Mamula M J, Gee R J, Elliott J I, Sette A, Southwood S, Jones P J, Blier P R
Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Biol Chem. 1999 Aug 6;274(32):22321-7. doi: 10.1074/jbc.274.32.22321.
The normal functioning immune system is programmed to attack foreign pathogens and other foreign proteins while maintaining tolerance to self-proteins. The mechanisms by which tolerance is broken in the initiation of autoimmunity are not completely understood. In the present study, mice immunized with the murine cytochrome c peptide 90-104 showed no response by the B or T cell compartments. However, immunization with the isoaspartyl form of this peptide, where the linkage of Asp(93) to Leu(94) occurs through the beta-carboxyl group, resulted in strong B and T cell autoimmune responses. Antibodies elicited by immunization with the isoaspartyl form of self-peptide were cross-reactive in binding to both isoforms of cytochrome c peptide and to native cytochrome c self-protein. In a similar manner, immunization of mice with the isoaspartyl form of a peptide autoantigen of human systemic lupus erythematosus (SLE) resulted in strong B and T cell responses while mice maintained tolerance to the normal aspartyl form of self-antigen. Isoaspartyl linkages within proteins are enhanced in aging and stressed cells and arise under physiological conditions. These post-translationally modified peptides may serve as an early immunologic stimulus in autoimmune disease.
正常运作的免疫系统被设定为攻击外来病原体和其他外来蛋白质，同时维持对自身蛋白质的耐受性。自身免疫起始过程中耐受性被打破的机制尚未完全明确。在本研究中，用鼠细胞色素c肽90 - 104免疫的小鼠，其B细胞和T细胞区室均无反应。然而，用该肽的异天冬氨酰形式（其中Asp(93)与Leu(94)通过β - 羧基连接）进行免疫，则会引发强烈的B细胞和T细胞自身免疫反应。用自身肽的异天冬氨酰形式免疫所引发的抗体，在结合细胞色素c肽的两种异构体以及天然细胞色素c自身蛋白时具有交叉反应性。同样，用人系统性红斑狼疮（SLE）的一种肽自身抗原的异天冬氨酰形式免疫小鼠，会引发强烈的B细胞和T细胞反应，而小鼠对正常天冬氨酰形式的自身抗原保持耐受性。蛋白质中的异天冬氨酰连接在衰老和应激细胞中会增强，并在生理条件下出现。这些翻译后修饰的肽可能在自身免疫性疾病中作为早期免疫刺激物。
