A Protein's Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins
A Protein's Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins
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DOI：
10.4049/jimmunol.0902249
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发表时间：
2010-10-01
影响因子：
4.4
通讯作者：
Ueda, Tadashi
中科院分区：
文献类型：
--
作者：
Ohkuri, Takatoshi;Nagatomo, Satoko;Ueda, Tadashi
外源蛋白AGS被结合到APC中，然后被内体酶降解。然后将这些多肽安装在APC表面的MHC II分子上。外源蛋白AGS的构象稳定程度决定了T细胞的触发反应和免疫反应。然而，几乎没有证据表明蛋白质的构象稳定性是免疫的主导因素。在这项研究中，我们证明了蛋白质有一个构象稳定的阈值来防止外来蛋白质的免疫原性。根据蛋清溶菌酶衍生物和突变小鼠溶菌酶对不同稳定性溶菌酶的蛋白质去折叠自由能变化与针对不同稳定性溶菌酶的免疫球蛋白生成量之间的相关性，发现针对溶菌酶的免疫球蛋白生成量与溶菌酶的去折叠自由能变化呈负相关和线性相关，其中107-116之间的序列被能产生自身抗体的蛋清溶菌酶取代。有趣的是，两种溶菌酶阻止其免疫原性的自由能变化阈值几乎相同(21-23千卡/摩尔)。为了证实这一结果，我们还发现，在生理条件下，完整的Ph1-p7的稳定性大于20kcal/mol，而完整的Ph1-p7的交联物在小鼠体内诱导了最低的免疫球蛋白生成，而完整的Phl-p7是抗原性的。根据以上结果，我们认为蛋白质构象稳定性是一个免疫显性因素。《免疫学杂志》，2010,185：4199-4205。
Foreign protein Ags are incorporated into APCs and then degraded by endosomal proteases. The peptides are then mounted on MHC II molecules on the surfaces of APCs. The T cell-triggering response and, therefore, the immune response, were suggested to be governed by the degree of conformational stability of the foreign protein Ags. However, there is little evidence that a protein's conformational stability is an immunologically dominant factor. In this study, we show that a protein has a threshold of conformational stability to prevent the immunogenicity of foreign proteins. Inverse and linear correlations were found between the amount of IgG production against lysozymes and the free-energy change for the unfolding of lysozymes, based on the correlation between the free-energy changes of the protein unfolding and the amount of IgG production against lysozymes with different stabilities in mice using hen egg white lysozyme derivatives and mutant mouse lysozymes, in which the sequence between 107 and 116 is replaced with that of hen egg white lysozyme, which can produce autoantibodies in mice. Interestingly, the thresholds of free-energy changes for both lysozymes to prevent their immunogenicity were almost identical (21-23 kcal/mol). To confirm the results, we also showed that the cross-linking of Phl p 7, in which intact Phl p 7 has stability greater than similar to 20 kcal/mol under physiological conditions, induced minimal IgG production in mice, whereas intact Phl p 7 was antigenic. From the above results, we suggest that protein conformational stability was an immunologically dominant factor. The Journal of Immunology, 2010, 185: 4199-4205.