Articulo 1

REVIEWS
Inflammation and immune dysfunction

in Parkinson disease
Malú Gámez Tansey 1,2 ✉, Rebecca L. Wallings1, Madelyn C. Houser 3
,
Mary K. Herrick1, Cody E. Keating1 and Valerie Joers1
Abstract | Parkinson disease (PD) is a progressive neurodegenerative disease that affects
peripheral organs as well as the central nervous system and involves a fundamental role
of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies
support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover,
numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest
alterations in markers of inflammation and immune cell populations that could initiate or
exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of
disease genes and risk factors have been identified as modulators of immune function in PD
and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations
in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex
gene-by-environment interactions combine with an ageing immune system to create the
‘perfect storm’ that enables the development and progression of PD. We discuss the evidence
for this hypothesis and opportunities to harness the emerging immunological knowledge from
patients with PD to create better preclinical models with the long-term goal of enabling earlier
identification of at-risk individuals to prevent, delay and more effectively treat the disease.
Substantia nigra
Bidirectional communication between the brain and Most cases of PD are considered idiopathic; however,
The midbrain nucleus, which other organ systems is essential for brain health and the with the advancement of technology and accessibility
supplies the basal ganglia with overall health of the organism. Once thought to be to patient populations, the genetic architecture of PD
dopamine, involved in reward, immune privileged, the brain is now acknowledged is becoming further defined. Mutations in more than
motivation and addiction.
as a highly immune-specialized organ with its own 20 genes have been identified that cause monogenic forms
Bradykinesia brain-resident immune cells. These cells shape neuronal of PD6, yet they are rare and account for ~30% of famil-
Slowness of movement. circuitry1 and lymphatic and glymphatic systems that ial PD and only ~3–5% of sporadic cases7. Interestingly,
regulate the complex efflux of immune cells and fluids patients exhibiting the same genetic mutation typically
exchanging from the cerebrospinal space with the rest of do not have similar clinical presentations, suggesting that
the circulation2. The study of the crosstalk between the the aetiology of the disease is compounded by a complex
central and peripheral immune systems has intensified interaction among environmental, age-associated and
1
Department of Neuroscience, in recent decades. genetic factors (Fig. 1). Genome-wide association studies
Center for Translational Parkinson disease (PD) is a progressive neurode- (GWAS) have identified over 90 risk variants, and the
Research in Neurodegenerative
generative disorder pathologically characterized by variants explain ~22% of the heritability of the disease8.
Disease, University of
Florida College of Medicine,
the loss of dopaminergic neurons in the substantia nigra Of the significant single-nucleotide polymorphisms
Gainesville, FL, USA. and the presence of protein inclusions termed Lewy (SNPs), several are found in genes associated with the
2
Department of Neurology, bodies. Previously, the disease was largely considered function of the immune system8,9. Furthermore, previous
Norman Fixel Institute to be a movement disorder, classically characterized studies have found common genetic variants between
for Neurological Diseases, by a tetrad of motor deficits, including resting tremor, patients with PD and other autoimmune and inflam-
University of Florida Health,
bradykinesia, postural instability, and rigidity of the neck, matory diseases10, including Crohn’s disease11, further
Gainesville, FL, USA.
trunk and limbs. However, PD is now understood to be a suggesting the influence of the immune system in PD
3
Nell Hodgson Woodruff
School of Nursing, Emory
multi-system disorder with notable neuroinflammation pathogenesis. Additionally, exposure to environmental
University, Atlanta, GA, USA. and immune dysfunction that has been implicated in insecticides heightened immune responses in HLA-DR
✉e-mail: mgtansey@ufl.edu the development of various non-motor symptoms such variant carriers and increased disease risk 2.48-fold12.
https://doi.org/10.1038/ as sleep and gastrointestinal dysfunction, which can Together, these findings place the immune system at
s41577-022-00684-6 precede the disease diagnosis by decades3–5. the intersection between genetic and environment
NATure RevIeWS | ImmunoloGy volume 22 | November 2022 | 657
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interactions that confer risk for PD. In this Review, we studies and mention animal studies that have served to
discuss clinical evidence from genetic, pharmacologi- interrogate and validate pathways that could be targeted
cal, immunological, neuroimaging and epidemiological for therapeutic intervention to delay, prevent or treat PD.
Lewy body pathology burden
Braak stages 1 and 2

Olfactory and autonomic
disturbances
Number of dopaminergic Motor symptoms
neurons in substantia nigra
Early Advanced
stages stages Tremor Rigidity
Disease progression
Bradykinesia Dystonia
Braak stages 3 and 4 Postural

Gait apraxia
Sleep and motor instability
disturbances
Non-motor symptoms
Cognitive Visual
impairment impairment
–20 –10 0 10 20 Impaired Gastrointestinal

Diagnosis time (years) olfaction dysfunction
Braak stages 5 and 6
Emotional and cognitive Urogenital Sleep
disturbances dysfunction disorders
Depression, Speech and

anxiety swallowing
impairment
Ageing Gene Environment

Immune cell function • Immunosenescence • LRRK2 • TMEM175 • Infections
• Inflammageing • GBA • PARKIN • Diet
• Age-acquired • VPS35 • SNCA • Pesticides
autoimmunity • PINK1 • DJ1 • Altered gut microbiota
• HLA • Caffeine, tobacco
Immune cells
Young Elderly
Age
Memory T cell Treg cell Antibody production Cytokines

Memory B cell Naive B cell Macrophage phagocytosis
Myeloid cell Naive T cell Neutrophil chemotaxis
Fig. 1 | Immune cell ageing interacts with genetic and environmental and progression of PD pathogenesis. Age-associated alterations in the
stressors to accelerate PD pathology. Although primarily considered a immune system include immunosenescence and inflammageing as well as
motor-related disorder, Parkinson disease (PD) affects multiple systems, and an impaired adaptive immune system defined by a decline in naive
patients commonly present with accompanying non-motor symptoms, T cells and B cells and memory cell accumulation and a reduction in T cell
which often start in the prodromal phase. The concept of prodromal PD is receptor and B cell receptor diversity and sensitivity to stimuli13–15. These
supported by the Braak theory (blue box), in which Lewy body pathologies deficiencies contribute to an increase in susceptibility to infection and a
begin in the periphery and olfactory bulb and advance to the brainstem and type of age-acquired autoimmunity where autoantibodies may begin to
towards higher brain centres following a predictable caudal-rostral appear. There are now multiple lines of evidence that suggest a relationship
pattern204. During the prodromal stage, when neuronal dysfunction begins, between environmental stressors, including viral and bacterial exposures,
a combination of factors, from an ageing immune system, genes and pesticides, diet, and alterations in gut microbiota, and the increased risk of
environment, can create the perfect storm to enable the development developing PD. Treg cell, regulatory T cell.
658 | November 2022 | volume 22 www.nature.com/nri
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5 Chronic neuroinflammation including activated

microglia, infiltrates and pro-inflammatory cytokines
Person with PD
1
Dysbiosis and gut inflammation
Lewy
Intestinal microbes Gut lumen body
FcRγ
4 Peripheral cell infiltration across the blood–brain barrier
↑ ROS ↑ Pro-inflammatory
cytokines
↑ α-Synuclein
Gut lamina propria
HLA complex
2
↑ Circulating pro-inflammatory
cytokines
T cell
3
• Increased pro-inflammatory
T cells
• Increased pro-inflammatory Activated
macrophages microglia
• Increased classical monocytes
Monocyte
Activated
astrocyte Degenerating
Brain parenchyma neuron
Fig. 2 | Inflammatory manifestations in PD. The figure highlights inflammatory manifestations that have been identified
in patients with Parkinson disease (PD). Intestinal dysbiosis and inflammation (step 1), increases in levels of circulating
pro-inflammatory cytokines (step 2), innate and adaptive immune cell activation and changes in frequency (step 3),
blood–brain barrier permeability and peripheral immune cell infiltration of the central nervous system (step 4) and
neuroinflammation (step 5) are hallmarks of a pro-inflammatory immune phenotype in PD. ROS, reactive oxygen species.
Inflammation in PD pathogenesis and progression One of the first pieces of evidence linking neuroinflam-
Considering age is the greatest risk factor for many neuro- mation to the pathogenesis of PD came in 1988, when
degenerative diseases, the ageing of the immune system is McGeer et al. showed HLA-DR+ reactive microglia in
the most underappreciated and understudied contributing post mortem tissue from patients who had PD18. The
factor in the neurodegeneration field. Immunosenescence number of HLA-DR+ microglia increases with neuronal
is characterized by two primary features, namely an degeneration throughout the nigrostriatal pathway19.
age-acquired immunodeficiency and inflammageing . Activated microglia are partially responsible for the ele-
Inflammageing is characterized by excess low-level vated levels of TNF, IL-1β, TGFβ, IL-6, reactive oxygen
production of circulating inflammatory mediators, or species (ROS), nitric oxide species and pro-apoptotic
cytokines — most notably C-reactive protein (CRP), IL-6 proteins found in the substantia nigra pars compacta,
and tumour necrosis factor (TNF) — from chronically striatum, and cerebrospinal fluid (CSF) of patients
stimulated innate and adaptive immune cells13–15. Both with PD20,21. In vivo evaluation of microglial activity
the innate and adaptive immune systems lose competence has been performed using positron emission tomogra-
with ageing and are also notably altered in PD16,17 (Fig. 2). phy (PET) ligands to measure and trace neuroinflam-
mation in the brains of patients with PD. The use of
Inflammageing
Innate immunity. Microglia are densely populated ligands such as [11C](R)-PK11195, which binds trans-
Low-grade inflammation that in the substantia nigra pars compacta and striatum locator protein (TSPO, formerly known as the periph-
occurs during ageing. of the brain — areas that are both affected in PD. eral benzodiazepine receptor), a receptor which was
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considered selectively expressed on activated microglia, Adaptive immunity. Ample evidence suggests a role for
showed increased microglial activation in the brains of adaptive immunity in disease pathogenesis. In the same
patients with PD but the levels of microglial activation incipient study that identified HLA-DR+ microglia in the
did not correlate with clinical severity22,23. Usage of this brains of patients with PD, McGeer et al. showed that
first-generation PET ligand allowed researchers to con- CD3+ T cells infiltrate the brains of patients with PD, a
clude that microglia are activated early in the disease finding which has been replicated in other studies and
process, leaving them to promote neuroinflammation in animal models18,38. Subsequent studies have focused
in vulnerable PD-associated brain regions. However, on T cell subsets in the brain and in the periphery to
the accuracy and interpretation of TSPO radioligand understand their role in the inflammatory pathogen-
binding may be influenced by a number of issues such esis associated with PD. In the brain, CD4+ and CD8+
as TSPO polymorphisms found with second-generation T cells were present in the substantia nigra pars com-
ligands, low TSPO density in the healthy brain and pacta of patients with PD at greater levels than in con-
multicellular expression, including infiltrating cells from trol patients38. Peripherally, multiple studies, including a
the periphery24. New, more accurate targets are necessary meta-analysis of 943 cases of PD, have identified a reduc-
to ensure microglia specificity and function. tion in circulating CD4+ T cells in patients39,40. More
Historically, microglia in the areas of neurodegener- specifically, HLA-DR+ T cells and CD45RO+ memory
ation have been termed ‘activated’ due to their ameboid T cells have been shown to be increased in patients with
morphology, a description often perceived as a dam- PD relative to healthy controls, while naive CD4+ T cells
aging inflammatory state. However, evidence suggests are reduced, and mixed results have been reported on
that microglia present along a spectrum of phenotypes the frequency of CD25+ regulatory T (Treg) cells40–42.
and play a number of distinct roles in PD pathogene- CD4+FOXP3+ Treg cells have increased suppressive activ-
sis. For example, microglia can contribute to neuronal ity in patients with PD43. This correlates with the finding
death through the production of inflammatory factors, that dopamine, which is deficient in patients with PD,
they may interact with α-synuclein to contribute to lowers Treg cell function40,44. Other functional studies
α-synuclein propagation and aggregation or can alter- have not demonstrated a difference between patients
natively have protective functions through production treated with dopamine-replacement medication com-
of neurotrophic factors25,26. Dysfunctional phagocytosis pared to untreated patients, suggesting that dopaminer-
in glial cells due to lysosomal defects imparted by gic drugs may not alter T cell activity42,43. Interestingly,
PD-related mutations may be one mechanism that the expression of specific dopamine receptors found on
contributes to microgliosis and neuroinflammation27. T cell subsets correlates with disease severity in patients
Extracellular α-synuclein can directly activate micro- with PD, highlighting a potential role of immune cell
glia in a conformation-specific and mutation-specific dopamine receptors in the development or progression
context, such that α-synuclein fibrils and mutations of PD45,46. T cell dysregulation in PD has been suggested
associated with early-onset PD induce the most robust as T cells exhibit increased TNF receptor expression47
immune responses in BV2 microglial-like cells28,29. The along with increased production of IFNγ and TNF
NOD-, LRR- and pyrin domain-containing 3 (NLRP3) by effector T cells, even in the presence of Treg cells42.
inflammasome signalling in microglia is a multiprotein In 2017, a ground-breaking study by Sulzer et al. was
complex involved in the activation of a pro-inflammatory the first to suggest that, in patients with PD, specific
state30. In PD models, NLRP3 inflammasome signalling T cell subsets — mainly CD4+ T cells — recognized cer-
in microglia is reportedly triggered by α-synuclein31 and tain α-synuclein peptides48, further supporting a role of
different α-synuclein species lead to specific NLRP3 adaptive immunity in PD pathogenesis. A more recent
inflammasome microglial responses, which can com- study has identified that α-synuclein T cell immunore-
prise α-synuclein degradation32, indicating its potential activity in peripheral blood mononuclear cells is associ-
role in PD. ated with preclinical and early motor PD, suggesting that
In addition to microglia, monocytes may contrib- monitoring this in at-risk populations could potentially
ute to disease pathogenesis. Within the total monocyte enable earlier detection of disease49. Although there are
population, frequencies of classical CD14+CD16– mono- discrepancies between findings in T cell populations
cytes are elevated in patients with PD, and these cells dis- concerning their dysregulation and their roles in PD
play an altered transcriptome33. CC-chemokine ligand 2 pathogenesis, some of the variability may be explained
(CCL2) is upregulated in patients with PD, suggesting by the heterogenous nature of the patient populations
an increase in monocyte recruitment and inflamma- that were evaluated in these studies. It remains clear that
tion. Leucine-rich repeat kinase 2 (LRRK2) levels are dysregulation in immune cell trafficking can promote a
elevated in monocyte populations from patients with pro-inflammatory environment that can contribute to
PD and contribute to monocyte dysregulation 34,35. the neuronal cell death associated with PD.
Distinct gene expression patterns of monocytes have The role of B cells in PD is less well understood
been noted in patients in early stages of the disorder, and is being actively explored. Reports suggest that
including genes involved in immune activation such as B cells are reduced in number in the blood of patients
HLA-DQB1, MYD88, REL and TNF 36. More recently, a with PD relative to controls 50,51 but these findings
transcriptome-wide association study positively iden- are not consistent across studies52. IgG deposits have
tified gene associations between lysosomal pathways been found on dopaminergic neurons in the brain,
and innate immune function in dorsolateral prefrontal and the IgG receptor FcγRI was found on activated
cortex and peripheral monocytes as risk factors for PD37. microglia53, suggesting that humoral immunity may
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play a role in neuroinflammation and neurodegener- neurodegenerative effects between lipopolysaccharide

ation. Autoantibodies against α-synuclein, dopamine (LPS)-induced inflammation involving IFNγ pathways
and melanin are present in the sera and CSF of patients and mutant LRRK2 in mice78 and in metabolic repro-
with PD54,55. The levels of α-synuclein autoantibodies in gramming of neurotoxic microglia from patient-derived
CSF and plasma in patients with mild or moderate PD induced pluripotent stem cells79. Interestingly, LRRK2
have been correlated with disease activity, supporting is an IFNγ target gene regulated in immune cells in
the hypothesis that α-synuclein autoantibodies could response to pathogens80–82; genetic polymorphisms
serve as a potential biomarker for PD56. Previous infec- in LRRK2 (discussed below) have been associated with
tions may be linked to the production of autoantibod- Crohn’s disease and leprosy, suggesting that patho-
ies through molecular mimicry as has been suggested genic mechanisms may be common to certain chronic
for infections with herpes simplex virus 1 (HSV1) and inflammatory conditions, infections and PD.
Helicobacter pylori 57,58.
Genetic evidence of immune involvement
Cytokines in PD. Collectively, data from the innate Although age remains the greatest risk factor for devel-
and adaptive immune systems provide evidence that oping sporadic PD, mutations in several genes cause
immune dysregulation in both the periphery and brain autosomal dominant and autosomal recessive mono-
can cause upregulation of inflammatory cytokines that genic forms of PD. Several genetic variants that modu-
initiate a cascade of pro-inflammatory signalling events late the risk of idiopathic disease have been identified;
that ultimately result in the neurotoxicity that is asso- some of these genes, including LRRK2, SNCA (which
ciated with PD. In a similar manner to what has been encodes α-synuclein), GBA (which encodes glucocere-
observed in the brain, levels of the pro-inflammatory brosidase (GBA); also known as lysosomal acid gluco-
cytokines TNF, IFNγ, IL-1β, IL-6, IL-2, CXC-chemokine sylceramidase), PRKN (encoding E3 ubiquitin-protein
ligand 8 (CXCL8) and CCL2 are elevated in the serum ligase parkin) and PINK1 (encoding PTEN-induced
of patients with PD and correlate with disease severity kinase 1 (PINK1)), encode proteins that also modulate
and disability59,60. This may be a consequence of altered immune function. The fundamentals of these genetic
lymphocyte populations that contribute to immune cell findings in PD are described in Box 1.
dysregulation as higher levels of IFNγ-producing T cells
relative to IL-4-producing T cells have been identified, LRRK2 variants in PD. Mutations in the gene encod-
which is in accordance with a reduced CD4 to CD8 ing LRRK2 are the most common cause of familial PD
T cell ratio in patients with PD61. and explain ~1% of sporadic cases83–85. LRRK2 expres-
While a number of different signalling pathways have sion is tightly regulated in peripheral immune cells
been implicated in PD pathogenesis, two of the ones and increases in response to microbial pathogens in
that have received increasing attention are the IFNγ human B cells, T cells, macrophages and non-classical
(also called type II interferon) and TNF pathways62. monocytes34,81,86,87. Furthermore, LRRK2 is a member
Multiple studies have reported TNF to be elevated in of the receptor interacting protein (RIP) kinase family,
the sera, CSF and brains of patients with PD19,20,63–66, and which is a group of proteins that detect and respond to
consistent with a role for TNF in nigral degeneration, cellular stress by regulating cell death and activation of
selective neutralization of soluble TNF signalling signif- the immune system88.
icantly attenuates dopaminergic (DA) neuron death in To date, eight pathogenic mutations have been iden-
rodent models67–70. As described in more detail below, tified in LRRK2 in patients with PD, with the G2019S
epidemiological evidence suggests that TNF signalling mutation being the most common89, as well as two
in individuals with autoimmune diseases is linked to non-coding variants that confer a twofold increase in the
increased risk of developing PD, whereas anti-TNF ther- risk for disease90. The G2019S mutation has consistently
apy in patients with autoimmunity has been associated been reported to increase LRRK2 kinase activity91–93,
with a decreased risk for PD71. Notably, as TNF is pro- which is associated with neuronal toxicity94,95. Peripheral
duced by intestinal epithelial cells72, it may alter the gut pro-inflammatory cytokine levels are higher in a sub-
environment, impacting inflammation and α-synuclein set of asymptomatic individuals carrying the G2019S
accumulation. mutation96. Taken together with the fact that overall
A significant amount of evidence implicates IFNγ LRRK2 levels are increased in immune cells of patients
signalling in PD pathophysiology. Near the end of with sporadic PD34, it is suggested that inflammation
World War I in 1918, an influenza pandemic gave rise plays an early role in the disease and may be driven
to a high incidence of postencephalitic parkinsonism, by increased LRRK2 kinase activity. This patholog-
suggesting vulnerability of basal ganglia DA neurons to ical mechanism is further supported by reports that
pathogen-driven immune response73, and a type II inter- LRRK2 toxicity, both in vitro and in vivo, is ameliorated
feron response was directly implicated by transcriptomic following pharmacological LRRK2 kinase inhibition97.
analysis in the selective vulnerability of DA neurons74. Interestingly, LRRK2 expression is also associated
In the midbrain regions of patients with PD, higher with a number of bacterial infections and infectious
levels of IFNγ have been reported along with signifi- diseases. Meta-analysis of human cell gene expression
cant co-expression of α-synuclein75. Preclinical rodent in response to a Mycobacterium tuberculosis infec-
models of PD-like degeneration have also implicated tion identified LRRK2 as a highly significant differen-
IFNγ signalling in progressive DA neuron death76,77. tially enriched gene98. Furthermore, Lrrk2-knockout
Two recent studies have demonstrated synergistic mice showed limited bacterial burdens and enhanced
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Box 1 | PD genetics indicate a role of the immune system in pathogenesis

A brief overview of the biological relevance of genetic variants that modulate the risk of idiopathic Parkinson disease
(PD) (see the figure) is provided below; their link to immune mechanisms is described in more detail in the main text.
GBA, PRKN and PINK1, SNCA, VPS35, and PARK7
The GBA gene encodes for the lysosomal enzyme glucocerebrosidase that mediates conversion of glucocerebroside to
glucose and ceramide. Heterozygous GBA mutation carriers have an increased risk of developing PD254; GBA mutations
are now identified as the most common genetic risk factor for PD255. The PRKN and PINK1 genes are two of the most
well-characterized autosomal recessive genes associated with PD256,257. Five missense point mutations, A30P258, E46K259,
H50Q260, G51D261 and A53T262, in the α-synuclein encoding gene SNCA may cause autosomal dominant PD. Moreover,
duplication and triplication of the α-synuclein gene locus has been described in familial and sporadic PD263 and in dementia
with Lewy bodies125,255,264,265. Heterozygous changes in the gene encoding the VPS35 cargo-binding component of the
retromer complex are associated with late-onset PD266,267, with D620N being the only mutation characterized to date268,269.
Mutations in the PARK7 gene, which encodes DJ1, cause autosomal-recessive PD270. DJ1 is a multifunctional redox-sensitive
protein that may mediate neuroprotection by dampening mitochondrial oxidative stress271 and regulating anti-apoptotic
and anti-oxidative gene expression272,273.
BST1, SYT11, TMEM175 and GRN
Genome-wide association studies have linked several further candidate genes with PD risk, with several of these genes
related to the immune system. The immune-associated gene BST1 has been proposed to play a role in neutrophil
adhesion and migration and may cause selective vulnerability of dopaminergic neurons in PD274. Synaptotagmin 11,
encoded by SYT11, localizes to the trans-Golgi network and recycling endosomes and is involved in cytokine secretion
and phagocytosis in microglia275. TMEM175 encodes a lysosomal K+ channel that stabilizes lysosomal pH and regulates
lysosome catalytic activity52,276. The GRN gene encodes progranulin (PGRN), the precursor to granulins, which possess
cytokine-like activity and regulate cellular proliferation, growth and tumorigenicity.
IL-1R2 Lysosome
GRN,
GPNMB
SCARB2
TNF,
IL-1β
TLR9 B cell
GBA
Endosome
Resting
microglia
Parkin,
PINK1,
GBA,
LRRK2,
VPS35, Phagosome
DJ1 SCARB2
IFNγ
SYT11
IL-6
Activated
microglia
DJ1
α-Synuclein
VPS35 mTOR–
HLA
AKT
LRRK2
T cell
Monocyte
GBA, glucocerebrosidase; GPNMB, glycoprotein NMB; PINK1, PTEN-induced kinase 1; TLR9, Toll-like receptor 9; TNF, tumour
necrosis factor.
inflammatory profiles, suggesting that LRRK2 may mice harbouring the G2019S mutation showed improved
control innate immune pathways following M. tuber- control of S. typhimurium infection with reduced
culosis infection99. LRRK2 has also been implicated bacterial growth and longer survival during sepsis.
in the regulation of the enteric pathogens Salmonella However, animals with the G2019S mutation that were
typhimurium100 and Listeria monocytogenes101. Knock-in subjected to reovirus-induced encephalitis exhibited
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increased mortality and had elevated ROS produc- found on the outer mitochondrial membrane with
tion and concentrations of α-synuclein in the brain102, K63-linked polyubiquitin chains, targeting these mito-
potentially suggesting antagonistic pleiotropic effects of chondria for lysosomal degradation. A loss of Pink1 or
the G2019S mutation. Similar effects are seen with the Prkn dysregulates mitophagy and increases mitochon-
gain-of-kinase function R1628P mutation, which is a dria stress, mitochondrial ROS and mitochondrial DNA
risk variant for PD but protective for leprosy, and asso- (mtDNA)119. Mito-inflammation has recently been directly
ciated with excessive inflammatory type 1 reactions103,104. connected to PD-like pathology in mice deficient in
These data highlight the versatility of LRRK2 in regu- Pink1 or Prkn that are subjected to acute (exhaus-
lating immune responses and imply potential opposing tive exercise induced) or chronic (mtDNA mutation
effects of LRRK2 kinase-mediated inflammation in the induced) mitochondrial stress120. This mitochondrial
central nervous system (CNS) versus the periphery that stress induced dopaminergic neurodegeneration in the
may also be dependent on additional complex genetic substantia nigra pars compacta in the absence of Prkn or
interactions (Box 2). Pink1 and increased pro-inflammatory cytokines in the
serum. These phenotypes were successfully rescued by
GBA mutations in PD. The neurodegenerative man- the genetic inactivation of Sting1, a component of the
ifestations of GBA-associated PD may arise from the DNA-sensing cyclic GMP–AMP synthase (cGAS)–
toxic effects of accumulated lipids, autophagic pertur- STING innate immune pathway that can be activated
bations and endoplasmic reticulum stress in neurons105. by mtDNA from damaged mitochondria121. STING
However, it is becoming more apparent that inflamma- signalling also exacerbates progression in other models
tion plays a key role in the pathology of GBA-associated of chronic neurodegenerative disease such as the ME7
PD. For example, selective deletion of GBA in neurons, prion disease model122. Nazmi et al. confirmed STING as
oligodendrocytes and astrocytes of mice increased a critical driver of type I interferon-mediated neurode-
inflammatory cytokine production, oxidative stress and generation and, in this model, mice deficient in STING
morphologically active microglia despite normal micro- or IFNAR1 displayed attenuated neuroinflammation122.
glial GBA expression106,107. Furthermore, deletion of the Interestingly, Lrrk2-/- macrophages exhibit chronic cGAS
Ripk3 gene (which encodes for the receptor-interacting engagement caused by mtDNA leakage into the cytosol,
kinase 3 that is essential for programmed cell death leading to altered innate immune gene expression123.
in response to TNF) attenuates microglial cell acti- These reports highlight a convergence between
vation and motor impairment upon glucocerebrosi- PD-associated genes and emphasize an important con-
dase (GCase) inhibition in mice108. Additionally, mice nection between mitochondrial stress and inflammation
expressing the L444P point mutation in the Gba gene in the context of PD.
exhibit multisystem inflammation, including evidence As in mito-inflammation, both PINK1 and parkin
of B cell hyperproliferation109. have been implicated in adaptive immunity via pres-
Induced pluripotent stem cell-derived macro entation of mitochondrial antigens. Although antigen
phages from individuals with a GBA mutation exhibit presentation can be mediated by autophagy, mitochon-
increased upregulation of TNF mRNA expression drial antigen presentation relies on the generation and
upon LPS stimulation110 and secrete higher levels of the trafficking of mitochondrially derived vesicles124. With
pro-inflammatory cytokines TNF, IL-6 and IL-1β111. the knockdown of Pink1, the amount of glycoprotein B
Patients with GBA-associated PD have higher plasma of HSV1 targeted to the mitochondrial matrix is upreg-
levels of CXCL8, CCL2 and CCL3 (also known as ulated in a murine macrophage cell line, with the over-
MIP1α) than patients with idiopathic PD112, suggesting expression of parkin eliciting the opposite phenotype124.
GBA may alter the immune environment. Additionally, Furthermore, when CD11c+ dendritic cells isolated from
enzymatic GBA activity is significantly reduced in mono- Pink1 or Prkn-knockout mice were treated with a single
cytes from both patients with idiopathic PD and patients dose of LPS, they exhibited increased presentation of an
with GBA-associated PD compared to controls113, sug- endogenous mitochondrial antigen, the mitochondrial
gesting that GBA dysfunction in immune cells may be matrix protein 2-oxoglutarate de-hydrogenase, relative
instrumental in both idiopathic and GBA-associated PD. to wild type controls. Such data provide support for a
Mitophagy non-cell-autonomous model in which autoimmune
The selective degradation of PRKN and PINK1 mutations in PD. Seventy-nine dif- mechanisms mediated by mitochondria-specific cyto-
mitochondria by autophagy. ferent PRKN mutations have been reported in familial toxic T cell activity may contribute to pathology in
Mito-inflammation
and sporadic PD, and these mutations are the most com- PRKN-associated and PINK1-associated PD. In addi-
Inflammation that arises mon cause of autosomal recessive early-onset cases114. tion to this role of PINK1 and parkin in mitochondrial
through mitochondrial The second most common cause are mutations in the quality control, the loss of their activity during PD may
pathways. PINK1 gene115, which are typically missense mutations, increase mitochondrial antigen presentation during
though copy number variants and exonic rearrange- inflammation. In support of this, intestinal infection
Substantia nigra pars
compacta ments, such as the homozygous deletion of exon 7, with Gram-negative bacteria in Pink1−/− mice engages
An area of the substantia have been described116–118. Parkin, a cytosolic protein, mitochondrial antigen presentation and autoimmune
nigra that contains the majority mediates mitophagy in conjunction with the ubiquitin mechanisms that elicit the establishment of cytotoxic
of neuromelanin-containing kinase PINK1. PINK1 accumulates on the outer mito- mitochondria-specific CD8+ T cells in the periphery
dopaminergic neurons, as
opposed to the pars reticulata,
chondrial membrane when mitochondria are damaged and in the brain124. Furthermore, these mice show a
which is comprised of mainly or depolarized. It assists in the recruitment of parkin to decrease in the density of dopaminergic axons in the
GABAergic neurons. mitochondria, where parkin then ubiquitinates proteins striatum, increased infiltrating monocytes and T cells
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Box 2 | Genes, risk factors and modifiers in PD converge on the lysosome

Many Parkinson disease (PD)-associated genes identified by familial Mendelian inheritance patterns (such as LRRK2,
ATP13A2, PINK1, PRKN, RAB39B and SCNA) have roles in lysosomal function. Candidate risk genes for PD, such as
TMEM175, TMEM230, CTSB, VPS13C, GBA, SYT11 and ATP6V0A1, are also linked with lysosomal functions149,150, with
a significant proportion of rare lysosomal disorder gene variants associated with PD risk277. These genes have been
implicated in various aspects of autophagy and lysosomal function, including in regulation of lysosomal pH, vesicular
trafficking, autophagosome biogenesis, phagocytosis and cargo-specific autophagy278–280 (see the figure). Such
cellular processes are crucial for efficient immune cell function but detailed mechanistic insight into the roles of these
PD-associated genes in inflammation remains lacking.
The involvement of aberrant microglial phagocytosis in PD is supported by the fact that microglia uptake and
remove dopaminergic neuronal cell debris in vivo and can engulf α-synuclein possibly via Toll-like receptor 4 (TLR4)281,282.
Extracellular α-synuclein can directly activate microglia, with α-synuclein fibrils and mutations associated with
early-onset PD leading to the most robust levels of immune activation in BV2 microglial-like cells283. Furthermore,
PD-associated genes have been shown to regulate phagocytosis in microglia82,284,285 and macrophages99,286,287.
However, the precise contribution of microglial to PD is still unknown.
It was recently shown that LRRK2 is recruited to ruptured lysosomal membranes and induces lysosomal tubule formation
(LTF), with increased LTF observed with the G2019S mutation288. Lysosomal tubules are crucial for two immune-related
functions: phagocytosis and antigen presentation289,290. This is intriguing as LRRK2 has been heavily implicated in
modulating phagocytosis284 and LRRK2 expression is also positively correlated with HLA-DR expression in human
monocytes34. Whether LTF is the mechanism underlying LRRK2’s role in antigen presentation is yet to be determined
and is an interesting avenue of research.
A recent report showed that inhibition of LRRK2 kinase activity normalizes lysosomal dysfunction and inflammatory
responses in GbaD409V knock-in mouse astrocytes291, suggesting functional interaction of LRRK2 and glucocerebrosidase
at the lysosome. Of note, astrocytes are crucial regulators of innate and adaptive immune responses in the injured central
nervous system292. Additionally, the frequency and incomplete penetrance of the LRRK2G2019S mutation293–295 strongly
suggests a role for environmental triggers or genetic modulators of risk296. Interestingly, the endolysosomal protein
Coronin 1C (CORO1C)297 has recently been identified as a modifier of LRRK2 penetrance in North Americans and
Europeans298. These data strongly support a functional interaction between these two proteins, as CORO1C expression
is markedly altered in LRRK2-deficient tissue299. Whether these interactions are functionally relevant in innate and
adaptive immune cells and their inflammatory responses is currently unknown but is of interest for future research.
From these findings, it is evident that a significant number of genes associated with PD are implicated in cellular
functions critical for endolysosomal trafficking and protein sorting in immune cells. The challenge remains to understand
how these genes mechanistically contribute to PD development.
α-Synuclein
LRRK2
LRRK2
Early
endosome
RAB39B
Stressed SYT11
LRRK2 lysosome
TMEM175 Phagosome
CORO1C
ATP13A2 VPS13C
Phagophore
H+
LRRK2
ATP6VOA1
LRRK2 CTSB/D
Damaged
PINK1 mitochondria GBA
GRN LRRK2
Parkin TMEM230
Autophagosome VPS35
Lysosome
trans-Golgi
ROS network
DJ1 ER
Mitochondria
PD risk
PD gene PD modifier Ubiquitin
factor
ER, endoplasmic reticulum; GBA, glucocerebrosidase; PINK1, PTEN-induced kinase 1; ROS, reactive oxygen species.
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into the CNS, and are affected by motor impairment. idiopathic PD and healthy controls142. Such data sup-
Collectively, these data support the idea that PINK1 is port the idea that the D620N mutation results in a toxic
a repressor of the immune system and provide a patho- gain-of-function in an upstream regulator of the LRRK2
physiological model in which intestinal infection acts as kinase pathway. How this interaction and PD-associated
a triggering event in PD, highlighting the relevance of mutations affect neutrophil and monocyte function has
the gut–brain axis in the disease. yet to be elucidated.
SNCA in PD. Due to the earlier onset and more rapid PARK7 in PD. DJ1, which is encoded by PARK7, regu-
disease progression observed in patients with SNCA lates TLR signalling in mouse primary astrocytes, sug-
gene triplications relative to those with duplications, gesting that DJ1 may play a role in innate immunity143.
a dosage effect of the SNCA gene is expected125. Such Indeed, DJ1-deficient Caenorhabditis elegans exposed to
observations indicate a neurotoxic effect of increased pathogenic Pseudomonas aeruginosa exhibit increased
α-synuclein, even when point mutations are not pres- p38 phosphorylation and hyper-induction of PMK1 tar-
ent, and have prompted the development of various get genes144, which are genes implicated in innate immu-
animal models of overexpression. Overexpression of nity in C. elegans145. More recently, it has been revealed
α-synuclein in dopaminergic neurons of the substantia that DJ1-deficient mice exhibit decreased generation
nigra pars compacta in an adeno-associated virus mouse of thymus-derived Treg cells and generate increased
model of PD robustly induces neuroinflammation126–128. levels of ROS146. Interestingly, DJ1-deficient Treg cells
This model also results in substantial infiltration of had higher levels of AKT–mTOR signalling and were
pro-inflammatory CC-chemokine receptor 2 (CCR2)+ less sensitive to TGFβ and IL-2. Treg cells are thought to
peripheral monocytes into the CNS, and genetic knock- be neuroprotective in PD via their role in suppressing
out of Ccr2 prevents α-synuclein-induced inflam- the inflammatory activity of microglial cells exposed to
mation and neuronal degeneration129. Furthermore, oxidative stress and inflammation147. Coupled with the
when in contact with α-synuclein fibrils or oligomers, observation that loss of DJ1 leads to constitutively active
both astrocytes and microglia exhibit increased BV2 microglia148, this suggests a mechanism behind the
neurotoxicity26,130–132. neuroprotective effects of DJ1 in PD.
Increased expression of α-synuclein also affects
immune cells outside the CNS. For example, α-synuclein PD risk factor SNPs and genes are associated with the
peptides can stimulate the secretion of TNF in lympho- immune system. In addition to the genetic mutations dis-
cytes from patients with PD but not from controls133 cussed above, 91 genes and/or risk loci for PD have been
and can trigger helper and cytotoxic T cells to secrete identified from GWAS9,149,150, with several of the candidate
cytokines, including IFNγ, IL-2 and IL-5 (ref.48). Fibrillar genes associated with the immune system (Box 1).
α-synuclein can act via Toll-like receptor (TLR) and Although the association between PD and the
inflammasome pathways in monocytes, leading to IL-1β HLA region is complex, the hits at HLA-DRB6 and
production134. Similarly, human peripheral blood mono HLA-DQA1 may imply regulation of antigen presenta-
nuclear cells increase inflammasome-related cytokines tion as a potential mechanism by which the immune
in response to treatment with α-synuclein monomers response links environmental factors to genetic
or fibrils135. Such data imply that increased α-synuclein susceptibility in conferring risk for PD 12. Indeed,
expression, in the form of monomers or fibrils, may α-synuclein-derived fragments may act as antigenic
stimulate cytokine production in the periphery, which epitopes displayed by MHC molecules48. Several SNPs
may be a major contributor to immune activation in PD. around the GPNMB gene (encoding glycoprotein NMB
Multiple lines of evidence indicate that inflammation (GPNMB)) have been linked to risk for developing
associated with infection triggers increased α-synuclein PD150,151. It has been suggested that GPNMB may reg-
expression in vivo, with examples including norovirus ulate systemic immune responses, including inhibition
infection in the human gastrointestinal tract136 and West of T cell activation and reducing macrophage inflam-
Nile virus in mice137. In preclinical models, LPS can matory responses to LPS152,153. Although the function
trigger increased α-synuclein expression138,139, which of transmembrane protein 175 (TMEM175) has been
may be a structurally distinct fibril strain that induces recently characterized in neurons, with TMEM175
specific pathological patterns of synucleinopathies in deficiency decreasing GCase activity and impairing
mice140. These reports suggest that α-synuclein may have lysosome-dependent clearance of α-synuclein fibrils154,
a bidirectional relationship with inflammation or that an TMEM175 function in glial and immune cells is not well
inflamed environment may affect α-synuclein processing. understood. Given that TMEM175 is heavily implicated
in the lysosomal pathway, and that lysosomal function
VPS35 mutations in PD. RAB10, a member of the small is critical for immune cell behaviour, it is highly likely
RAB GTPase family, is a known substrate of LRRK2 that TMEM175 dysfunction may also affect immune
(ref. 141) and the D620N mutation in Vps35 leads to cells. Mutations in the GRN gene that lead to haplo-
Synucleinopathies LRRK2-dependent increases in RAB10 phosphoryla- insufficiency of the progranulin (PGRN) protein have
A group of neurodegenerative tion in the spleens of Vps35D620N knock-in mice relative been reported to cause frontotemporal dementia155,
disorders in which the protein to non-transgenic littermates142. Furthermore, neutro- with the rs5848 SNP increasing PD risk156. Additionally,
α-synuclein accumulates
abnormally to form inclusions
phils and monocytes from patients with PD who carry reduced serum levels of PGRN have been reported in
in the cell bodies or axons of the D620N mutation exhibited this same increase in PD157. Although a number of receptors, such as Ephrin
neurons or oligodendrocytes. LRRK2-mediated RAB10 phosphorylation relative to 2A receptors158, are regulated by PGRN, current data
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Pernicious anaemia
suggest that PGRN also fulfils receptor-independent humans during recreational drug use, has become one of
A condition in which the body intracellular functions, which appear to converge on the main methods to induce dopaminergic neuronal loss
cannot make enough healthy the lysosome149. and degeneration in animal models181–183. Studies have
red blood cells because it does Interestingly, several histological markers and shown that paraquat, rotenone and MPTP all induce
not have enough vitamin B12.
cytokines upregulated in patients with PD are risk fac- both central and peripheral inflammation and oxidative
Polymyalgia rheumatica tors for PD. An interaction between IL-6 and oestrogen stress184–188.
An inflammatory disorder receptor polymorphisms increases the risk for early-
that causes muscle pain and onset PD 159. Polymorphisms in the TNF gene also Links to autoimmune conditions. With overwhelming
stiffness, especially in the
increase the risk of PD and earlier disease onset160,161. evidence for a role of inflammation in PD pathogene-
shoulders and hips.
Similarly, IL1B polymorphisms are more abundant in sis, epidemiological studies have focused on identify-
patients with PD relative to healthy controls and may ing genetic overlap or pleiotropic loci between PD and
affect the onset of disease162,163. Despite not being a autoimmune disorders to identify potential common
risk factor for PD, allelic distribution of IFNG is sig- genetic pathways. PD has been epidemiologically linked
nificantly different between early-onset and late-onset to several organ-specific and multi-organ autoimmune
PD164, implicating a role of T cells in PD pathogenesis as disorders. Patients with multiple sclerosis, Graves dis-
T cells are major producers of IFNγ. In addition, path- ease (hyperthyroidism), Hashimoto disease (hypothy-
way analysis has implicated genes involved in the ‘reg- roidism), pernicious anaemia or polymyalgia rheumatica
ulation of leukocyte/lymphocyte activity’ as conferring have a 33% increased risk of developing PD, and this risk
an increased susceptibility to PD165. increases further after hospitalization with an autoim-
Four loci associated with PD relate to the transcrip- mune disorder189. A recent GWAS identified 17 shared
tion factor nuclear factor-κB (NF-κB) that regulates a loci between PD and 7 autoimmune diseases, including
number of immune genes in response to different stim- type 1 diabetes, Crohn’s disease, ulcerative colitis, rheu-
uli. These loci include DDRGK1 (ref.149) and SCARB2 matoid arthritis, coeliac disease, psoriasis and multiple
(encoding lysosomal integral membrane protein 2 sclerosis10. In addition, it is well established that muta-
(LIMP2); also known as SCARB2) as reported in an tions in the LRRK2 gene increase risk of developing PD
earlier GWAS meta-analysis150. Interestingly, SCARB2 in patients with Crohn’s disease10 or ulcerative colitis190.
is a receptor for GCase and regulates the production Furthermore, LRRK2 has been identified by GWAS
of type I interferon through TLR9, another known PD as a major susceptibility gene for Crohn’s disease190,
risk locus149. and the PD-associated G2019S mutation contributed
genetic risk for Crohn’s disease11,191. Collectively, auto-
Epidemiological evidence immune diseases represent a group of disorders in
Given the heterogeneity of manifestations and spo- which the peripheral immune system is chronically
radic incidence of PD, it is no surprise that disease activated and producing inflammatory mediators that
incidence has been associated with numerous envi- may stimulate neuroinflammation and thereby promote
ronmental factors that either increase or decrease the PD pathogenesis.
risk of its development166. These include links between
caffeine consumption167, exercise168, use of nonsteroidal NSAIDs and PD. Given that NSAIDs may reduce the
anti-inflammatory drugs (NSAIDs), and smoking169 and risk of other neurodegenerative diseases192, it is unsur-
reduced incidence of PD and increased incidence after prising that this association has been observed in PD.
pesticide exposure170, traumatic brain injury171, con- One of the first reports linking NSAIDs and PD showed
sumption of dairy products172, and exposure to certain that ibuprofen, acetaminophen and aspirin protect dopa-
viral or bacterial infections173,174. These findings suggest minergic neurons in vitro, thus promoting dopamin-
that inflammation or immunological challenges may ergic neuronal integrity193. Furthermore, the NSAIDs
synergize with genetic predisposition to trigger PD sodium salicylate, aspirin and meloxicam protect against
pathogenesis and progression (Fig. 1). For an in-depth MPTP-induced dopaminergic neurotoxicity in animal
discussion of how gene-by-environment interactions models194–196. Following these initial reports, an epide-
converge on immune and inflammatory pathways and miological study found that patients with regular use of
contribute to lifetime risk of PD, we refer the reader to non-aspirin NSAIDs (two or more tablets per day) had a
a recent review175. lower risk of developing PD relative to non-regular users
of non-aspirin NSAIDs197. This was further supported by
Pesticides and PD risk. Pesticides and occupational a follow-up study showing that ibuprofen users but not
exposure to chemicals can increase the risk of PD176,177. acetaminophen or aspirin users had a 35% lower risk of
Paraquat is the chemical most linked to risk, and even developing PD than non-users198. This was corroborated
rotenone, a ‘natural’ plant-derived pesticide used by by a study which found that, while NSAIDs as a class did
home gardeners, has been associated with disease178. not modify the risk, ibuprofen had a slightly protective
Both compounds inhibit mitochondrial respiration, effect on risk for PD, indicating that certain NSAIDs may
which could impact an already dysfunctional endolyso provide protective benefits199. These protective proper-
somal pathway in individuals with particular genetic ties may be based on the well-known role of NSAIDs
mutations179,180. In addition to paraquat and rotenone, in inhibiting cyclooxygenase 1 (COX1) and COX2,
exposure to the toxin 1-methyl-4-phenyl-1,2,3,6- thereby reducing the generation of nitric oxide radicals
tetrahydropyridine (MPTP), after its accidental discovery and oxidative stress, to which dopaminergic neurons are
as an agent that caused dopaminergic neuronal loss in particularly susceptible200. In 2006, a study reported that
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non-aspirin NSAIDs reduced the risk for PD by 20% in inflammation contributes to PD pathogenesis 11,221.
men but increased the incidence in women by 20%, being Additional research is needed to identify therapeutic
one of the first studies to indicate sex differences with windows, time and duration of therapy, and whether it
NSAID use and PD incidence201. Some studies have not should be prophylactic or prior to clinical (motor) symp-
been able to replicate the link between incidence of PD toms. More importantly, the current FDA-approved
and NSAID use but have suggested that patients with anti-TNF biologics may not be the most suitable drug
PD have a higher rate of immediate-type hypersensitivity candidates for long-term chronic use because they
(asthma, hay fever or allergic rhinitis), providing further immunosuppress the patient due to their ability to
evidence for an inflammatory link in the pathogenesis block both membrane-bound and soluble forms of
of PD and the need to effectively evaluate the impact of TNF. In addition, they have very limited brain pene-
NSAID use prior to the development of PD202,203. trance. Pegipanermin — a second-generation biologic
that is a non-immunosuppressive soluble TNF-selective
Gut dysbiosis and inflammatory bowel disease. In 2003, drug due to its unique dominant-negative mechanism
Braak et al. introduced a hypothesis that PD patho- of action222 — crosses the blood–brain barrier and has
genesis originates in the gut204 and that the associated been shown to have neuroprotective activity in multiple
gastrointestinal dysfunction, including a history of con- preclinical models of ageing, neuronal dysfunction and
stipation, preceded motor symptoms and a PD diagnosis neurodegeneration223–226. This drug is currently in clini-
in the clinic by decades3,205. Since then, the hypothesis cal trials for the treatment of pulmonary complications in
has been further developed to incorporate contributions COVID-19 under the name QUELLOR (ClinicalTrials.
from the gut microbiota and intestinal inflammation as gov identifier NCT04370236) and may be worth explor-
a mechanism driving pathology206,207. Differences in ing in PD and other chronic neuroinflammatory brain
gut microbial composition between patients with PD disorders.
and controls have been extensively reported, indicating
that the gastrointestinal environment and its microbial Therapeutic landscape
inhabitants are impacted in PD208. Although several stud- Given the overwhelming evidence that immune activa-
ies have identified changes in relative abundance of cer- tion and inflammation are hallmarks of PD, it is unsur-
tain bacteria, including Prevotellaceae, Bifidobacterium, prising that anti-inflammatory drugs and interventions
Akkermansia and Lactobacillus, in patients with PD, targeting the immune system have moved forward in
results often vary given differences in study design the PD clinic as they have in other neurodegenerative
and methodology, patient populations, and choice of diseases like amyotrophic lateral sclerosis and Alzheimer
controls209. While it remains unknown how specific taxa disease. Table 1 lists clinical trials that involve immuno
of gut bacteria could contribute to or trigger PD, several therapies against α-synuclein and immunomodulatory
studies have shown associations between motor symp- or anti-inflammatory approaches that have been com-
toms or disease progression as well as conditions associ- pleted or are in progress. Most of these trials have clin-
ated with early, pre-motor stages of PD and the relative ical (motor) and not immunological end points, and
abundance of certain bacterial families within faecal some include measures of target engagement, which is
samples from patients210–212. Furthermore, changes in gut deemed critical for hypothesis-driven decision-making.
bacterial composition have been associated with intes- As in other neurodegenerative diseases, the outcome of
tinal inflammation in PD206,213. Higher levels of numer- anti-inflammatory drug trials in PD has been terribly dis-
ous inflammatory mediators have been found in stool of appointing thus far, and changes in the approach to such
patients with PD compared to controls, including IL-1α, trials are warranted. The addition of immune-related
IL-1β, CXCL8, CRP and calprotectin213–216, and the lev- end points may be an important clinical consideration
els of some of these molecules are inversely associated that could impact the design of future, potentially more
with the age of PD symptom onset, suggesting that they successful studies using combination therapies that
could contribute to the development of the disorder213. target multiple processes, including immunological
Levels of Bacteroides and Verrucomicrobia also correlate responses. Additionally, the selection of patient cohorts
with plasma levels of TNF and IFNγ217, respectively. and enrolment criteria for any clinical study is critical
These findings are consistent with the hypothesis that to the outcome as is the point at which any given ther-
gut dysbiosis is linked to an inflammatory environment apy or drug is initiated. Specifically, for inflammation
that may contribute to the initiation of PD pathology. in PD pathogenesis, if the inflammatory process or
How to effectively target the gut microbiome to delay immune dysfunction begins early in the disease process,
or mitigate the development of PD remains an area of an anti-inflammatory intervention that is started after
active research. a clinical (motor) diagnosis is made in a neurologist’s
Several epidemiological studies have associated risk office is unlikely to have a disease-modifying effect.
for PD with inflammatory bowel disease (IBD)11,218,219. Based on the abundant data supporting a prodromal,
A meta-analysis suggests that patients with IBD have a preclinical stage of PD that includes sleep, olfactory and
28–30% increased risk of developing PD220. A system- gastrointestinal dysfunction that begins decades before
atic review and meta-analysis also found that patients motor symptoms develop, biofluids and immune cells
with IBD who are on chronic anti-inflammatory ther- should be collected from individuals with these features
apy with anti-TNF biologics had 78% lower odds of and interrogated for dysfunction and inflammation in
developing PD than patients with IBD not on anti-TNF order to find inflammatory endophenotypes for enrol-
drugs, further supporting the hypothesis that chronic ment into these trials in order to directly test hypotheses
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Table 1 | Clinical trials in PD involving immunomodulatory and anti-inflammatory therapeutics

Drug type Drug name Clinical trial phase Status of Enrolment Immune outcomes Clinical trial ID Refs
(year valuate) clinical trial criteria collected/reported
Recombinant Sargramostim Phase I (2013) Completed PD (diagnosis PBMC and T cell sorting; NCT01882010 235
GM-CSF (Leukine) >3 years) Treg cell function

Phase Ib (2019) Active, not PD (diagnosis Immunophenotype PBMC; NCT03790670 236
recruiting >3 years) lymphocyte immune cell

number and function;
antibodies to GM-CSF
GLP1 analogue Exenatide Phase II (2013) Completed PD (H&Y <2.5 on No immune-specific NCT01971242 237
mediation) treatment outcomes; motor

and non-motor outcomes
PPARγ agonist Pioglitazone Phase II (2015) Completed Early PD (H&Y No immune-specific NCT01280123 238
<2 and diagnosis treatment outcomes; motor

<5 years) and non-motor outcomes
Cannabinoid Nabilone Phase II (2018) Completed PD No immune-specific NCT03769896 239
system agonists treatment outcomes; motor

Phase III (2018) Recruiting PD (previous No immune-specific NCT03773796 240
NMS-Nab study treatment outcomes; motor

participant) and non-motor outcomes
GWP42003-P Phase II (2019) Completed Idiopathic PD No immune-specific NCT02818777 241
(cannabidiol) treatment outcomes; motor

mAb targeting Prasinezumab Phase I (2014) Completed PD (H&Y 1–3) Immunogenicity determined NCT02157714 242,243
carboxy-terminal (PRX002) by anti-PRX002 antibodies

epitope of Phase II (2017) Active, not Early PD Immunogenicity determined NCT03100149 244
α-synuclein recruiting (H&Y 1–2) by anti-PRX002 antibodies
mAb targeting BIIB054 Phase I (2015) Completed Early idiopathic Immunogenicity determined NCT02459886 245
amino-terminal PD by anti-BIIB054 antibodies

epitope of Phase II (2017) Active, not Early PD Immunogenicity determined NCT03318523 246
α-synuclein recruiting (H&Y <2.5 and by anti-BIIB054 antibodies
diagnosis
<3 years)
Vaccine targeting AFFITOPE Phase I (2014) Completed PD Titre of antibodies specific NCT02216188 247
carboxy terminus PD01A for the immunizing peptide

of α-synuclein Phase I (2015) Completed PD No immune-specific NCT02618941 248
treatment outcomes; motor

Phase I (2013) Completed PD (same Antibodies specific for the NCT01885494 249
patients valuate immunizing peptide

in NCT02618941)
Phase I (2012) Completed Early PD (H&Y Antibodies directed towards NCT01568099 250
<2 and diagnosis vaccine components

<4 years)
Vaccine targeting AFFITOPE Phase I (2014) Completed Early PD (H&Y Antibodies directed towards NCT02267434 251
α-synuclein PD03A <2 and diagnosis vaccine components

<4 years)
Synthetic UB-312 Phase I (2019) Recruiting Part A in healthy Immunogenicity determined NCT04075318 252
peptide-based participants; by anti-α-synuclein

vaccine targeting part B in PD antibodies in blood and CSF
α-synuclein (H&Y <3)
BCR–ABL Nilotinib Phase II (2016) Active, not Moderate PD No immune-specific NCT02954978 253
tyrosine kinase recruiting (H&Y 2.5–3) treatment outcomes

inhibitor
The table was generated from a literature search conducted on ClinicalTrials.gov with the search terms “Parkinson disease” and “inflammatory”. Results were subsequently
filtered for relevance. No date restrictions were set for articles retrieved from the search. CSF, cerebral spinal fluid; H&Y, Hoehn & Yahr staging; mAb, monoclonal antibody;
NMS-Nab, Nabilone for non-motor symptoms in Parkinson disease; PBMC, peripheral blood mononuclear cell; PD, Parkinson disease; Treg cell, regulatory T cell.
about inflammation and target engagement. This could Challenges and future directions
position the neurodegeneration field for greater success As the field of neurodegeneration moves forward to
at the level of the FDA by proposing the performance critically interrogate the role of central and peripheral
of shorter biomarker-directed clinical trials with a clear inflammation in the pathogenesis and progression of
target engagement study design that will inform better PD, one major challenge is the development of new tech-
decision-making going forward into phase III trials. niques, such as single-cell multi-omics, machine learning
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or advanced patient-derived models227, that will enable individuals are relatively rare. As an example, heterozy-
the field to rigorously test whether or not the immune gote carriers of the LRRK2G2019S mutation are prevalent
system and inflammation are critical components of the in the Ashkenazi Jewish ancestry community; however,
disease, how immune cells protect or predispose neurons when trials with LRRK2 kinase inhibitors begin in
to injury, and at which stages immune processes play crit- the clinic, their participation will be highly sought by
ical roles and are predictive of disease trajectory. To do a large number of pharmaceutical companies, and the
this, we need to have a better understanding of how genes interpretation of results from individuals participating
and the environment impact immune function over time. in multiple trials will be complex. Enrolling specific clin-
To this end, the field will need to engage in longitudinal ical populations for assessment of immunomodulatory
collection of immune cells and tissues from individuals therapies, including patients of genetic risk tied to the
at genetic and environmental risk for PD, and not just immune system, will be crucial to determine the neu-
from those with clinical motor features, to perform deep roprotective effects as a response to a genetic contribu-
genetic, transcriptional and immune profiling. This will tion. Additionally, while the field has made significant
enable researchers to look for meaningful changes in strides in identifying genes and gene variants associated
responses to immune challenges as opposed to compar- with PD risk in individuals with European ancestry,
ing baseline differences between disease cases and healthy better efforts are needed to perform similar studies in
controls — specifically, the detection of an immune dys- diverse populations. These efforts have been severely
functional trait rather than an immune dysfunctional lagging, a serious problem since immune-related genes
state. A second challenge will be the development of are expected to vary widely based on ethnicity and geog
non-invasive tools to identify individuals exhibiting raphy. Immune-based therapies are therefore unlikely to
neuroinflammation. Currently, PET imaging is the best have equivalent efficacy in all populations and should be
technique available to the field. However, high costs, low tested in cohorts with diverse ethnic backgrounds.
signal-to-noise ratio and genetic polymorphisms in the Perhaps the most pressing challenge in the field is
TSPO gene in the human population significantly curtail the need to develop tools enabling earlier diagnosis to
its widespread use228,229. Perhaps the use of non-invasive deliver effective therapies to prevent, delay or arrest dis-
breath volatile organic compound mass-spectrometry ease. The overall sentiment in the field from preclinical
technology230 will enable monitoring of treatment respon- data is that, if PD begins outside the brain and in periph-
siveness and measurement of target engagement simul- eral organs and then progresses into the brain, diagnosis
taneously. Another promising technology is free-water in the pre-motor stages of the disease must be achieva-
measurement in diffusion-tensor magnetic resonance ble. A deeper understanding and accurate detection of
imaging (DT-MRI), which is a sensitive method widely the immunological mechanisms underlying the earliest
used in patients with Alzheimer disease and PD to iden- signs of parkinsonism will lead to new therapies and may
tify clinical pathology. This technology could be lever- one day enable clinicians to intervene effectively with
aged to also identify neuroinflammatory changes in the novel or repurposed anti-inflammatory and immuno-
vicinity of white-matter tracts in the CNS231–234. modulatory therapies to slow or delay the progression
While genetic research is informative, obtaining of disease from the periphery to the CNS.
clinical samples from patients with monogenic forms
of PD or specific risk SNPs is not trivial because these Published online 4 March 2022
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660 | November 2022 | volume 22 www.nature.com/nri

play a role in neuroinflammation and neurodegener- neurodegenerative effects between lipopolysaccharide

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Box 1 | PD genetics indicate a role of the immune system in pathogenesis

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Box 2 | Genes, risk factors and modifiers in PD converge on the lysosome

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Table 1 | Clinical trials in PD involving immunomodulatory and anti-inflammatory therapeutics

GM-CSF (Leukine) >3 years) Treg cell function

recruiting >3 years) lymphocyte immune cell

mediation) treatment outcomes; motor

<2 and diagnosis treatment outcomes; motor

system agonists treatment outcomes; motor

NMS-Nab study treatment outcomes; motor

(cannabidiol) treatment outcomes; motor

carboxy-terminal (PRX002) by anti-PRX002 antibodies

amino-terminal PD by anti-BIIB054 antibodies

carboxy terminus PD01A for the immunizing peptide

treatment outcomes; motor

patients valuate immunizing peptide

<2 and diagnosis vaccine components

α-synuclein PD03A <2 and diagnosis vaccine components

peptide-based participants; by anti-α-synuclein

tyrosine kinase recruiting (H&Y 2.5–3) treatment outcomes

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NATure RevIeWS | ImmunoloGy volume 22 | November 2022 | 673

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