Activation of Rheumatoid Factor-Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model
Activation of Rheumatoid Factor-Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model
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DOI：
10.4049/jimmunol.1303000
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发表时间：
2014-08-15
影响因子：
4.4
通讯作者：
Morel, Laurence
中科院分区：
文献类型：
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作者：
Sang, Allison;Niu, Haitao;Morel, Laurence
MRL/lpr小鼠中的AM 14类风湿因子（RF）B细胞通过双重BCR和TLR 7/9连接活化，并通过滤泡外（EF）途径分化成浆母细胞。目前还不清楚RF B细胞的这种激活机制是否适用于其他狼疮易感小鼠模型。我们研究了RF B细胞破坏NZM 2410衍生的B6.Sle1.Sle2.Sle3（TC）菌株耐受性的机制，并与C57 BL/6（B6）对照进行了比较，每种细胞在存在或不存在IgG 2a（a）自身抗原的情况下表达AM 14 H链转基因。在自身抗原存在下，TC而不是B6的遗传背景促进RF B细胞分化为Ab形成细胞（AFC）。激活的RF B细胞优先分化为EF区的浆母细胞。与MRL/lpr株相反，TC RF B细胞也位于生发中心，但只有EF灶的形成与RF AFC的产生呈正相关。年轻TC的免疫接种。具有IgG 2a（a）抗染色质免疫复合物（IC）的AM 14 H链转基因小鼠以BCR和TLR 9依赖性方式激活RF B细胞。然而，这些IC免疫并不导致RF AFC的产生。这些结果表明，RF B细胞在TC和MRL/lpr狼疮易感遗传背景中以相同的一般机制破坏耐受性，即BCR和TLR 9途径的双重激活。还存在明显差异，例如GC中存在RF B细胞，以及RF AFC完全分化需要慢性IgG 2a（a）抗染色质IC。
AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2a(a) autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC. AM14 H chain transgenic mice with IgG2a(a) anti-chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2a(a) anti-chromatin ICs for full differentiation of RF AFCs.