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 ~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.

中文翻译：

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免疫球蛋白重链中的生殖系遗传变异在自发性高血压大鼠中产生中风敏感性。

中风易发性高血压大鼠（SHR-A3 / SHRSP）患脑血管疾病的风险来自自然发生的遗传变异。在本研究中，我们显示了SHR遗传变异参与中风发病机理中的抗体形成和功能的影响。我们已经测试了IgH遗传变异对卒中的易感性，IgH是通过同基因取代编码免疫球蛋白重链的基因。该基因在SHR-A3中包含功能性自然变异，与抗中风性SHR-B2不同。我们创建了一个SHR-A3同系品系，其中IgH基因被SHR-B2的相应单倍型取代。与SHR-A3大鼠相比，IgH基因座[SHR-A3（IgH-B2）]的同基因替代显着减少了脑血管疾病。鉴于IgH基因在抗体形成中的作用，我们使用包含约20,000个重组蛋白的高密度蛋白阵列研究了IgG和IgM自身抗体及其靶标的存在。检测到针对主要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。这些自身抗体的血清水平在SHR-A3（IgH-B2）同系中降低。