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J IMMUNOL :固有自身抗体的表达可预防狼疮肾炎

2012-12-28 J IMMUNOL 手牵手博客 沈颖

  固有的自身抗体(natural autoantibodies, NAA)及其相关的B细胞是机体内正常抗体(antibody,Ab)和B细胞系统的一部分。NAA是一类在没有外来抗原(antigen, Ag)刺激下自发产生的Abs,存在于脐带血、新生儿体内。这类细胞对许多自身抗原,例如DNA、核蛋白和磷脂等都具有较弱的反应度。   NAA对自身免疫性疾病究竟有着促进还是抑制作用,对此,一直存在着

  固有的自身抗体(natural autoantibodies, NAA)及其相关的B细胞是机体内正常抗体(antibody,Ab)和B细胞系统的一部分。NAA是一类在没有外来抗原(antigen, Ag)刺激下自发产生的Abs,存在于脐带血、新生儿体内。这类细胞对许多自身抗原,例如DNA、核蛋白和磷脂等都具有较弱的反应度。

  NAA对自身免疫性疾病究竟有着促进还是抑制作用,对此,一直存在着争议。为了研究NAA的起源和生理功效,美国马里兰大学医学院的Kaiissar Mannoor等研究人员利用定点转基因(sd-tg)技术建立小鼠模型,他们在NAA基因的H链插入IgH基因座。这种转基因的NAA称为ppc1-5,能靶定DNA、肌动蛋白和PC以及另一些Ags。研究人员在自身免疫性疾病的SLE小鼠模型(MRL-lpr小鼠)中研究了这种NAA及产生NAA的B细胞在疾病发展中的作用。

  研究结果显示,MRL-lpr小鼠体内表达NAA能够防止尿蛋白的形成并降低肾脏免疫复合物肾小球IC沉淀物的形成,这表明NAA的表达能起到保护机体,防止狼疮肾炎发生的作用。这类小鼠的存活率也得到大大改善,显著高于野生型小鼠。此外,小鼠表达IgM -NAA后,还能延迟其肾炎的发病。研究人员还观察到sd-tg MRL-lpr小鼠体内的抗dsDNA抗体、抗Hep2核抗体和抗Sm/抗糖核蛋白抗体的水平都出现了下降,而且IgG的子类IgG2a、IgG3都转换为IgG1。此外,sd-tg MRL-lpr小鼠体内的CD4+T细胞比野生型的能分泌更多的负刺激分子CTLA-4和IL-10。而且产生NAA的B细胞在TLR的刺激下能产生大量的IL-10。

  这些研究结果显示,NAA和产生NAA的B细胞在保护机体预防狼疮肾炎中具有重要作用, NAA-B细胞可能通过产生IL-10来发挥免疫调控的作用。

狼疮肾炎相关的拓展阅读:


Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival
Abstract
Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Faslpr (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4+ T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.                      
    

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    2012-12-30 villahu
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