型能夠充分表現(xiàn)SS患者的疾病特征,但通過BAFF轉(zhuǎn)基因和敲除小鼠模型在SS發(fā)病機制中B細胞作用的研究已經(jīng)取得一定進展。BAFF轉(zhuǎn)基因小鼠模型的主要特點是唾液腺中B細胞的增生和浸潤,且其血清中IgG及抗核抗體表達水平增高[14]。有研究發(fā)現(xiàn)缺乏淋巴毒素β/δ的BAFF轉(zhuǎn)基因小鼠脾組織的病理也發(fā)生改變,其主要表現(xiàn)為邊緣區(qū)B細胞減少、周圍淋巴結(jié)增大、以及缺乏T細胞依賴的免疫反應等[15]。缺乏TNF的BAFF轉(zhuǎn)基因小鼠中過渡區(qū)Ⅱ型B細胞和邊緣區(qū)B細胞顯著增加,T細胞依賴的免疫應答增強,且B細胞淋巴瘤的發(fā)病率也升高[16]。有研究發(fā)現(xiàn)NF-κB激活劑1(NF-κB activator 1,ACT1)可以降低自身反應性B細胞的存活率,敲除ACT1后可引起B(yǎng)細胞過度活化,且缺乏ACT1的BALB/C小鼠可以逐漸發(fā)展成SLE和SS樣系統(tǒng)性自身免疫病,然而通過CD40介導的T細胞依賴性反應可以調(diào)控抗SSA和抗SSB抗體的產(chǎn)生[17]。有研究表明在NOD小鼠中封閉BAFF-R可顯著減輕唾液腺炎癥并降低其抗核抗體滴度[18]。同時,在小鼠模型上分析各種治療方式的療效,發(fā)現(xiàn)給予貝利單抗(belimumab)49天后開始利妥昔單抗(rituximab)療程(375 mg/m2,四周1次),可以明顯改善SS相關的B細胞增殖[19]。

        然而,這些模型缺乏SS的一些特異性臨床特征,如女性性別優(yōu)勢、一些自身抗體的產(chǎn)生、唾液腺中T細胞的浸潤及除唾液腺以外其他器官B淋巴細胞的浸潤等[20],具體體現(xiàn)在以下幾個方面:①BAFF小鼠模型唾液腺中浸潤的淋巴細胞主要是邊緣區(qū)B細胞,T細胞的數(shù)量極少[21];②在小鼠模型中的SS樣的臨床表現(xiàn)僅在全身高反應性和淋巴器官中B細胞大量增多的基礎上產(chǎn)生的,而SS患者血清中雖然記憶B細胞減少但是B細胞的數(shù)量正常[22];③BAFF轉(zhuǎn)基因小鼠的SS樣病理變化是T細胞依賴性的[23],并依賴于邊緣區(qū)B細胞的活化[24]。因此,由于這些原因,目前還不清楚這些機制是否與更復雜的T細胞依賴性自身免疫性反應(例如SS)相關,這就要求進一步探討B(tài)AFF在SS患者中的作用。

        4 BAFF在SS中的作用

        BAFF由干擾素(interferons,IFN)誘導表達[2],可影響SS動物模型和患者疾病的發(fā)生發(fā)展。眾所周知,BAFF是外周血中B細胞存活的關鍵[25],在SS的次級和三級淋巴器官生發(fā)中心中BAFF的表達也顯著升高,另外在病毒感染或I型IFN的刺激的情況下,唾液腺上皮細胞分泌大量BAFF,從而進一步激活B細胞[1]。SS唾液腺細胞中BAFF的高表達也有助于減少B細胞凋亡,但是隨后導致的B細胞過度活化增加了非霍奇金淋巴瘤發(fā)生的風險[1,26]。干擾素調(diào)節(jié)因子4(interferon regulatory factor-4,IRF-4)和IRF-8可通過調(diào)節(jié)BAFF的表達,控制自身反應性B細胞及自身抗體的產(chǎn)生,從而緩解SS癥狀[27]。且除嗜酸性粒細胞趨化因子和IFN-γ外,BAFF是能夠最精確判斷患者有無生發(fā)中心樣結(jié)構(gòu)的生物標志物[18],Li等[28]人觀察到IFN-α處理過的SS患者唾液腺上皮細胞中BAFF的表達增加。有研究發(fā)現(xiàn)SS患者血清、唾液腺組織和唾液中BAFF表達水平均升高[29-30],且腺體生發(fā)中心中BAFF的水平與球蛋白血癥、抗SSA/SSB自身抗體滴度相關[31]。另外,BAFF也與單核細胞活化有相關性,有研究發(fā)現(xiàn)從SS患者的外周血中分離出的單核細胞也可以產(chǎn)生大量的BAFF[32]和白介素6(interleukin-6,IL-6),同時BAFF-R和調(diào)節(jié)IL-6表達的轉(zhuǎn)錄因子的表達水平也顯著增高[33]。

        在SS中,B細胞可能以自分泌方式分泌BAFF,通過結(jié)合BAFF-R激活B細胞,引發(fā)B細胞分泌自身抗體;也可能以旁分泌方式,刺激腺體組織中其它免疫細胞分泌BAFF。Nezos等[34]認為研究SS患者外周血和腺組織的不同變異體BAFF(ΔBAFF)的表達有助于確定其在疾病發(fā)生發(fā)展中的作用機制,其中ΔBAFF的產(chǎn)生可能由于細胞特異性所致,BAFF/ΔBAFF的比率也在SS發(fā)病機制中起重要作用,另有研究表明ΔBAFF可以抑制BAFF的分泌和活性,進一步抑制SS淋巴浸潤并改善唾液流率[35]。

        一項利妥昔單抗治療SS的臨床試驗發(fā)現(xiàn)利妥昔單抗治療SS效果并不顯著,且血清中BAFF的水平反而升高[36],因此,在臨床應用中貝利單抗的應用尤為重要。最近一項關于貝利單抗的開放性二期臨床試驗表明:貝利單抗可以減輕患者干燥和腮腺腫大癥狀,并抑制患者B細胞的激活[37],顯著降低患者疾病活動度評分[38-39],但是對于患者唾液腺和淚液的分泌功能的改善無效;除了對臨床癥狀的有效性,貝利單抗還可以減少B細胞各種亞型的水平,規(guī)范記憶B細胞BAFF-R的表達,且治療24周后,BAFF和BAFF-R的表達基本恢復到正常水平,更重要的是,貝利單抗治療后,患者血清中免疫球蛋白、類風濕因子、抗核抗體的表達減少,補體C4的表達升高,并且可以維持到整個療程結(jié)束[40]。另外Raphaèle等[41]研究者通過檢測貝利單抗治療后患者的血清和唇腺活檢,發(fā)現(xiàn)患者體內(nèi)NK細胞的增多加強了患者對貝利單抗的有效應答。

        5 小結(jié)

        SS是一種慢性自身免疫性疾病,其發(fā)病機制目前尚不清楚,然而B細胞的高反應性是SS的一個重要特點。BAFF特異性地與其受體結(jié)合,對B細胞的存活、增殖、發(fā)育和分化起著關鍵作用,且BAFF的異常表達與SS患者血清中自身抗體的產(chǎn)生呈正相關關系,可見,對BAFF及其受體BAFF-R的進行深入研究,有助于闡明SS的相關發(fā)病機制,并進一步為SS的治療提供新思路。

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        (收稿日期:2016-10-19 本文編輯:李岳澤)

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