Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease
Alon Monsonego, … , Dennis J. Selkoe, Howard L. Weiner
Alon Monsonego, … , Dennis J. Selkoe, Howard L. Weiner
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):415-422. https://doi.org/10.1172/JCI18104.
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Article Immunology

Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease

Abstract

Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid β protein (Aβ) in brain regions serving memory and cognition. In animal models of AD, immunization with Aβ results in the clearance of Aβ deposits from the brain. However, a trial of vaccination with synthetic human Aβ1–42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Aβ in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Aβ-reactive T cell responses than occurred in middle-aged adults. The immunodominant Aβ epitopes in humans resided in amino acids 16–33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Aβ in humans has implications for the design of Aβ vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.

Authors

Alon Monsonego, Victor Zota, Arnon Karni, Jeffery I. Krieger, Amit Bar-Or, Gal Bitan, Andrew E. Budson, Reisa Sperling, Dennis J. Selkoe, Howard L. Weiner

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Activated Aβ-reactive T cells exhibit Th1, Th2, and Th0 phenotypes after...
Activated Aβ-reactive T cells exhibit Th1, Th2, and Th0 phenotypes after stimulation with autologous PBMCs and Aβ peptides. Aβ-reactive T cells were established from a secondary stimulation assay as described in Methods. Resting cells were cultured with autologous PBMCs alone or stimulated in the presence of Aβ1–42, Aβ15–42, or Aβ1–28 and harvested after 30 hours. Cells were stained with Cy-chrome–labeled anti-CD4 and FITC-labeled anti-CD69 (a) followed by intracellular staining with phycoerythrin-labeled anti–IFN-γ, –IL-13, –IL-5, –IL-10, and –IL-12 (b). Cells also were stained with Cy-chrome–labeled anti-CD4 followed by intracellular staining with FITC-labeled anti–IFN-γ and phycoerythrin-labeled anti–IL-13 or anti–IL-5 (c). Positive cells were not observed when intracellular staining was performed with isotype controls (data not shown). For (b) and (c), analysis was gated on CD4+ cells. No Ag., no antigen.