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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900620v1 183/5/3522    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zota, V. Articles by Monsonego, A. PubMed PubMed Citation Articles by Zota, V. Articles by Monsonego, A. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Alzheimer's Disease

HLA-DR Alleles in Amyloid β-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele¹

Victor Zota^2,*, Anna Nemirovsky^2,, Rona Baron, Yair Fisher, Dennis J. Selkoe^*, Daniel M. Altmann, Howard L. Weiner^* and Alon Monsonego^3,

^* Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA; The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, and The National Institute for Biotechnology, in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and Human Disease Immunogenetics Group, Department of Infectious Diseases and Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Alzheimer’s Association and the Israel Science Foundation.

² These authors contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Alon Monsonego, The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel. E-mail address: alonmon{at}bgu.ac.il

⁴ Abbreviations used in this paper: Aβ, amyloid β-peptide; AD, Alzheimer’s disease; APP, amyloid precursor protein; MHC-II, MHC class II; PTX, pertussis toxin; SI, stimulation index; Tg, transgenic.