Anti-tribbles pseudokinase 2 (TRIB2)-immunization modulates HYPOCRETIN/OREXIN neuronal functions.
Anti-tribbles pseudokinase 2 (TRIB2)-immunization modulates HYPOCRETIN/OREXIN neuronal functions.
复制标题
抗 tribbles 假激酶 2 (TRIB2) 免疫调节 HYPOCRETIN/OREXIN 神经元功能。
作者：
Tanaka S;Honda Y;Honda M;Yamada H;Honda K;Kodama T
研究目的最近的研究结果表明，16%–26%的发作性睡病患者抗Tribbles假激酶2（TRIB2）抗体呈阳性，脑室内注射从抗TRIB2阳性发作性睡病患者中纯化的免疫球蛋白-G会导致下丘脑分泌素/食欲素神经元丢失。我们使用TRIB2免疫大鼠和下丘脑分泌素/ataxin-3转基因(ataxin-3)小鼠研究了TRIB2抗体的病理生理学作用。方法收集TRIB2免疫大鼠的血浆、脑脊液(CSF)和下丘脑组织。研究了抗TRIB2滴度、下丘脑分泌素含量、mRNA表达、下丘脑分泌素神经元的细胞计数以及抗TRIB2抗体对下丘脑分泌素神经元的免疫反应性。来自ataxin-3小鼠的血浆也用于测定下丘脑分泌素神经元丢失后抗TRIB2抗体滴度的变化。结果TRIB2免疫大鼠的血浆和脑脊液中TRIB2抗体滴度增加。用 TRIB2 免疫大鼠的血清对下丘脑组织进行免疫染色，显示垂体胰岛素神经元细胞质中出现阳性信号。虽然下丘脑下丘脑分泌素含量或细胞计数没有发现变化，但下丘脑分泌素 mRNA 水平和释放到脑脊液中的量显着降低。 26周以上的ataxin-3小鼠的血浆，在下丘脑分泌素细胞破坏的晚期阶段，对TRIB2抗原表现出阳性反应，阳性血浆也与小鼠下丘脑下丘脑分泌素神经元发生反应。结论我们的结果表明，免疫系统的总体激活调节了下丘脑分泌素神经元的功能。下丘脑分泌素细胞群没有变化表明，除了抗TRIB2抗体之外，其他因素也导致了发作性睡病中下丘脑分泌素神经元的丧失。下丘脑分泌素神经元破坏后抗TRIB2抗体的增加表明，发作性睡病患者中的抗TRIB2抗体是下丘脑分泌素细胞破坏的结果而不是刺激原因。
Study ObjectivesRecent findings showed that 16%–26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice.MethodsPlasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons.ResultsTRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons.ConclusionsOur results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.