HLA-DR Alleles in Amyloid beta-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele

Active amyloid beta-peptide (A beta) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in similar to 6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of A beta Ab responses, which correlate with the extent of A beta clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing A beta T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with A beta-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of A beta. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of A beta challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-gamma and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, A beta was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific A beta T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring A beta-reactive T cells and A beta immunogenicity among humans. The Journal of Immunology, 2009, 183: 3522-3530.