HLA-DR alleles in amyloid β-peptide autoimmunity: A highly immunogenic role for the DRB1*1501 allele

Victor Zota, Anna Nemirovsky, Rona Baron, Yair Fisher, Dennis J. Selkoe, Daniel M. Altmann, Howard L. Weiner, Alon Monsonego

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Active amyloid β-peptide (Aβ) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in ∼6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Aβ Ab responses, which correlate with the extent of Aβ clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Aβ 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 Aβ-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of Aβ. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Aβ challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-γ 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, Aβ 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 Aβ 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 Aβ-reactive T cells and Aβ immunogenicity among humans.

Original languageEnglish
Pages (from-to)3522-3530
Number of pages9
JournalJournal of Immunology
Volume183
Issue number5
DOIs
StatePublished - 1 Sep 2009

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