Wållberg Maja, Bergquist Jonas, Achour Adnane, Breij Esther, Harris Robert A
Department of Clinical Neurosciences, Applied Immunology, Centre for Molecular Medicine, Karolinska University Hospital at Solna, Stockholm, Sweden.
Eur J Immunol. 2007 Jul;37(7):1986-95. doi: 10.1002/eji.200636912.
Self proteins may become autoantigenic through structural modification. We studied malondialdehydation of recombinant rat (rr) myelin oligodendrocyte glycoprotein (MOG), an autoantigen in multiple sclerosis. Malondialdehyde (MDA) modification changed protein weight and charge, the location of these adducts being mapped by Fourier transform ion cyclotron resonance. Molecular modelling revealed significant differences in the MDA-rrMOG three-dimensional structure. DBA/1 mice immunised with MDA-rrMOG developed greater proliferative responses and more severe experimental autoimmune encephalomyelitis than mice immunised with unmodified rrMOG. MDA-rrMOG was taken up more effectively by antigen-presenting cells (APC), at least partially through scavenger receptors. Exposure to MDA-rrMOG led to increased expression of IL-23, IL-12 and IL-12R, indicating a role not only for increased antigen uptake but also for activation of APC. We thus provide biochemical, structural, immunological and clinical data that suggest that the post-translationally modified form of this myelin autoantigen is a more relevant form of the molecule.
自身蛋白可通过结构修饰而成为自身抗原。我们研究了重组大鼠（rr）髓鞘少突胶质细胞糖蛋白（MOG，多发性硬化症中的一种自身抗原）的丙二醛化。丙二醛（MDA）修饰改变了蛋白质的重量和电荷，这些加合物的位置通过傅里叶变换离子回旋共振进行定位。分子建模揭示了MDA-rrMOG三维结构的显著差异。与用未修饰的rrMOG免疫的小鼠相比，用MDA-rrMOG免疫的DBA/1小鼠产生了更强的增殖反应和更严重的实验性自身免疫性脑脊髓炎。MDA-rrMOG被抗原呈递细胞（APC）更有效地摄取，至少部分是通过清道夫受体。暴露于MDA-rrMOG导致IL-23、IL-12和IL-12R的表达增加，这表明不仅抗原摄取增加，而且APC的激活也起作用。因此，我们提供了生化、结构、免疫和临床数据，表明这种髓鞘自身抗原的翻译后修饰形式是该分子更具相关性的形式。
