Immunological memory to hyperphosphorylated tau in asymptomatic individuals.
Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Gabriel
G
Pascual
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|Janssen R&D US, 3210 Merryfield Row, San Diego, CA, 92121, USA.
Jehangir S
JS
Wadia
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Xueyong
X
Zhu
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Elissa
E
Keogh
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Başak
B
Kükrer
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Jeroen
J
van Ameijde
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Hanna
H
Inganäs
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Berdien
B
Siregar
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Gerrard
G
Perdok
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Otto
O
Diefenbach
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Tariq
T
Nahar
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Imke
I
Sprengers
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Martin H
MH
Koldijk
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Els C Brinkman-van
EC
der Linden
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.
Laura A
LA
Peferoen
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Heng
H
Zhang
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Wenli
W
Yu
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Xinyi
X
Li
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|Janssen R&D US, 3210 Merryfield Row, San Diego, CA, 92121, USA.
Michelle
M
Wagner
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|Janssen R&D US, 3210 Merryfield Row, San Diego, CA, 92121, USA.
Veronica
V
Moreno
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Julie
J
Kim
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Martha
M
Costa
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 2 Royal College Street, London, NW1 0NH, UK.
Kiana
K
West
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|Informa, Pharma Intelligence, 3655 Nobel Drive, San Diego, CA, 92122, USA.
Zara
Z
Fulton
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|TTP Labtech Inc, One Kendall Square, Cambridge, MA, 02139-1594, USA.
Lucy
L
Chammas
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.|Cidara Therapeutics, 6310 Nancy Ridge Drive, San Diego, CA, 92121, USA.
Nancy
N
Luckashenak
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Lauren
L
Fletcher
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Trevin
T
Holland
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Carrie
C
Arnold
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 2 Royal College Street, London, NW1 0NH, UK.
R
R
Anthony Williamson
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.
Jeroen J
JJ
Hoozemans
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.
Adrian
A
Apetri
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210, Merryfield Row, San Diego, CA, 92121, USA.
Frederique
F
Bard
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.|Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Ian A
IA
Wilson
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands. WKoudsta@its.jnj.com.
Wouter
0000-0001-9845-9036
W
Koudstaal
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333 CN, Leiden, The Netherlands.|Department of Neurology, Amsterdam Neuroscience, Academic Medical Center, Meidreefberg 9, Amsterdam, 1105 AZ, The Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
Jaap
J
Goudsmit
D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology*; D000595:Amino Acid Sequence / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation; D055815:Young Adult; D016875:tau Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000939:Epitopes; C054369:MAPT protein, human; D016875:tau Proteins
Alzheimer’s disease; Memory B cell; Monoclonal antibody; Tau protein