Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease.
Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta 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 Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta 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 Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.
Monsonego
Alon
A
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Zota
Victor
V
Karni
Arnon
A
Krieger
Jeffery I
JI
Bar-Or
Amit
A
Bitan
Gal
G
Budson
Andrew E
AE
Sperling
Reisa
R
Selkoe
Dennis J
DJ
Weiner
Howard L
HL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D000544:Alzheimer Disease / Q000276:immunology*; D023582:Alzheimer Vaccines / Q000276:immunology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D018604:Epitope Mapping; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D001324:Autoantigens; D016207:Cytokines; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)