2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649104摘要：許多自體抗原平時位於細胞內，並不會接觸到其他細胞，但在細胞受到傷害或死亡時，自體抗原便可能會被釋放出來或分佈到細胞表面。最近研究發現自體抗原不僅可擔任組織特異性的化學趨化物質，也會引起發炎反應。La或SSB此自體抗原為含有RNA recognition motif的48kD核糖核酸蛋白。我們目前正在進行的研究首度發現La/SSB及其La/SSB合成胜肰 (尤其是pep349-364片段)可當成autoadjuvants來增加週邊血液單核細胞產生發炎性的細胞激素 (TNF-α) 與chemokines (MCP-1 and IL-8)。La/SSB也可增加多形核嗜中性白血球(PMN)分泌IL-8的能力與吞噬作用。研究也發現La/SSB可能經由與細胞膜蛋白間的交互作用來活化p38-MAPK and ERK-1/2 等pathway，繼而引起自體免疫反應。因為integrins的訊息傳遞對嗜中性白血球與巨噬細胞(macrophages)的功能特別重要，可用來調節這些細胞的附著、移動、散佈、趨化作用、產生氧化物質與分泌包括細胞激素在內的許多物質，且integrins訊息傳遞路徑被活化時，包括Syk、ERK與p38 MAPK在內的許多分子都會被磷酸化，我們計劃花二年的時間來研究La/SSB此自體抗原、anti-La/SSB自體抗體與其免疫複合體對不同吞噬細胞與cell lines的integrins所調控功能之影響與它們之間的交互作用，以進一步釐清SSB-anti-SSB system的生物活性與訊息傳遞路徑等分子機制。。我們將探討SSB-anti-SSB系統對integrins與costimulatory molecules表現量與此系統對integrins所調控功能的影響。我們也將分析SSB-anti-SSB系統對integrins功能影響所牽涉的訊息傳遞路徑(主要是Src family kinase , Syk tyrosine kinase, ERK與p38 MAPK)。這項研究將有助於探討SSB-anti-SSB system在發炎與免疫反應、正常組織修補與恆定性及此系統在自體免疫疾病的病生理學中所扮演的角色，並可能提供自體免疫疾病一嶄新的治療方式。<br> Abstract: La/SSB autoantigen is a 48kD ribonucleoprotein that binds to the RNA polymerase III transcripts and anti-La/SSB is one of the serologic markers in systemic lupus erythematosus (SLE) or Sjogren syndrome. Furthermore, the expression of La/SSB can be increased and redistributed to the cell surface that may act as a danger signal after different inflammatory stimuli or various transformation processes.More importantly, our preliminary study is novel that La/SSB and its synthetic peptides might act as autoadjuvants to increase proinflammatory cytokine (TNF-α) and chemokines (MCP-1 and IL-8) production from PBMC, neutrophils and U937 cell line, and thus act as endogenous (inducible) danger signals. ERK-1/2 and p38-MAPK pathway were activated during this process.Integrins are crucial for neutrophils and macrophages and they mediated cellular function such as firm adhesion、cell spreading、chemotaxis、migration、the production of reactive oxygen intermediates and the release of antimicrobial granule proteins or various cytokines. Moreover, after activation of integrins, many downstream substrates such as Syk，ERK and p38 MAPK are phosphorylated.Hence, we plan to spend two years to study the effect of La/SSB、anti-La/SSB and their immune complex on the expression and function of integrins and to analyze the involved signal transduction pathway. We will focus on the integrins-mediated cellular function on neuttrophils, monocytes and/or macrophages from both normal controls and patients with different autoimmune rheumatic diseases. This study will help to understand the role of La/SSB and anti-La/SSB in the normal tissue repair process and in the pathogenesis of autoimmune disease, and may provide a novel therapy to the autoimmune disease.