復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院免疫學(xué)系王繼揚(yáng)課題組在最新研究中發(fā)現(xiàn)了免疫球蛋白IgM的受體,。免疫球蛋白IgM被譽(yù)為機(jī)體預(yù)防病毒和細(xì)菌感染的“第一道防線”,IgM與受體結(jié)合后,不僅可促進(jìn)機(jī)體免疫功能增強(qiáng),,而且能抑制自身“有害”抗體的產(chǎn)生。該研究對治療人的免疫缺陷病和自身免疫疾病有重大意義,。相關(guān)成果日前在線發(fā)表于美國《國家科學(xué)院院刊》,。
據(jù)了解,免疫球蛋白IgM是初次免疫應(yīng)答中最早出現(xiàn)的抗體,。IgM抗體直接與病原體結(jié)合后,,可抑制病原體的活性,不讓其發(fā)病,、發(fā)展,,并可通過特殊途徑來溶解病原體,阻止感染的擴(kuò)大,。早在40年前,,世界各地的科學(xué)家就發(fā)現(xiàn)B淋巴細(xì)胞表面有IgM的受體,并有證據(jù)支持這一推斷,,但一直沒有找到該受體,。
王繼揚(yáng)課題組運(yùn)用基因敲除技術(shù),成功培育了一種缺乏“FcμR基因”的敲除小鼠,,并分析了這種小鼠在缺乏該基因的狀態(tài)下,,在免疫功能和自身抗體方面會產(chǎn)生的結(jié)果。經(jīng)過3年努力,,他們終于首次發(fā)現(xiàn)了該受體的基因FcμR,。
研究發(fā)現(xiàn),外來病原體侵入FcμR基因被敲除的小鼠后,,出現(xiàn)明顯的免疫缺陷狀況,,其抗體下降至正常小鼠的1/3以下。進(jìn)一步研究表明,,該免疫缺陷是由于FcμR基因敲除后,,B淋巴細(xì)胞在受到外來病原體刺激后,不但不容易被激活,,反而容易造成死亡,。相反,缺乏FcμR基因的敲除小鼠在沒有任何刺激的情況下,,會產(chǎn)生大量有害的自身抗體,,包括會產(chǎn)生有害的系統(tǒng)性紅斑狼瘡的抗核抗體和抗DNA抗體或誘發(fā)機(jī)體關(guān)節(jié)炎的類風(fēng)濕性因子等。
相關(guān)專家表示,,未來可通過激活B淋巴細(xì)胞表面的IgM受體,,促進(jìn)機(jī)體內(nèi)有益抗體的產(chǎn)生,,以增強(qiáng)人體免疫力,或采用抑制性抗體來治療因B淋巴細(xì)胞活化異常而引起的各種免疫性疾病,。(生物谷Bioon.com)
doi:10.1073/pnas.1210706109
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PMID:
Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses
Rika Ouchida, Hiromi Mori, Koji Hase, Hiroyuki Takatsu, Tomohiro Kurosaki, Takeshi Tokuhisa, Hiroshi Ohno, and Ji-Yang Wang
IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM–antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.