B-cell epitope spreading is a critical step for the switch from C-protein-induced myocarditis to dilated cardiomyopathy
B-cell epitope spreading is a critical step for the switch from C-protein-induced myocarditis to dilated cardiomyopathy
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DOI：
10.2353/ajpath.2007.060544
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发表时间：
2007-01-01
影响因子：
6
通讯作者：
Kohyama, Kuniko
中科院分区：
文献类型：
--
作者：
Matsumoto, Yoh;Park, Il-Kwon;Kohyama, Kuniko
心脏反复炎症是扩张型心肌病(DCM)的发病因素之一。在以前的研究中，我们用重组心脏C蛋白片段2(CC2)免疫大鼠建立了一种新的DCM动物模型。本研究调查了与扩张型心肌病发展相关的因素。重叠多肽分析表明，主要致病表位仅位于残基615-647[CC2肽12(CC2P12)]。然而，CC2P12免疫诱导了中度炎症，没有随后的DCM。T细胞CDR3分型分析表明，CC2和CC2P12免疫的大鼠体内Vβ4阳性T细胞优先扩增。免疫后4周，CC2免疫组和CC2P12免疫组的T细胞特性无显著差异，但B细胞表位的检测显示CC2免疫组有明显的表位扩散，而CC2P12免疫组则无明显变化。与这一发现一致的是，CC2P12免疫并同时转移抗肽抗血清比单独免疫CC2P12引起更严重的炎症和纤维化。然而，在没有CC2P12免疫的情况下转移抗血清并未引起任何病理改变。这些发现提示，CC2分子中微弱的T细胞活化和R细胞表位的扩散是心肌炎向DCM转变的关键步骤。
Repeated inflammation in the heart is one of the initiation factors of dilated cardiomyopathy (DCM). in a previous study, we established a new animal model for DCM by immunization of rats with recombinant cardiac C-protein fragment 2 (CC2). The present study examined factors involved in the development of DCM. Analysis using overlapping peptides revealed that the major carditogenic epitope resides only in the residue 615-647 [CC2 peptide 12 (CC2P12)]. However, immunization with CC2P12 induced moderate inflammation without subsequent DCM. CDR3 spectratyping analysis of the T-cell repertoire demonstrated that V beta 4-positive T cells were preferentially expanded in both CC2- and CC2P12-immunized rats. Although there was no significant difference in the T-cell characteristics, examinations of the B-cell epitope revealed that marked epitope spreading occurred in CC2-immunized but not CC2P12-immunized rats from 4 weeks after immunization. Consistent with this finding, immunization with CC2P12 and simultaneous transfer of anti-peptide antisera induced significantly more severe inflammation and fibrosis than CC2P12 immunization alone. However, the transfer of the antisera without CC2P12 immunization did not induce any pathology. These findings suggest dim T-cell activation and R-cell epitope spreading in the CC2 molecule is a key step for the switch from myocarditis to the development of DCM.