Genetic Interaction between Lyn, Ets1, and Btk in the Control of Antibody Levels.
Genetic Interaction between Lyn, Ets1, and Btk in the Control of Antibody Levels.
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DOI：
10.4049/jimmunol.1500165
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发表时间：
2015-09-01
期刊：
影响因子：
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通讯作者：
Satterthwaite AB
中科院分区：
文献类型：
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作者：
Mayeux J;Skaug B;Luo W;Russell LM;John S;Saelee P;Abbasi H;Li QZ;Garrett-Sinha LA;Satterthwaite AB
严格控制B细胞分化为浆细胞(PC)对于正确的免疫反应和预防自身免疫至关重要。Ets1转录因子在B细胞中起作用，阻止PC分化。ETS1−/−小鼠积聚PC并产生自身抗体(AutoAbbs)。Ets1的表达通过BCR和TLRs下调B细胞的活化，并由Lyn、CD22和SiglecG以及SHP-1介导的抑制信号通路维持。在缺乏这些抑制成分的情况下，B细胞中的Ets1水平会以BTK依赖的方式降低。这会导致PC、自体抗体的增加，以及一种与ETS1−/−小鼠相似的自身免疫表型。抑制性信号分子的缺陷，包括Lyn和Ets1，与人类狼疮有关，尽管其影响比基因敲除小鼠的完全缺陷更微妙。在这里，我们探索了LYN/ETS1通路的部分中断对B细胞耐受性的影响，发现LYN+/−Ets1+/−小鼠比LYN+/−或Ets1+/−小鼠表现出更多和更早的IgM，而不是Ig G自身抗体的产生。我们还表明，当抑制信号完整时，依赖于BTK的Ets1下调对于正常的PC动态平衡是重要的。在BTK−/−小鼠中观察到的稳态PC和抗体水平的下降可以恢复Ets1缺陷。因此，根据对Ets1的激活和抑制信号的平衡，对自身抗体的产生和PC的维持有一系列的影响。这包括从完全丧失Ets1维持信号的全面自身免疫到Ets1下调受损的PC和Ab水平降低。
Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The Ets1 transcription factor acts in B cells to prevent PC differentiation. Ets1−/− mice accumulate PCs and produce autoantibodies (autoAbs). Ets1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, Ets1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoAbs, and an autoimmune phenotype similar to that of Ets1−/− mice. Defects in inhibitory signaling molecules, including Lyn and Ets1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. Here, we explore the effect of partial disruption of the Lyn/Ets1 pathway on B cell tolerance and find that Lyn+/−Ets1+/− mice demonstrate greater and earlier production of IgM, but not IgG, autoAbs compared to Lyn+/− or Ets1+/− mice. We also show that Btk-dependent downregulation of Ets1 is important for normal PC homeostasis when inhibitory signaling is intact. Ets1-deficiency restores the decrease in steady state PCs and Ab levels observed in Btk−/− mice. Thus, depending on the balance of activating and inhibitory signals to Ets1, there is a continuum of effects on autoAb production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of Ets1-maintaining signals to reduced PC and Ab levels with impaired Ets1 downregulation.