The role of noradrenergic nerves in the development of the lymphoproliferative disease in fas-deficient, lpr/lpr mice
The role of noradrenergic nerves in the development of the lymphoproliferative disease in fas-deficient, lpr/lpr mice
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DOI：
10.4049/jimmunol.176.11.7079
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Besedovsky, HO
中科院分区：
文献类型：
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作者：
del Rey, A;Roggero, E;Besedovsky, HO
Lp/lpr小鼠发生淋巴增生性自身免疫性狼疮样疾病。这些小鼠缺乏功能性Fas（CD 95）表达并且对Fas配体（CD 178）介导的细胞凋亡具有抗性，细胞凋亡是维持外周耐受的关键机制。在这项研究中，我们表明，去甲肾上腺素（NA），主要的交感神经递质，可以诱导淋巴细胞凋亡的功能Fas无关。基于这一发现，我们使用lpr/lpr小鼠作为模型来研究去甲肾上腺素能神经在淋巴组织增生性疾病表达中的作用。在个体发育早期，NA的浓度显着增加，在lpr/lpr小鼠的脾脏，与正常的同窝仔。然而，脾交感神经支配逐渐下降，随着疾病的进展，IgM血液水平和脾NA浓度呈负相关，当疾病明显表现。当lpr/lpr小鼠在成年生活期间自然发生的去甲肾上腺素能纤维的损失通过新生儿交感神经切除术实验性地提前时，血液中IgM和IgG 2a的浓度显著高于对照lpr/lpr小鼠，并且淋巴结病的出现加速。而且，虽然新生儿去神经不影响正常动物的寿命，但显著缩短了lpr/lpr小鼠的生存时间。这些数据表明，除了Fas通路的缺陷，lpr/lpr小鼠中改变的交感神经支配也有助于自身免疫性疾病的发病机制，并强烈支持交感神经系统可以调节淋巴组织增生性疾病的表达的假设。
Lp/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD 178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.