Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.
Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.
复制标题
作者：
Henry RA;Kendall PL;Thomas JW
消除自身抗原特异性B细胞是用于自身免疫性疾病治疗的整体B细胞耗竭的有吸引力的替代方案。为了确定针对1型糖尿病中关键自身免疫B细胞特异性的潜力，使用重链B细胞受体（BCR）转基因（VH 125 Tg）小鼠在多克隆库中追踪胰岛素结合B细胞。胰岛素特异性B细胞在非自身免疫性VH 125 Tg/C57 BL/6小鼠和WT/NOD自身免疫性小鼠的外周中是罕见的，而在VH 125 Tg/NOD小鼠中它们明显占据1%的成熟B细胞亚群。自身抗原上调抗胰岛素B细胞中的CD 86，表明它们能够与T细胞相互作用。内源性胰岛素占据抗胰岛素BCR，从骨髓实质中的抗原定型开始，如第二种抗胰岛素单克隆抗体所鉴定。该单克隆抗体的施用选择性地消除体内胰岛素反应性B细胞，并预防WT/NOD小鼠的疾病。出乎意料的是，尽管BCR敏感性增加，发育中的B细胞不太容易耗竭。这些发现阐明了关键的1型糖尿病B细胞特异性如何逃脱免疫耐受检查点。通过消除这种B细胞特异性来纠正疾病倾向，为自身免疫性疾病的新治疗方法提供了概念证明。
Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.
登录
查看更多内容
影响因子：
3.2
作者：
Henry, Rachel A.;Kendall, Peggy L.;Thomas, James W.
通讯作者：
Thomas, James W.
影响因子：
15.9
作者：
Menard, Laurence;Saadoun, David;Meffre, Eric
通讯作者：
Meffre, Eric
DOI：
10.4049/jimmunol.0803121
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Henry RA;Acevedo-Suárez CA;Thomas JW
通讯作者：
Thomas JW
影响因子：
15.3
作者：
Benschop, RJ;Melamed, D;Cambier, JC
通讯作者：
Cambier, JC
影响因子：
64.8
作者：
BAEKKESKOV, S;NIELSEN, JH;LERNMARK, A
通讯作者：
LERNMARK, A