Germ-line genetic variation in the immunoglobulin heavy chain creates stroke susceptibility in the spontaneously hypertensive rat
Germ-line genetic variation in the immunoglobulin heavy chain creates stroke susceptibility in the spontaneously hypertensive rat
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DOI：
10.1152/physiolgenomics.00054.2019
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发表时间：
2019-11-01
影响因子：
4.6
通讯作者：
Doris, Peter A.
中科院分区：
文献类型：
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作者：
Dhande, Isha S.;Kneedler, Sterling C.;Doris, Peter A.
卒中易感自发性高血压大鼠(SHR-A3/SHRSP)脑血管疾病的风险源于自然发生的基因变异。在目前的研究中，我们展示了影响抗体形成和功能的SHR基因变异在卒中发病机制中的作用。我们通过同源替换检测了编码免疫球蛋白重链的基因IgH基因变异与卒中易感性的关系。该基因包含SHR-A3的功能性自然变异，而SHR-A3不同于抗中风的SHR-B2。我们建立了一个SHR-A3同源系，用SHR-B2中相应的单倍型替换了Ig H基因。与SHR-A3大鼠相比，Ig H基因[SHR-A3(Ig H-B2)]的同源替换显著减少了脑血管疾病的发生。考虑到IgH基因在抗体形成中的作用，我们使用包含大约20,000个重组蛋白的高密度蛋白质阵列，研究了免疫球蛋白和免疫球蛋白M自身抗体的存在及其靶点。检测到针对关键脑血管应激蛋白的高滴度自身抗体，包括FABP4、HSP70和Wnt信号蛋白。在SHR-A3(IgH-B2)同源系中，这些自身抗体水平降低。
The risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study we show the involvement of SHR genetic variation that affects antibody formation and function in the pathogenesis of stroke. We have tested the involvement in susceptibility to stroke of genetic variation in IgH, the gene encoding the immunoglobulin heavy chain by congenic substitution. This gene contains functional natural variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which the IgH gene was substituted with the corresponding haplotype from SHR-B2. Compared with SHR-A3 rats, congenic substitution of the IgH locus [SHR-A3(IgH-B2)] markedly reduced cerebrovascular disease. Given the role in antibody formation of the IgH gene, we investigated the presence of IgG and IgM autoantibodies and their targets using a high-density protein array containing similar to 20,000 recombinant proteins. High titers of autoantibodies to key cerebrovascular stress proteins were detected, including FABP4, HSP70, and Wnt signaling proteins. Serum levels of these autoantibodies were reduced in the SHR-A3(IgH-B2) congenic line.