B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity.
B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity.
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DOI：
10.4049/jimmunol.163.7.3592
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发表时间：
1999-10
影响因子：
4.4
通讯作者：
O. Chan;M. Madaio;M. Shlomchik
中科院分区：
文献类型：
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作者：
O. Chan;M. Madaio;M. Shlomchik
在MRL-Faslpr小鼠(MRL/LPR)中，狼疮性肾炎的表达和自发性T细胞激活/记忆细胞的聚集都需要B细胞。MRL/LPR株的自身免疫是Fas缺陷和多个背景基因共同作用的结果，然而，背景基因与Fas缺陷之间的确切作用尚未完全明确。B细胞的Fas缺陷(即LPR缺陷)是获得最佳自身抗体表达所必需的，这增加了B细胞在MRL/LPR小鼠中的中心作用可能不会延伸到MRL/+小鼠，从而延伸到不依赖于Fas缺乏的狼疮模型(多基因狼疮)。为了解决这个问题，建立了B细胞缺陷、Fas完整的MRL/+小鼠(JHd-MRL/)；并在老年动物(>；9mo)中评估了疾病。当B细胞完整的小鼠患上严重疾病时，JHd-MRL/+小鼠没有发生肾炎或脉管炎。此外，尽管激活/记忆的CD4+和CD8+T细胞在B细胞完整的小鼠体内积累，但在没有B细胞的情况下，这种积累基本上受到抑制。这种影响似乎仅限于MRL品系，因为它在年龄相近的B细胞缺陷BALB/c小鼠(JHd-BALB)中没有看到。结果表明，在Fas非依赖模型中，B细胞在促进系统自身免疫中起着至关重要的作用。因此，B细胞在狼疮的发病机制中具有重要作用，即使在Fas表达完整的情况下，B细胞也可推广到依赖于多基因的狼疮模型。这些结果为抑制B细胞作为系统性红斑狼疮的治疗提供了进一步的理论基础。
B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Faslpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency ("polygenic lupus"). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (JHd-MRL/) were created; and disease was evaluated in aged animals (>9 mo). The JHd-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4+ and CD8+ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (JHd-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus.