Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice
Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice
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DOI：
10.3109/08916934.2012.746671
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发表时间：
2013-05-01
期刊：
影响因子：
3.5
通讯作者：
Foster, Mary H.
中科院分区：
文献类型：
--
作者：
Clark, Amy G.;Fan, Qihua;Foster, Mary H.
在系统性红斑狼疮中，针对不同抗原的自身抗体在多种易感基因的影响下逃脱调节。为了深入了解不同遗传背景对控制狼疮自身抗体产生的耐受机制的不同影响，我们在四个近交系小鼠狼疮株上建立了单一的狼疮性肾炎相关抗基底膜Ig转基因，包括杜克大学和达勒姆退伍军人事务医学中心动物护理和使用委员会批准的BXSB、(NZBxNZW)F1、NZB和MRL/LPR。在非自身免疫性C57BL/6小鼠中，携带这种抗层粘连蛋白Ig转基因的B细胞受到中心缺失、编辑和无能的严格调控。在这里，我们表明，在未经处理的Ig转基因BXSB、(NZBxNZW)F1和NZB小鼠中，由于缺乏血清转基因抗层粘连蛋白自身抗体和未能恢复自发抗层粘连蛋白单抗，其耐受性总体上是完整的。在这些品系的转基因小鼠以及MRL/LPR转基因小鼠中，脾B细胞减少了4到6倍，而且IgM+骨髓B细胞的频率降低，这表明中心缺失大体上是完整的。然而，这4个菌株表现出不同的转基因B细胞表型，包括内毒素刺激转基因NZB小鼠产生抗层粘连蛋白抗体的B细胞，以及来自转基因BXSB小鼠的内毒素和BCR刺激的B细胞在体外高度增殖，显示出CD21高边缘带细胞的丰富。罕见的抗层粘连蛋白转基因B细胞在MRL/LPR小鼠中自发逃脱耐受。进一步研究这些菌株特异性B细胞命运的机制将为狼疮体液自身免疫的遗传修饰提供洞察力。
Autoantibodies to diverse antigens escape regulation in systemic lupus erythematosus under the influence of a multitude of predisposing genes. To gain insight into the differential impact of diverse genetic backgrounds on tolerance mechanisms controlling autoantibody production in lupus, we established a single lupus-derived nephritis associated anti-basement membrane Ig transgene on each of four inbred murine lupus strains, including BXSB, (NZBxNZW)F1, NZB, and MRL/lpr, as approved by the Duke University and the Durham Veterans Affairs Medical Centers' Animal Care and Use Committees. In nonautoimmune C57BL/6 mice, B cells bearing this anti-laminin Ig transgene are stringently regulated by central deletion, editing, and anergy. Here, we show that tolerance is generally intact in unmanipulated Ig transgenic BXSB, (NZBxNZW) F1, and NZB mice, based on absence of serum transgenic anti-laminin autoantibodies and failure to recover spontaneous anti-laminin monoclonal antibodies. Four-to six-fold depletion of splenic B cells in transgenic mice of these strains, as well as in MRL/lpr transgenic mice, and reduced frequency of IgM+ bone marrow B cells suggest that central deletion is grossly intact. Nonetheless the 4 strains demonstrate distinct transgenic B cell phenotypes, including endotoxin-stimulated production of anti-laminin antibodies by B cells from transgenic NZB mice, and in vitro hyperproliferation of both endotoxin-and BCR-stimulated B cells from transgenic BXSB mice, which are shown to have an enrichment of CD21-high marginal zone cells. Rare anti-laminin transgenic B cells spontaneously escape tolerance in MRL/lpr mice. Further study of the mechanisms underlying these strain-specific B cell fates will provide insight into genetic modification of humoral autoimmunity in lupus.