白藜蘆醇調控B細胞抑制性Fc受體緩解系統性紅斑性狼瘡之機轉

Abstract

FcγRIIB是B細胞上最重要的抑制性受體。FcγRIIB主要是透過免疫複合體和B細胞活化性受體BCR在細胞表面結合，進而負調控B細胞的活化、增生及分化。然而，在免疫複合體不被BCR辨認下，FcγRIIB本身亦可經由自體結合引起細胞的凋亡。在過去的研究中顯示，FcγRIIB的基因剔除老鼠會產生類似於人類紅斑性狼瘡的症狀出現，包括：B細胞的過度活化及在不同組織器官中免疫複合體的堆積。而在紅斑性狼瘡的患者中，FcγRIIB受體在B細胞上的表現量也有減少的現象，自然也助長了自體抗體的製造和免疫複合體的產生。綜上，顯見FcγRIIB受體在預防自體免疫疾病中扮演著重要的角色。我們想藉由藥物調控來增加FcγRIIB的表現以達到治療紅斑性狼瘡的目的。在先前利用螢光系統來篩選藥物，我們成功的找到白藜蘆醇 (Resveratrol)可以增加FcγRIIB的轉錄，但其機轉不清楚。因此，本篇論文使用了不同種類的專一性化學抑制劑來釐清白藜蘆醇調控FcγRIIB上升的分子機制。在我們的研究中發現白藜蘆醇透過抑制IKK或是活化SIRT1最終達到抑制NF-κB的轉錄活性，使得FcγRIIB轉錄增加並表現在細胞膜表面上，其中組蛋白乙醯酶 (HDAC)及p53也參與了調控FcγRIIB。此外，在B細胞株、周邊血B細胞以及動物實驗中，我們皆觀察到白藜蘆醇經由活化FcγRIIB可促使B細胞走向凋亡，進而緩解紅斑性狼瘡。總結，我們的研究提供了利用天然藥物白藜蘆醇透過抑制NF-κB的路徑調控FcγRIIB受體上升，使之傳遞抑制性訊息來清除過度活化的自體免疫B細胞，對於治療紅斑性狼瘡應可發展為一種新療法，單獨使用或與現今盛行毒殺B細胞的標靶治療合併使用，可能有更佳療效及具廣泛應用價值。

FcγRIIB is a key negative regulator that blocks B cell activation, proliferation and differentiation through coengagement with BCR in the presence of cognate immune complexes. In addition, homo-aggregation of FcγRIIB by non-cognate immune complexes can trigger signal for B-cell apoptosis. The crucial role of FcγRIIB can be demonstrated in FcγRIIB deficient mice that produce massive autoantibodies and develop immune complexes related autoimmune disease resembling systemic lupus erythematosus (SLE). In human lupus patients, the reduced expression of FcγRIIB is readily found in memory B cells, presumably fueling a heightened humoral response. Thus, we reasoned that using an agent to up-regulate FcγRIIB on B cells might serve as a therapeutic. To this end, we have performed drug screens. Resveratrol is one of the top lead compounds that can up-regulate transcription of FcγRIIB and surface expression in B cells. In this study, we focused on investigation of the molecular mechanisms of how resveratrol up-regulates FcγRIIB. Our results show that resveratrol can induce up-regulation of FcγRIIB through direct or indirect inhibition of NF-κB, which is modulated by SIRT1, HDAC1 and HDAC3. In addition, resveratrol increases and activates p53 to induce expression levels of FcγRIIB. The up-regulation of FcγRIIB in response to resveratrol can enhance immune complex mediated apoptosis of B cells through FcγRIIB. All these data provide a rationale via targeting FcγRIIB to allow immune complexes to trigger B-cell apoptosis. In support of these findings we demonstrate that resveratrol can result in a decrease of B cell number and relief of symptoms of lupus in MRL/lpr mice. In summary, my thesis work has unraveled the molecular basis of how resveratrol eliminate autoreactive B cells through FcγRIIB and also provided a feasible strategy for FcγRIIB-based therapy in the treatment of systemic lupus erythematosus.