Functional silencing is initiated and maintained in immature anti-insulin B cells.
Functional silencing is initiated and maintained in immature anti-insulin B cells.
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DOI：
10.4049/jimmunol.0803121
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Thomas JW
中科院分区：
文献类型：
--
作者：
Henry RA;Acevedo-Suárez CA;Thomas JW
B细胞耐受机制在骨髓和外周发育过程中起作用，消除或限制自身反应克隆，以预防自身免疫性疾病。携带抗胰岛素bcr转基因(125Tg)的小鼠脾中的B细胞由内源性激素维持在功能沉默或无能状态，但尚不清楚何时何地诱导无能。因此，一个体外骨髓培养系统被用来探索小蛋白激素，一种关键的自身抗原，是否可以与BCR相互作用，在B细胞发育的早期诱导无能。在胰岛素作用下，抗胰岛素(125Tg)未成熟B细胞表现出与成熟脾B细胞相似的无反应特征。这些包括BCR下调，对抗CD40的增殖反应受损，以及在BCR依赖和独立刺激刺激下钙动员减少。抑制钙调神经磷酸酶也会以类似的方式导致未成熟B细胞增殖减少，这表明细胞内钙动员减少可能是改变细胞增殖的潜在机制。短期暴露于胰岛素后会出现损害的迹象，这种损害在停用银后是可逆的。这表明在这个阶段保持了高度的功能可塑性，需要持续的Ag参与才能保持功能失活。这些发现表明，在成熟的脾125Tg B细胞中观察到的耐受是由发育中的B细胞室中的胰岛素启动的，因此为预防胰岛素自身免疫提供了一个重要的治疗窗口。
Mechanisms of B cell tolerance act during development in the bone marrow and periphery to eliminate or restrict autoreactive clones to prevent autoimmune disease. B cells in the spleens of mice that harbor anti-insulin BCR transgenes (125Tg) are maintained in a functionally silenced or anergic state by endogenous hormone, but it is not clear when and where anergy is induced. An in vitro bone marrow culture system was therefore used to probe whether small protein hormones, a critical class of autoantigens, could interact with the BCR to induce anergy early during B cell development. Upon exposure to insulin, anti-insulin (125Tg) immature B cells show similar hallmarks of anergy as those observed in mature splenic B cells. These include BCR down-regulation, impaired proliferative responses to anti-CD40, and diminished calcium mobilization upon stimulation with BCR-dependent and independent stimuli. Inhibition of calcineurin also results in reduced immature B cell proliferation in a similar manner, suggesting a potential mechanism through which reduced intracellular calcium mobilization may be altering cellular proliferation. Signs of impairment appear after short-term exposure to insulin, which are reversible upon Ag withdrawal. This suggests that a high degree of functional plasticity is maintained at this stage and that constant Ag engagement is required to maintain functional inactivation. These findings indicate that tolerance observed in mature, splenic 125Tg B cells is initiated by insulin in the developing B cell compartment and thus highlight an important therapeutic window for the prevention of insulin autoimmunity.
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DOI：
10.1084/jem.179.2.425
发表时间：
1994-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
4.4
作者：
Acevedo-Suarez, Carlos A.;Kilkenny, Dawn M.;Thomas, James W.
通讯作者：
Thomas, James W.
影响因子：
16
作者：
Baksh, S;Widlund, HR;Burakoff, SJ
通讯作者：
Burakoff, SJ
影响因子：
5.4
作者：
Meade, J;Tybulewicz, VLJ;Turner, M
通讯作者：
Turner, M
DOI：
10.1084/jem.177.4.1165
发表时间：
1993-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Radic MZ;Erikson J;Litwin S;Weigert M
通讯作者：
Weigert M