Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease
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
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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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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Epitope specificity and cytokine profile of Aβ-reactive T cell lines. Sp...
Epitope specificity and cytokine profile of Aβ-reactive T cell lines. Split-well assays were performed as described in Methods. To generate Aβ-reactive T cell lines, positive wells were restimulated in the presence of irradiated PBMCs and Aβ and then maintained with 10 U/ml IL-2. To determine Aβ and epitope specificity, T cell lines were stimulated with Aβ1–42 and two overlapping peptides, Aβ1–28 or Aβ15–42, followed by their stimulation with nested peptides of the Aβ15–42 region. To measure Aβ-induced cytokine production, supernatants were collected 48 hours after stimulation and examined by ELISA. T cell proliferation of three representative lines is shown: (a–c) induced by Aβ1–42 (a and c) Aβ15–42, and (b) Aβ1–28. T cell proliferation was also induced by (d) Aβ16–30 (e) Aβ19–33, and (f) Aβ28–42. Aβ-induced secretion of IFN-γ and IL-13 is shown in g through l.