Is Peripheral Immunity Regulated by Blood-Brain Barrier Permeability Changes?
Is Peripheral Immunity Regulated by Blood-Brain Barrier Permeability Changes?
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DOI：
10.1371/journal.pone.0101477
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发表时间：
2014-07-02
期刊：
影响因子：
3.7
通讯作者：
Janigro, Damir
中科院分区：
文献类型：
--
作者：
Bargerstock, Erin;Puvenna, Vikram;Janigro, Damir
S100 B是血脑屏障（BBB）完整性的报告基因，当BBB被破坏时，S100 B出现在血液中。循环S100 B来源于颅外来源或通过BBB完整性的正常波动或病理性BBB破坏（BBBD）释放到循环中。升高的S100 B与BBBD指数（钆增强或白蛋白系数）的临床存在相匹配。在反复的亚震荡发作后，血清S100B触发抗原驱动的抗S100B自身抗体的产生。我们测试的假设，即S100 B的存在下，在颅外组织是由于外周细胞摄取血清S100 B的抗原呈递细胞，这可能会诱导抗S100 B的自身抗体的生产。为了验证这一假设，我们使用了癫痫发作的动物模型，招募了反复BBBD的患者，并收集了癫痫患者的血清样本。我们采用了广泛的技术，包括免疫组织化学，RNA分析，示踪剂注射和血清分析。S100B的mRNA被分离到屏障器官（睾丸、肾脏和脑），而S100B蛋白在脾脏、胸腺和淋巴结的免疫活性细胞、常驻免疫细胞（Langerhans细胞、心肌卫星细胞等）中被检测到。和BBB内皮。大鼠脾脏CD4+或CD8+和CD86+树突状细胞对标记S100 B的摄取被匹罗卡品诱导的癫痫持续状态（伴有BBBD）加剧。临床癫痫发作前血清S100B激增。在接受反复治疗BBBD的患者中，测量了针对S100 B的自身免疫应答。除了其在中枢神经系统中的作用及其作为BBBD报告基因的诊断价值外，S100 B可能通过涉及免疫细胞活化的机制将血脑屏障破坏整合到全身免疫的控制中。我们提出了一种情况下，外渗的S100 B可能会引发病理性自身免疫反应连接全身和中枢神经系统的免疫反应。
S100B is a reporter of blood-brain barrier (BBB) integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD). Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient). After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain) but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc.) and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.