Klehmet Juliane, Shive Carey, Guardia-Wolff Rocio, Petersen Ines, Spack Edward G, Boehm Bernhard O, Weissert Robert, Forsthuber Thomas G
Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Clin Immunol. 2004 Apr;111(1):53-60. doi: 10.1016/j.clim.2003.12.012.
Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined. To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB10401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97-108 (MOG(97-108); TCFFRDHSYQEE), the T cell response diversifies over time to MOG(181-200) (core: MOG(183-191); FVIVPVLGP) and MBP. The spreading epitope MOG(181-200) binds with high affinity to HLA-DRB10401 and is presented by human HLA-DRB10401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB10401 transgenic mice. This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in "humanized" HLA-DR4 transgenic mice.
表位扩展与实验性自身免疫性脑脊髓炎（EAE）和人类多发性硬化症（MS）的发病机制有关。在啮齿动物中已证实针对髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）决定簇存在T细胞表位扩展，但对于另一种重要的髓鞘抗原髓鞘少突胶质细胞糖蛋白（MOG）则未发现表位扩展。此外，包括HLA - DR2和DR4在内的人类自身免疫相关MHC分子在表位扩展中的作用尚未得到正式研究。为了解决这些问题，我们研究了EAE期间HLA - DR4（DRB10401）转基因小鼠中向MOG决定簇的表位扩展情况。数据显示，在用免疫显性的HLA - DR4限制性MOG肽97 - 108（MOG(97 - 108); TCFFRDHSYQEE）诱导HLA - DR4转基因小鼠发生EAE后，T细胞反应随时间推移多样化，扩展到MOG(181 - 200)（核心：MOG(183 - 191); FVIVPVLGP）和MBP。扩展表位MOG(181 - 200)与HLA - DRB10401具有高亲和力结合，并由人类HLA - DRB10401 +抗原呈递细胞呈递。此外，该表位在HLA - DRB10401转基因小鼠中具有致脑炎作用。本研究证明了在“人源化”HLA - DR4转基因小鼠中存在向MOG和MBP的分子内和分子间表位扩展。
