Autoimmunity to the glutamate receptor in mice - A model for Rasmussen's encephalitis?
Autoimmunity to the glutamate receptor in mice - A model for Rasmussen's encephalitis?
复制标题
DOI：
10.1006/jaut.1999.0297
复制
发表时间：
1999-08-01
影响因子：
12.8
通讯作者：
Hermelin, A
中科院分区：
文献类型：
--
作者：
Levite, M;Hermelin, A
我们研究了谷氨酸/AMPA受体亚单位3（GluR 3）肽的小鼠自身免疫的体内致病潜力。GluR 3的抗体存在于人类癫痫、拉斯穆森脑炎（RE）中。在我们在这个问题的相关论文中，我们发现GluR 3B肽（氨基酸372-395）的鼠抗体结合培养的神经元，引起GluR通道活性，并以补体非依赖性兴奋性毒性方式杀死神经元，模拟过量谷氨酸的病理生理作用。在本研究中，我们用GluR 3B肽免疫四种小鼠品系（BALB/c，C3 H/HeJ，SJL/J和C578 L/6），并研究（1）抗GluR 3B抗体的产生;（2）抗GluR 3 T细胞;（3）临床症状和异常行为;（4）脑病理学。我们发现BALB/c、C3 H/HeJ和SJL/J小鼠品系产生了高滴度的抗GluR 3B抗体。在C57 BL/6小鼠中产生的低水平抗GluR 3B抗体表明小鼠的遗传背景影响其对GluR 3B肽产生体液自身免疫应答的能力。GluR 3B免疫的小鼠也产生了抗GluR 3B T细胞，并且它们的脾细胞显示出特定（V β 11、V β 7和V β 8）TCR V β家族的显著偏置频率。令人惊讶的是，GluR 3B免疫的小鼠也提高了高抗ssDNA体液免疫反应性。GluR 3B免疫的小鼠表现出多种脑病理学，部分类似于RE中观察到的，和亚临床行为异常，但没有癫痫，即使在通过削弱血脑屏障促进自身反应性抗体进入大脑后。综上所述，这些结果表明，对GluR 3B表位的自身免疫可能是神经退行性疾病（如RE）中观察到的神经元死亡和脑病理学的原因，但可能不足以引起癫痫，至少在小鼠中不是。(C)北京：科学出版社.
We investigated the in vivo pathogenic potential of murine autoimmunity to peptides of the glutamate/AMPA receptor subunit 3 (GluR3). Antibodies to GluR3 are found in human epilepsy, Rasmussen's encephalitis (RE). In our accompanying paper in this issue we found that murine antibodies to the GluR3B peptide (amino acids 372-395) bind neurons in culture, evoke GluR channel activity, and kill neurons in a complement-independent excitotoxic manner, mimicking the pathophysiologic effects of excess of glutamate. In the present study, we immunized four mouse strains (BALB/c, C3H/HeJ, SJL/J and C578L/6) with the GluR3B peptide, and investigated the development of (1) anti-GluR3B antibodies; (2) anti-GluR3 T cells; (3) clinical symptoms and abnormal behaviour; (4) brain pathology. We found that BALB/c, C3H/HeJ and SJL/J mice strains developed high titres of anti-GluR3B antibodies. The low levels anti-GluR3B antibodies raised in C57BL/6 mice suggest that the genetic background of mice influences their ability to mount a humoral autoimmune response towards the GluR3B peptide. The GluR3B-immunized mice also developed anti-GluR3B T cells, and their splenocytes showed significantly biased frequencies of particular (V beta 11, V beta 7 and V beta 8) TCR V beta families. Surprisingly, GluR3B-immunized mice also raised high anti-ssDNA humoral immunoreactivity. GluR3B-immunized mice exhibited multiple brain pathology, partially resembling that observed in RE, and subclinical behavioral abnormalities, but no epilepsy, even upon facilitating the entry of the autoreactive antibodies into the brain, by weakening the blood-brain barrier. Taken together, these results suggest that autoimmunity to the GluR3B epitope may account for the neuronal death and brain pathology seen in neurodegenerative diseases Like RE, but may not be sufficient to underly epilepsy, at least not in mice. (C) 1999 Academic Press.