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研究生:王蕙芬
研究生(外文):Hui-Fen Wang
論文名稱:雙股DNA單株自體免疫抗體與PGK-1之反應點及對免疫細胞作用訊息傳遞之研究
論文名稱(外文):The epitope of PGK-1 and effects on signal transduction pathways of monoclonal anti-dsDNA autoantibody
指導教授:孫光蕙
指導教授(外文):Kuang-Hui Sun
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:75
中文關鍵詞:紅斑性狼瘡PGK抗雙股DNA自體抗體鈣離子p38ERK
外文關鍵詞:SLEAnti-dsDNA AbPGKMAPKp38ERK
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全身紅斑性狼瘡(SLE)是一種慢性自體免疫疾病,患者臉部有明顯的蝴蝶狀紅斑,身上並伴隨有狼瘡腎炎、關節炎等症狀,最大特徵是血液中有大量抗核抗體等自體抗體的存在。自體抗體與自體抗原結合後會沈積在器官中,造成器官的損害。
之前本研究室已發現抗雙股DNA單株自體抗體(9D7)會與Jurkat細胞中的phosphoglycerate kinase 1(PGK-1)有交叉反應,因此本論文進一步探討9D7抗體與PGK-1的交叉反應點。PGK-1的結構兩端各有一個催化區(catalytic domain, CD),中間為核甘酸反應區(nucleotide binding domain, NBD),最主要的功能是參與催化糖解作用。我們利用大腸桿菌生產出四種剔除變異型PGK-1(PGK△CDII、PGK△CDI、PGK-CDI、PGK-NBD),以西方墨點法分析發現,9D7抗體對PGK-1之反應點主要為靠近5’端的催化區(PGK- CDI)。
此外,之前研究發現9D7抗體處理Jurkat細胞,會抑制Jurkat細胞IL-2 promoter活性及IL-2 mRNA之表現量,因此進一步瞭解9D7抗體是如何調控細胞的訊息傳遞,進而影響IL-2細胞激素的表現。我們先將9D7抗體和Jurkat細胞共同培養後,再加入phytohemaggl- utinin(PHA)刺激,發現9D7抗體不會改變細胞內鈣離子的濃度。此外,將9D7抗體和Jurkat細胞共同培養24小時後,再加入PHA及phorbol 12-myristate 13-acetate(PMA)刺激細胞,由西方墨點法分析發現,9D7抗體會明顯增加Jurkat細胞中p38及ERK的磷酸化,但對於Akt的磷酸化沒有影響;當先加入p38抑制物SB203580及ERK抑制物PD98059,則發現到實驗組與對照組IL-2蛋白質的產生沒有差異,無法看到原先9D7抗體造成IL-2產生量減少的現象,推測MAPK家族中,p38及ERK的活化對於Jurkat細胞產生IL-2是必須的,而9D7抗體抑制Jurkat細胞分泌IL-2可能經由這兩條路徑。
之前研究發現9D7抗體會抑制PGK-1之酵素活性,而9D7抗體辨認PGK-1的交叉點為酵素作用的催化區,因此推測9D7抗體可能藉由與PGK-1的催化區結合,降低PGK-1的酵素功能,已知PGK-1的缺乏會引起神經錯亂、心智遲緩,所以推測抗雙股DNA抗體對PGK-1的影響可能和SLE病人神經病變的現象有關連。另外,9D7抗體會促進細胞中MAPKs的磷酸化,進而調控細胞激素產生,並促進抗體生成,導致抗體沈積於腎臟中,造成腎臟衰竭。
Anti-dsDNA autoantibodies are not only specific for systemic lupus erythematosus (SLE) but also play an important role in the pathogenesis and activity of this disease. The anti-DNA monoclonal antibodies (anti- DNA mAb) 9D7 derived from lupus-prone mice may cross-react with two protein antigens (35 KDa and 50 KDa) in several cell lines. The 35 KDa protein antigen has been identified as the heterogenous nuclear ribonucleoprotein A2 (hnRNP A2) and its RGG domain is cross-reactive with 9D7. The 50KDa protein antigen has been demonstrated to be phosphoglycerate kinase-1 (PGK-1). However, the region of this protein antigen that interacts with anti-DNA mAb remains unclear. Since PGK-1 contains the catalytic domain I (CDI), nucleotide binding domain (NBD), and catalytic domain II (CDII), four mutants of PGK-1 (PGKΔCDII, PGKΔCDI, PGK-CDI, and PGK-NBD) were expressed and purified. PGK-CDI was demonstrated to be cross-reactive with 9D7 by Western blotting. This finding suggests that arginine is an important component in the region cross-reactive with anti-DNA mAb, since the RGG domain of hnRNPA2 and CDI of PGK-1 are arginine enriched areas.
In our previous studies, 9D7 has been demonstrated to suppress the promoter activity as well as expression of IL-2 gene in Jurkat T cells. After co-culturing Jurkat T cells with 9D7 for 24 h and activating with phytohemagglutinin (PHA) and phorbol 12-myristate 13-acetate (PMA), the levels of phospho-p38 and phospho-ERK in Jurkat T cells significantly increased whereas the level of phosphor-AKT remained unchanged. Moreover, no significant differences in the level of IL-2 were observed in the activated cells co-cultured with 9D7 (experimental group) and IgG2b (control group) by pre-treating the cultures with p38 inhibitor (SB203580) or ERK inhibitor (PD98059). These findings suggest that anti-dsDNA autoantibodies may regulate cytokine secretion by increasing T cell MAPKs phosphorylation and, in turn, trigger the cellular events
associated with SLE.
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