人類微小病毒B19蛋白對狼瘡小鼠肝臟影響之研究

感染人類微小病毒B19已知與自體抗體及自體免疫疾病有關，但詳細機轉仍不清楚。先前許多文獻指出感染B19病毒可能會加重或誘發紅斑性狼瘡(SLE)的病情，因此我們利用NZB/W F1狼瘡小鼠探討B19 病毒蛋白對於紅斑性狼瘡之肝臟影響。在第一部份的研究結果發現免疫注射抗B19-VP1u抗體的狼瘡小鼠，會增加其anti-dsDNA抗體及抗磷脂質抗體的表現，並且也會促進肝臟MMP-9酵素活性及蛋白的表現且經由磷酸化蛋白PI3K與ERK訊息傳遞路徑。由此實驗結果證明B19-VP1u在誘導抗磷脂質抗體及抗磷脂質症候群的發生扮演著相當重要的角色。在第二部份的研究結果發現皮下注射非結構蛋白(NS1)的NZB/W F1狼瘡小鼠相較於注射VP1u和結構蛋白VP2的NZB/W F1狼瘡小鼠，會促進肝臟誘導型一氧化氮合成酶(iNOS)與環氧合酶2(COX2)蛋白表現，組織病理切片中肝臟細胞也發現有明顯淋巴細胞浸潤的現象。此外，免疫注射非結構蛋白NS1的NZB/W F1狼瘡小鼠肝臟腫瘤壞死因子(TNF-α)及腫瘤壞死因子接受器(TNF-αR)蛋白表現也明顯增加且經由訊號傳遞分子IKK-α、IκB與NF-κB訊息傳遞路徑。另一方面，免疫注射非結構蛋白NS1的NZB/W F1狼瘡小鼠肝臟金屬基質蛋白酶(MMP9)與尿素激酶型胞漿素原活化子(uPA)蛋白表現也有明顯增加。由此實驗結果首度發現非結構蛋白NS1會加重紅斑性狼瘡肝臟的損傷而非VP1u和VP2結構蛋白，並且也瞭解B19病毒NS1蛋白對於紅斑性狼瘡肝臟損傷扮演的重要角色。

Human Parvovirus B19 (B19) infection has been associated with the production of various autoantibodies and recognized as a cause or trigger of autoimmune diseases. However, the precise mechanism is still unclear. Previous studies have reported that B19 may exacerbate or induce systemic lupus erythematous (SLE). Herein, we aimed to inves-tigate the effects of B19 on liver in NZB/W F1 mice by injecting B19 viral proteins. In Part I, we passive transfer of rabbit anti-B19-VP1u IgG was injected intravenously into NZB/W F1 mice. Significant increases of APhL, and anti-dsDNA antibody binding activity were detected in immunized anti-B19-VP1u mice. Additionally, significant increases of MMP9 activity and protein expression were detected in B19-VP1u IgG group. Notably, PI3K and phosphorylated ERK proteins were involved in the induction of MMP9. These results are indicated that the aggravated effects of anti-B19-VP1u antibody in disease activity of SLE. In part II, the recombinant B19 NS1, VP1u or VP2 proteins were injected subcutaneously into NZB/W F1 mice. Significant expressions of iNOS and COX2 proteins were detected and markedly hepatocyte disarray and lymphocyte infiltration were observed in livers from NZB/WF 1 mice receiving B19 NS1. Furthermore, significant increases of TNF-α, TNF-α receptor, IKK-α, IκB and NF-κB (p65) were detected in livers from NZB/W F1 mice re-ceiving B19 NS1. Accordingly, the MMP9 and uPA proteins were significantly increases in livers from receiving B19 NS1. These findings firstly demonstrated the aggravated effects of B19 NS1 but not VP1u or VP2 protein on hepatic injury and provide a clue in under-standing the role of B19 NS1 on hepatic injury in SLE.