Abstract
Human leukocyte antigen (HLA), the most highly polymorphic region of the human genome, is increasingly recognized as an important genetic contributor to dementia risk and resilience. HLA is involved in protection against foreign antigens including human herpes viruses (HHV), which have been widely implicated in dementia. Here we used an in silico approach1 to determine binding affinities of glycoproteins from 9 human herpes virus (HHV) strains to 113 HLA alleles, and to examine the association of a previously identified HLA-dementia risk profile2 to those affinities. We found a highly significant correlation between high binding affinities of HLA alleles to HHV 3 and 7 and the dementia risk scores of those alleles, such that the higher the estimated binding affinity, the lower the dementia risk score. These findings suggest that protection conferred by HLA alleles may be related to their ability to bind and eliminate HHV3 and HHV7 and point to the possibility that protection against these viruses may reduce dementia incidence.
Highlights
The human leukocyte antigen (HLA) region is increasingly recognized as an important genetic contributor to dementia risk and resilience[2,3,4,5,6,7,8,9,10]
These findings suggest that protection conferred by Human leukocyte antigen (HLA) alleles may be related to their ability to bind and eliminate HHV3 and HHV7 and point to the possibility that protection against these viruses may reduce dementia incidence
We found that the HLA alleles that were protective against dementia had significantly higher binding affinity to human herpes viruses (HHV) epitopes than the neutral alleles, with the most significant differences found for HHV6 glycoproteins
Summary
The human leukocyte antigen (HLA) region is increasingly recognized as an important genetic contributor to dementia risk and resilience[2,3,4,5,6,7,8,9,10]. Class I HLA molecules (HLA-A, B, and C genes) present intracellular antigen peptides to CD8+ cytotoxic T cells to signal destruction of infected cells whereas Class II HLA molecules (HLA-DR, DQ, and DP genes) present endocytosed extracellular antigen peptides to CD4+ T cells to promote B-cell mediated antibody production and immune memory. These two classes of HLA work in concert to facilitate pathogen elimination. We have used a population immunogenetic epidemiological approach in 14
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