Antigen-specific responses in autoimmunity and tolerance
Antigen-specific responses in autoimmunity and tolerance
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DOI：
10.1385/ir:23:2-3:235
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发表时间：
2001-01-01
影响因子：
4.4
通讯作者：
Thomas, JW
中科院分区：
文献类型：
--
作者：
Thomas, JW
胰岛素自身免疫综合征和I型糖尿病前驱症状中会自发产生胰岛素自身抗体。此外，对没有自身免疫性疾病的个体施用胰岛素通常会产生结合自体激素的抗体。这些观察结果表明，生理水平的激素，如胰岛素，低于临界阈值的信号耐受诱导，一种状态称为克隆无知。相反，我们实验室对胰岛素抗体所用V基因的遗传起源和结构的研究表明，抗胰岛素库受到严格调控。我们已经证明，小鼠体内携带胰岛素抗体转基因的B细胞在功能上是沉默的。这些发现证实了对小分子的耐受性是活跃的，即使它们以低浓度存在。尽管存在主动耐受性，但胰岛素抗体通过几种机制在正常动物的所有成分中得以维持，包括通过TI抗原信号的活化、构象表位的独特展示以及通过对其它抗原的应答而预先选择的B细胞的募集。本文就抗胰岛素B细胞逃逸途径的研究进展作一综述。
Autoantibodies to the hormone insulin arise spontaneously in the insulin autoimmune syndrome and in the prodrome of type I diabetes. Further, administration of insulin to individuals without autoimmune disease routinely results in antibodies that bind autologous hormone. These observations suggest that physiological levels of hormones, such as insulin, are below critical thresholds for signaling tolerance induction, a state termed clonal ignorance. In contrast, studies from our laboratory on the genetic origins and structure of V genes used by insulin antibodies suggest that the anti-insulin repertoire is tightly regulated. We have shown that B cells in mice harboring an insulin antibody transgene are functionally silenced. These findings verify that tolerance is active for small molecules, even when they are present at low concentrations. Despite active tolerance, insulin antibodies are sustained in the repertoire of normal animals by several mechanisms, including activation by TI antigen signals, unique display of conformational epitopes, and the recruitment of B cells previously selected by responses to other antigens. This essay reviews our current understanding of escape pathways for anti-insulin B cells.