SCIENCE science.orgGRAPHIC: KELLIE HOLOSKI/
SCIENCE
By M aria Krot1,2and Asya Rolls1,2L
ewy body dementia (LBD) is the sec-
ond most prevalent form of dementia.
In LBD, a neurodegenerative process
driven by pathological accumulation
of the presynaptic neuronal protein a-
synuclein in the central nervous system
(CNS) leads to motor and cognitive deficits
( 1 ). Existing therapies are unable to slow or
arrest the progression of LBD. T cells that are
reactive to a-synuclein were found in blood
samples of LBD patients ( 2 ), adding to the
evidence suggesting that the adaptive im-
mune system is involved in LBD pathogen-
esis. However, the role of T cells in the neuro-
degenerative process is still unclear, limiting
the potential of therapeutic intervention. On
page 868 of this issue, Gate et al. ( 3 ) demon-
strate the involvement of inflammatory and
autoimmune T helper 17 (TH17) cells in neu-
rodegeneration in LBD patients. A specific
signaling axis that induces TH17 cell traffick-
ing to the CNS could be a therapeutic target
for LBD.
The CNS is an immune-privileged site, con-
fined by barriers that were assumed to iso-
late it from the systemic immune response.
However, it is now clear that the immune sys-
tem is required for nervous system activity.
Because the immune system is much more
accessible for manipulation than the brain,
immune-modulating drugs could be repur-
posed to treat nervous system disorders—
for example, targeting inhibitory immunecheckpoints to unleash the adaptive immune
system to treat Alzheimer’s disease ( 4 ).
LBD encompasses two disorders, demen-
tia with Lewy bodies (DLB) and Parkinson’s
disease dementia (PDD), both characterized
by formation of Lewy bodies (abnormal
deposits of a-synuclein) in the brain and
progressive loss of dopaminergic neurons.
Gate et al. characterized T cell populations
in the cerebrospinal fluid (CSF) of PDD and
DLB patients relative to healthy controls us-
ing single-cell RNA sequencing (scRNA-seq).
In line with previous data showing higher
amounts of the pro-inflammatory cytokine
interleukin-17A (IL-17A) in the blood of LBD
patients ( 5 ), the authors revealed alterations
in a specific memory subset of TH17 cells in
the CSF of LBD patients.
TH17 cells are a proinflammatory CD4+ T
cell population that secretes mainly IL-17A
( 6 ). TH17 cells are involved in the pathogene-
sis of autoimmune diseases such as psoriasis,
rheumatoid arthritis, inflammatory bowel
disease, and multiple sclerosis (MS) ( 7 ). In
MS, for example, TH17 cells infiltrate the
brain, leading to autoimmunity, neuroinflam-
mation, and neurodegeneration ( 6 ). Gate et
al. propose that autoimmunity also plays
a role in LBD. They show that TH17 cells in
the CSF of LBD patients are more active, are
clonally expanded, and show higher activa-
tion levels after stimulation with a-synuclein
peptides ex vivo. The presence of a-synuclein-
reactive TH17 cells in the CSF of LBD patients
suggests that these cells may home to the
LBD brain and induce specific autoimmune
proinflammatory responses against a-synu-
clein deposits, leading to neuronal cell death
(see the figure). Indeed, Gate et al. confirmed
the presence of IL-17A–expressing CD4+ Tcells near dopaminergic neurons that were
undergoing neurodegeneration. Several ther-
apies are currently available to target TH 17
cells: Monoclonal antibodies that neutralize
IL-17A activity treat psoriasis ( 7 ), or monoclo-
nal antibodies that block cell adhesion mol-
ecules required for leukocyte trafficking to
the brain are a treatment for MS ( 8 ).
Although some studies show an increase
in T cell infiltration into the LBD brain ( 9 ),
it is not clear what mechanisms regulate the
trafficking of these cells. Chemokines, such as
C-X-C motif chemokine ligand 12 (CXCL12),
play a role in directing C-X-C motif chemo-
kine receptor 4 (CXCR4)–expressing immune
cells into the brain ( 10 ). Gate et al. found that
TH17 cells in the CSF of LBD patients highly
express CXCR4, suggesting that traffick-
ing of activated TH17 cells to the LBD brain
occurs through CXCR4-CXCL12 signaling.
In further support of this, Gate et al. found
CXCR4-expressing T cells that reside in the
perivascular space near CXCL12-expressing
cerebrovascular endothelial cells in post-
mortem PDD brains. Moreover, the CSF con-
centrations of CXCL12 were increased and
positively correlated with neurodegeneration
in PDD and DLB patients. Activation of the
CXCR4-CXCL12 axis has been implicated in a
variety of pathological conditions in the CNS,
including neurodegeneration and autoim-
munity. For example, expression of CXCL12
is up-regulated in microvessel endothelial
cells in MS lesions ( 11 ). The activation of this
pathway may reflect a potential endogenous
repair mechanism: It was suggested that in-
creased expression of CXCL12 by reactive vas-
culature in neurodegenerative lesions signals
the initiation of tissue repair by enhancing
recruitment of neural progenitor cells ( 12 ).NEURODEGENERATIONAutoimmunity in neurodegeneration
A signaling axis in adaptive immunity is a potential target in Lewy body dementia
(^1) Department of Immunology, Rappaport Faculty of
Medicine, Technion–Israel Institute of Technology, Haifa,
Israel.^2 Department of Neuroscience, Rappaport Faculty of
Medicine, Technion–Israel Institute of Technology, Haifa,
Israel. Email: [email protected]
Blood vessel lumen
Dendritic cells
Macrophages
I L-17 A
I L- 2 3
I L- 6
Transcription
factors
Homing
Adhesion
Differentiation
CXCL12
Antigen-
presenting
cell
I L-17 A
Dopaminergic
neuron
Lewy
body
Neuroaxonal
damage
Perivascular space Brain parenchyma
α−Synuclein
epitope
CXCR4
TH17 cell
Immunotherapy targets in Lewy body dementia
In Lewy body dementia (LBD), a proinflammatory subset of T helper 17 (TH17) cells recognizes a-synuclein, the major component in Lewy bodies. These T cells express
C-X-C motif chemokine receptor 4 (CXCR4) and infiltrate the brain through recognition of C-X-C motif chemokine ligand 12 (CXCL12) produced by endothelial cells.
Here, TH17 cells recognize a-synuclein epitopes and become activated, secreting the inflammatory cytokine interleukin-17A (IL-17A), potentially leading to autoimmune
neuroaxonal damage. Targeting TH17 differentiation or CXCR4-CXCL12–mediated homing to the brain are potential therapeutic strategies for LBD.
12 NOVEMBER 2021 • VOL 374 ISSUE 6569 823