Germ-line genetic variation in the immunoglobulin heavy chain creates stroke susceptibility in the spontaneously hypertensive rat.

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.