PMID- 34648304
OWN - NLM
STAT- MEDLINE
DCOM- 20211119
LR  - 20220716
IS  - 1095-9203 (Electronic)
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 374
IP  - 6569
DP  - 2021 Nov 12
TI  - CD4(+) T cells contribute to neurodegeneration in Lewy body dementia.
PG  - 868-874
LID - 10.1126/science.abf7266 [doi]
AB  - Recent studies indicate that the adaptive immune system plays a role in Lewy body 
      dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is 
      unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic 
      neurons in postmortem LBD brains. Single-cell RNA sequencing of cerebrospinal 
      fluid (CSF) identified up-regulated expression of C-X-C motif chemokine receptor 
      4 (CXCR4) in CD4(+) T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C 
      motif chemokine ligand 12 (CXCL12), were associated with neuroaxonal damage in 
      LBD. Furthermore, we observed clonal expansion and up-regulated interleukin 17A 
      expression by CD4(+) T cells stimulated with a phosphorylated alpha-synuclein 
      epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for 
      inhibiting pathological interleukin-17-producing T cell trafficking in LBD.
FAU - Gate, David
AU  - Gate D
AUID- ORCID: 0000-0003-0481-9657
AD  - Department of Neurology, Northwestern University, Chicago, IL, USA.
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
FAU - Tapp, Emma
AU  - Tapp E
AUID- ORCID: 0000-0001-7900-5645
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
FAU - Leventhal, Olivia
AU  - Leventhal O
AUID- ORCID: 0000-0002-6371-9464
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
FAU - Shahid, Marian
AU  - Shahid M
AUID- ORCID: 0000-0002-8515-3238
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
FAU - Nonninger, Tim J
AU  - Nonninger TJ
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
FAU - Yang, Andrew C
AU  - Yang AC
AUID- ORCID: 0000-0002-6756-4746
AD  - Department of Bioengineering, Stanford University, Stanford, CA, USA.
AD  - Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford 
      University, Stanford, CA, USA.
FAU - Strempfl, Katharina
AU  - Strempfl K
AD  - Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 
      Salzburg, Austria.
AD  - Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical 
      University, Salzburg, Austria.
AD  - QPS Austria GmbH, Parkring 12, 8074 Grambach, Austria.
FAU - Unger, Michael S
AU  - Unger MS
AUID- ORCID: 0000-0002-8677-0983
AD  - Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 
      Salzburg, Austria.
AD  - Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical 
      University, Salzburg, Austria.
FAU - Fehlmann, Tobias
AU  - Fehlmann T
AUID- ORCID: 0000-0003-1967-2918
AD  - Chair for Clinical Bioinformatics, Saarland University, Saarbrucken, Germany.
FAU - Oh, Hamilton
AU  - Oh H
AUID- ORCID: 0000-0001-8192-7593
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
FAU - Channappa, Divya
AU  - Channappa D
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
FAU - Henderson, Victor W
AU  - Henderson VW
AUID- ORCID: 0000-0003-1198-9240
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
FAU - Keller, Andreas
AU  - Keller A
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Chair for Clinical Bioinformatics, Saarland University, Saarbrucken, Germany.
FAU - Aigner, Ludwig
AU  - Aigner L
AD  - Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 
      Salzburg, Austria.
AD  - Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical 
      University, Salzburg, Austria.
FAU - Galasko, Douglas R
AU  - Galasko DR
AUID- ORCID: 0000-0001-6195-3241
AD  - Department of Neurosciences, University of California, San Diego, La Jolla, CA, 
      USA.
FAU - Davis, Mark M
AU  - Davis MM
AUID- ORCID: 0000-0001-6868-657X
AD  - Department of Microbiology and Immunology, School of Medicine, Stanford 
      University, Stanford, CA, USA.
AD  - Howard Hughes Medical Institute, Stanford University School of Medicine, 
      Stanford, CA, USA.
FAU - Poston, Kathleen L
AU  - Poston KL
AUID- ORCID: 0000-0003-3424-7143
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
FAU - Wyss-Coray, Tony
AU  - Wyss-Coray T
AUID- ORCID: 0000-0001-5893-0831
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA, USA.
AD  - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
AD  - Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford 
      University, Stanford, CA, USA.
LA  - eng
GR  - R01 AG045034/AG/NIA NIH HHS/United States
GR  - U19 AG065156/AG/NIA NIH HHS/United States
GR  - U19 AI057229/AI/NIAID NIH HHS/United States
GR  - P50 NS062684/NS/NINDS NIH HHS/United States
GR  - P50 AG047366/AG/NIA NIH HHS/United States
GR  - R00 NS112458/NS/NINDS NIH HHS/United States
GR  - F32 AG055255/AG/NIA NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 NS115114/NS/NINDS NIH HHS/United States
GR  - P30 AG066515/AG/NIA NIH HHS/United States
GR  - K99 NS112458/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20211014
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (alpha-Synuclein)
SB  - IM
CIN - Nat Rev Neurol. 2021 Dec;17(12):726. PMID: 34754098
CIN - Science. 2021 Nov 12;374(6569):823-824. PMID: 34762456
CIN - Mov Disord. 2022 Feb;37(2):268. PMID: 34859506
MH  - Animals
MH  - Brain/blood supply/*immunology/metabolism/*pathology
MH  - CD4-Positive T-Lymphocytes/*immunology/metabolism
MH  - Cerebrospinal Fluid/immunology
MH  - Chemokine CXCL12/metabolism
MH  - Female
MH  - Humans
MH  - Lewy Body Disease/cerebrospinal fluid/*immunology/metabolism/*pathology
MH  - Lymphocyte Activation
MH  - Male
MH  - Meninges/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Nerve Degeneration
MH  - Receptors, CXCR4/genetics/metabolism
MH  - Signal Transduction
MH  - T-Lymphocyte Subsets/immunology
MH  - Th17 Cells/immunology
MH  - Up-Regulation
MH  - alpha-Synuclein/analysis
PMC - PMC9122025
MID - NIHMS1780000
COIS- Competing interests: K.L.P. has stock options and has received paid consulting 
      fees from CuraSen Therapeutics, Inc.
EDAT- 2021/10/15 06:00
MHDA- 2021/11/20 06:00
PMCR- 2022/05/20
CRDT- 2021/10/14 17:13
PHST- 2021/10/15 06:00 [pubmed]
PHST- 2021/11/20 06:00 [medline]
PHST- 2021/10/14 17:13 [entrez]
PHST- 2022/05/20 00:00 [pmc-release]
AID - 10.1126/science.abf7266 [doi]
PST - ppublish
SO  - Science. 2021 Nov 12;374(6569):868-874. doi: 10.1126/science.abf7266. Epub 2021 
      Oct 14.