B cell tolerance to epidermal ribonuclear-associated neo-autoantigen in vivo.
B cell tolerance to epidermal ribonuclear-associated neo-autoantigen in vivo.
复制标题
B 细胞对体内表皮核糖核相关新自身抗原的耐受性。
DOI：
10.1111/cei.13066
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发表时间：
2018
影响因子：
4.6
通讯作者：
Carroll,MC
中科院分区：
文献类型：
--
作者：
Degn,SE;Alicot,E;Carroll,MC
确定自身抗原如何被免疫系统感知对于理解耐受性如何在稳态条件下维持至关重要。在例如系统性红斑狼疮（SLE）中，由自身抗体靶向的临床相关的天然自身抗原通常具有不仅接合B细胞受体（BCR）而且接合B细胞中的共刺激途径（例如Toll样受体（TLR）-7途径）的内在能力。在这里，我们开发了一种新的小鼠模型，其显示携带OT-II T细胞表位、B细胞抗原和能够刺激TLR-7的相关核糖核酸的荧光表皮新自身抗原的诱导表达。新的自身抗原在皮肤中表达，但并没有以完整的形式流入引流淋巴结，即使在紫外线B（UVB）刺激诱导基底层细胞凋亡。连续转移的自身反应性B细胞被滤泡排斥，并在脾脏的T-B边界死亡，阻止了它们的再循环和与抗原的外周相遇。通过将报告基因与C4缺陷背景下的BCR敲入系交叉，绕过了该过渡检查点。连续转移的OT-II T细胞迅速归巢到皮肤淋巴结中并上调CD 69。然而，令人惊讶的是，耐受性并没有被打破，因为T细胞随后下调了活化标志物并收缩。我们的研究结果强调了细胞内和外周抗原的隔离、过渡性B细胞耐受检查点和T细胞调节是如何合作来维持体内免疫耐受的。
Defining how self-antigens are perceived by the immune system is pivotal to understand how tolerance is maintained under homeostatic conditions. Clinically relevant, natural autoantigens targeted by autoantibodies, in e.g. systemic lupus erythematosus (SLE), commonly have an intrinsic ability to engage not only the B cell receptor (BCR), but also a co-stimulatory pathway in B cells, such as the Toll-like receptor (TLR)-7 pathway. Here we developed a novel mouse model displaying inducible expression of a fluorescent epidermal neo-autoantigen carrying an OT-II T cell epitope, B cell antigen and associated ribonucleic acids capable of stimulating TLR-7. The neo-autoantigen was expressed in skin, but did not drain in intact form into draining lymph nodes, even after ultraviolet B (UVB)-stimulated induction of apoptosis in the basal layer. Adoptively transferred autoreactive B cells were excluded follicularly and perished at the T–B border in the spleen, preventing their recirculation and encounter with antigen peripherally. This transitional check-point was bypassed by crossing the reporter to a BCR knock-in line on a C4-deficient background. Adoptively transferred OT-II T cells homed rapidly into cutaneous lymph nodes and up-regulated CD69. Surprisingly, however, tolerance was not broken, as the T cells subsequently down-regulated activation markers and contracted. Our results highlight how sequestration of intracellular and peripheral antigen, the transitional B cell tolerance check-point and T cell regulation co-operate to maintain immunological tolerancein vivo.