Epilepsy Research 172 (2021) 106588

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Epilepsy Research
journal homepage: www.elsevier.com/locate/epilepsyres

Review article

The role of inflammatory mediators in epilepsy: Focus on developmental

and epileptic encephalopathies and therapeutic implications
Alessandro Orsini a, 1, Thomas Foiadelli b, *, 1, Giorgio Costagliola a, Alexandre Michev b,
Rita Consolini a, Federica Vinci b, Diego Peroni a, Pasquale Striano c, d, Salvatore Savasta b
a
Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Via Roma 67, 56126 Pisa, Italy
b
Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy
c
Paediatric Neurology and Muscular Diseases Unit, “G. Gaslini” Institute, Via Gaslini 5, 16147 Genova, Italy
d
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gaslini 5, 16147 Genova, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: In recent years, there has been an increasing interest in the potential involvement of neuroinflammation in the
Neuroinflammation pathogenesis of epilepsy. Specifically, the role of innate immunity (that includes cytokines and chemokines) has
Epilepsy been extensively investigated either in animal models of epilepsy and in clinical settings. Developmental and
Cytokine
epileptic encephalopathies (DEE) are a heterogeneous group of epileptic disorders, in which uncontrolled
Chemokine
West syndrome
epileptic activity results in cognitive, motor and behavioral impairment. By definition, epilepsy in DEE is poorly
Steroid controlled by common antiepileptic drugs but may respond to alternative treatments, including steroids and
immunomodulatory drugs. In this review, we will focus on how cytokines and chemokines play a role in the
pathogenesis of DEE and why expanding our knowledge about the role of neuroinflammation in DEE may be
crucial to develop new and effective targeted therapeutic strategies to prevent seizure recurrence and devel­
opmental regression.

1. Introduction
Developmental and epileptic encephalopathies (DEE) are a hetero­
geneous group of epileptic disorders, in which the epileptic activity in­
terferes with the normal neuronal development, resulting in cognitive,
motor, and behavioral impairment, with a poor prognosis (Kalser and
Cross, 2018). Different epileptic syndromes with various etiologies are
comprised among DEE, including West syndrome (WS), Epilepsy with
myoclonic-atonic seizures, Landau-Kleffner, Dravet, Lennox-Gastaut
syndromes, and others (Helbig and Tayoun, 2016).
Epilepsy in DEE is drug-resistant, and alternative treatment strate­
gies include adrenocorticotropic hormone (ACTH), high-dose cortico­
steroids, neurostimulation, ketogenic diet, and surgery, with various
degrees of response (Nariai et al., 2018; Shandra et al., 2017). During the
last decade, there has been an increasing interest in the potential
involvement of inflammation in the pathogenesis of epilepsy, with
particular attention to DEE. Inflammation is a non-specific biological
defense response against different mechanisms of injury and is part of
the innate immune response. Inflammation involves both cells (e.g.
macrophages and dendritic cells) and soluble inflammatory mediators
(e.g. cytokines and chemokines) and can induce activation of the
adaptive immunity (Skaper et al., 2018). In the central nervous system
(CNS), neuroinflammation is mostly dependent on the activation of
microglial cells and astrocytes, the main cellular effectors of the cere­
brospinal innate immune system (Shandra et al., 2017; Graeber et al.,
2011).

Abbreviations: ACTH, adrenocorticotropic hormone; BBB, blood-brain barrier; CD, cluster of differentiation; CNS, central nervous system; COX-2, cyclooxygenase-
2; CRH, corticotropin-releasing hormone; CSF, cerebrospinal fluid; DEE, developmental and epileptic encephalopathies; ESES, encephalopathy with status epilepticus
during sleep; FIRES, febrile infection-related epilepsy syndrome; GABA, gamma-aminobutyric acid; GC, glucocorticoids; HMGB1, high mobility group box 1; IFN,
interferon; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; NF-κB, nuclear factor κB; NMDA, N-methyl-D-aspartate; non-WS-DEE, developmental and
epileptic encephalopathies other than West Syndrome; PCDH19, protocadherin-19; RE, Rasmussen encephalitis; STAT3, signal transducer and activator of tran­
scription 3; TGF, transforming growth factor; Th17, T-helper 17; TLR, toll-like receptors; TNF, tumor necrosis factor; WS, West syndrome.
* Corresponding author.
E-mail address: t.foiadelli@smatteo.pv.it (T. Foiadelli).
1
Shared co-first authors.

https://doi.org/10.1016/j.eplepsyres.2021.106588
Received 14 December 2020; Received in revised form 28 January 2021; Accepted 16 February 2021
Available online 18 February 2021
0920-1211/© 2021 Elsevier B.V. All rights reserved.
A. Orsini et al. Epilepsy Research 172 (2021) 106588

Specifically, the role of innate immunity (including cytokines, che­
mokines, and their molecular pathways) has been extensively studied in
animal models of epilepsy and epileptic patients, with a focus on West
syndrome (WS). However, the molecular mechanisms of its involvement
in the process of epileptogenesis, as well as its role in other forms of DEE,
are yet to be fully clarified. There is only a limited number of studies
analyzing neuroinflammation in both DEE and other epilepsies, and
studies directly comparing the degree of inflammation between
childhood-onset epilepsies with different etiology are lacking (Kagita­
ni-Shimono et al., 2021; Choi et al., 2009b). However, the research on
the role of inflammation in the pathogenesis of DEE has a peculiar
clinical relevance. This priority derives from the previous scientific
works, which have demonstrated a significant elevation of different
inflammatory markers in children with DEE, and by the therapeutic
response to ACTH and corticosteroids, which act also (but not exclu­
sively) through anti-inflammatory mechanisms, as showed by children
suffering from WS and other DEE (Shandra et al., 2017). As a conse­
quence, there is an increasing interest in the identification of new
therapeutic approaches targeting inflammation for the treatment of
drug-resistant epilepsy and, potentially, for the improvement of the
long-term neurodevelopmental outcome.
We review the available evidence for the association between
inflammation and epileptogenesis in DEE. We will focus on the role of
cytokines and chemokines and describe pathogenic mechanisms and
potential therapeutic strategies targeting inflammation in these
conditions.
2. Inflammation and epilepsy
Our knowledge of the molecular and immunological mechanisms
responsible for immune-mediated epileptic encephalopathies (Greco
et al., 2016) is increasing, along with the evidence of the efficacy of
immunomodulatory treatments in these conditions. On the other hand,
the role of neuroinflammation in the pathogenesis of seizures, and the
etiology of other epilepsies and DEE has been extensively studied in the
last years (Vezzani et al., 2013; Ravizza et al., 2011; Vitaliti et al., 2019).
The association between inflammation and seizures is complex and not
unidirectional: seizures can cause neuroinflammation and, conversely,
systemic or regional inflammation can contribute to the development
and persistence of seizures (Vezzani et al., 2013, 2008; Xanthos and
Sandkuhler, 2014; Wilson, 2015) (Fig. 1).
In the brain tissue of rodents with epilepsy, high levels of Interleukin
(IL)-1β, Tumor Necrosis Factor (TNF)-α, and IL-6 have been demon­
strated by different authors (Vezzani et al., 2008; De Simoni et al., 2000;
Vezzani et al., 1999; Minami et al., 1990; Balosso et al., 2008; Marcon
et al., 2009). Moreover, murine models of epilepsy evidenced that
inflammation occurs before the development of seizures, suggesting a
direct role of inflammation in the complex process of epileptogenesis
(Vezzani et al., 2013; De Simoni et al., 2000; Ravizza et al., 2008). On
the other hand, the electrical induction of seizures in rodents is followed
by the release of pro-inflammatory cytokines, including IL-1β, TNF-α,
IL-6, and other mediators of inflammation, such as the danger molecule
high mobility group box 1 (HMGB1) (Vezzani et al., 2013; Heida and
Pittman, 2005). Among cytokines, IL-1β seems to have a major role in
the pathogenesis of seizures and epileptogenesis. Intrathecal adminis­
tration of IL-1β causes the exacerbation of kainate and
bicuculline-induced seizures (Vezzani et al., 1999), and a seizure
threshold reduction in experimental models of febrile seizures (Heida
and Pittman, 2005; Dube et al., 2005).
Neuroinflammation is extremely difficult to study in vivo. The use of
imaging is increasing but, currently, its clinical application is not yet
defined. In a study by Chugani and Kumar, the use of translocator pro­
tein (TPSO)-PET, which evidences the microglial activation, demon­
strated a reduction in the uptake of the radioligand in children with WS
after the treatment with corticosteroids, suggesting that this method
could be a promising tool to dynamically study neuroinflammation

Fig. 1. Inflammation and epileptogenesis: molecular mechanisms.

Neuroinflammation contributes to epileptogenesis through several mechanisms. HMGB1, released after neuronal or glial injury, is responsible for the activation of
TLR-4, which activates the inflammasome complex, thus causing the production of other pro-inflammatory mediators. Moreover, HMGB1 promotes chemotaxis and
participates in BBB dysfunction, causing an enhancement of the inflammatory response. IL-1β and TGF-β cause increased activity of glutamate, responsible for both
epileptogenesis and neuronal toxicity, while TNF-α, produced also after the interaction between CXCL12 and CXCL4, acts on both glutamatergic and GABA-ergic
response. Concerning chemokines, CCL2 has an important role in promoting the production of IL-1β, causing neuronal cell death and altering calcium signaling,
while CX3CL1 negatively influences GABA-ergic activity. Finally, the BB dysfunction and the epileptic activity itself are enhancers of neuroinflammation.
BBB: blood-brain barrier; HMGB1: high mobility group box 1; IL: interleukin, TNF: tumor necrosis factor; TGF: transforming growth factor.

2
A. Orsini et al.
(Chugani and Kumar, 2020). However, the analysis of serum or cere­
brospinal fluid (CSF) cytokines represents the most widely used instru­
ment to analyze the presence of inflammation and its molecular features
in epileptic patients. Studies on patients with epilepsy showed high
serum and CSF levels of several pro-inflammatory cytokines (Liba et al.,
2019; Choi et al., 2009a; Mao et al., 2013; Aronica and Crino, 2011),
including IL-1β (with consequently altered IL-1β/IL-1 Receptor Antag­
onist [RA] ratio), IL-6, IL-17, TNF-α, Transforming Growth Factor
(TGF)-β and Interferon (IFN)-γ (Vitaliti et al., 2019; de Vries et al., 2016;
Gao et al., 2017). When compared to healthy controls, patients with
focal epilepsy show increased activation of different inflammatory
pathways, including serum Nuclear Factor kB (NF-kB,) (Ulusoy et al.,
2020). Other in vivo studies, performed on brain tissue resected from
patients with temporal lobe epilepsy, showed an up-regulation of genes
associated with inflammation (Aronica and Gorter, 2007). The associ­
ation between inflammation and epileptogenesis is also supported by a
recent study by Numis et al., which demonstrated that high levels of
pro-inflammatory cytokines in newborns with neonatal encephalopathy
are associated with an increased risk of developing epilepsy later in life
(Numis et al., 2019). Recently, the association between serum levels of
cytokines, in particular IL-6, and disease activity in patients with en­
cephalopathy with electrical status epilepticus during sleep (ESES) was
demonstrated (van den Munckhof et al., 2016). Inflammation has also
been associated with drug-resistance. Patients with drug-resistant epi­
lepsy have higher serum levels of IL-1β, IL-6, and reduced IL-1RA
compared to controls (Hulkkonen et al., 2004). The molecular mecha­
nism responsible for drug-resistance could be partly dependent on
altered expression of the P-glycoprotein, which mediates drug efflux
through the blood-brain barrier (BBB) (Roberts and Goralski, 2008), in
addition to the neuronal excitability that is consequent to an uncon­
trolled inflammation (Vitaliti et al., 2019).
Several additional markers of inflammation increase during the ictal
phase, including nitric oxide, prostaglandins, produced through the
activation of the inducible enzyme cyclooxygenase-2 (COX-2), classical
complement pathway, the plasminogen system, and metalloproteases
(Vezzani et al., 2013; Sayyah et al., 2003; Riazi et al., 2010; Shimada and
Takemiya, 2014; Aronica et al., 2007; Iyer et al., 2010; Quirico-Santos
et al., 2013).
BBB alterations play an important role in the brain’s immune ho­
meostasis by affecting its function and permeability (Kovacs et al.,
2012). Inflammatory mediators enhance BBB permeability, and che­
mokines can promote the adhesion and recruitment of leukocytes. BBB
leakage can be the result of epileptic activity but also participates in its
progression, as evidenced by several studies on human and animal brain
tissue (van Vliet et al., 2007; Oby and Janigro, 2006). The mechanism
underlying the seizure-associated BBB dysfunction involves both the
direct action of pro-inflammatory cytokines and the activation of mast
cells during inflammation (Vezzani et al., 2013; Oby and Janigro, 2006;
Suemitsu et al., 2010). Among the consequences of an altered BBB, there
is a rise in brain concentration of albumin, which activates the tran­
scription signaling related to TGF-β (Friedman et al., 2009) and con­
tributes to the maintenance of inflammation and epileptogenesis
(Cacheaux et al., 2009).
Finally, it is important to consider that cytokines and the other me­
diators of neuroinflammation play a physiological role in normal neu­
rodevelopment, being involved in neurogenesis, synaptic function,
plasticity, brain modeling, and other functions (Vezzani et al., 2013;
Boulanger, 2009). It is, therefore, possible that enhanced inflammation
in the early stages of brain maturation could affect neuronal develop­
ment. This intriguing hypothesis could partly explain the association
between DEE and their numerous neurodevelopmental comorbidities.
However, further studies are needed to confirm this hypothesis and to
clarify the role of inflammation in epileptogenesis and the influence of
inflammation control on the progression of cognitive, developmental
and non-epileptic comorbidities.
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Epilepsy Research 172 (2021) 106588
3. Cytokines and chemokines: role in neuroinflammation and
epileptogenesis
Cytokines represent a wide family of soluble mediators implicated in
inflammatory and immune responses. They regulate cellular growth,
differentiation, and activity (Vilcek and Feldmann, 2004), and play a
critical role even in the immune homeostasis of the brain. As distinct
cytokines may be secreted by different cellular sources and have vari­
able biological effects, they can induce epilepsy through multiple mo­
lecular mechanisms.
Toll-like receptors (TLR) are implicated in the production of a wide
range of cytokines following the recognition of exogenous or endoge­
nous ligands able to activate the immune response (Vidya et al., 2018).
IL-1β, one of the main cytokines involved in epileptogenesis, is released
after the activation of TLR4, which is triggered by multiple typologies of
ligands, including lipopolysaccharides (Kigerl et al., 2007; Rossol et al.,
2011). When TRL4 binds its ligands, the molecular complex of the
inflammasome is activated and causes the release of the soluble form of
IL-1β and HMGB1 with a caspase-1-mediated mechanism (Diamond
et al., 2015; Yang et al., 2015).
IL-1β can participate in the development of seizures and epilepto­
genesis through the influence on the calcium influx across the N-methyl-
D-aspartate (NMDA) receptor, the reduction of glutamate uptake by
astrocytes, and the increase of glutamate release by glial cells (Vitaliti
et al., 2019; Kigerl et al., 2007; Hu et al., 2000). These mechanisms
cause an enhanced effect of glutamate that induces neuronal excitation
and potential excitotoxicity leading to a reduction of the seizure
threshold. Consequently, the TLR4-IL-1β axis appears to be central in the
inflammation-mediated epileptogenesis, as confirmed by the reduced
epileptic activity in TLR4 knockout animal models of epilepsy (Iori et al.,
2013).
Preclinical studies also highlighted the role of HMGB1 (Maroso et al.,
2010; Ravizza et al., 2018), which is similarly involved in the TLR4-
IL-1β axis, and potentially implicated in the genesis and maintenance of
seizures. HMGB1 binds TLR4, activating the pro-inflammatory NF-κB
pathway, and can play a chemoattractant action on leukocytes by
generating a molecular complex with the chemokine CXCL12. HMGB1
also interferes with the function of the NMDA receptors (Maroso et al.,
2011a). These pieces of evidence suggest that HMGB1 may enhance
neuroinflammation through TLR4-mediated and TLR4-independent
pathways, and directly modulate neurotransmitter activity. Despite
the absence of specificity for the CNS, HMGB1 is strictly involved in the
inflammatory events related to epilepsy, thus representing an intriguing
target for further therapies (Vitaliti et al., 2019; Yang et al., 2015;
Maroso et al., 2011b). On the other hand, IL-10 inhibits IL-1β produc­
tion, suggesting a protective role against the progression of epilepto­
genesis (Sun et al., 2019).
Noteworthy, other cytokines can influence seizure development
through non-inflammatory mechanisms, such as the production and
signaling of neurotransmitters. TNF-α reduces the expression of GABA-A
receptors on neuronal membranes (Viviani et al., 2007), lowering the
seizure threshold. Moreover, and similarly to TGF-β, it influences the
release and the response to glutamate (Bezzi et al., 2001; Diniz et al.,
2014; Bae et al., 2011).
IL-6 has a complex role in the pathogenesis of several CNS diseases,
and its role in the brain inflammatory response is not clear. IL-6 is
secreted not only by immune cells but also by microglial cells, astro­
cytes, and occasionally even by neurons (Munoz-Fernandez and Fresno,
1998). Additionally, it can be released by perivascular and brain endo­
thelial cells in response to inflammatory stimuli and neurotropic in­
fections (Jirik et al., 1989; Fabry et al., 1993; Joseph et al., 1993). Some
studies reported raised IL-6 levels in the serum and CSF after tonic-clonic
seizures (Liimatainen et al., 2009), although it is not known whether
IL-6 can directly be responsible for epileptogenesis. IL-6 can also in­
crease the production of ACTH, thus highlighting the complex in­
teractions between this cytokine, the endocrine system, and CNS (Akira
A. Orsini et al.
et al., 1993). Finally, IL-6 represents a target of IL-17 and is involved in
the positive feedback that drives the activation of T-helper 17 (Th17)
cells (Miossec et al., 2009). It is well known that Th17 cells play a key
role in the immune response against pathogens at mucosal and epithelial
surfaces (Munoz-Fernandez and Fresno, 1998). The IL-17/Th17
pathway is involved in the pathogenesis of several autoimmune condi­
tions including inflammatory and demyelinating diseases such as mul­
tiple sclerosis and Guillain-Barré syndrome (Matusevicius et al., 1999; Li
et al., 2012). IL-17 produces tissue inflammation and blood-brain barrier
disruption in in-vitro studies (Kebir et al., 2007). Elevated CSF and
serum concentrations of IL-17 are detectable in patients with epilepsy of
unknown origin, and there may be a correlation between IL-17 levels
and seizure burden (Miossec et al., 2009) that could be linked to a BBB
dysfunction (Kebir et al., 2007).
Chemokines are a subclass of cytokines that are implicated in cellular
homing and trafficking. These are small proteins (8− 12 kDa), classified
into four subfamilies according to the characteristics of their N-terminal
region: CXC, C, CC, Cx3C (Zlotnik and Yoshie, 2012; Charo and Ran­
sohoff, 2006). The interaction between chemokines and their receptor
participates in a large number of processes of the immune and inflam­
matory response, including leukocyte recruitment to the injured size,
integrin-mediated endothelial adhesion, tissue repair, and lymphocyte
migration to lymphoid stations (Moser and Loetscher, 2001). Chemo­
kines and their receptors are widely represented in the central nervous
system, mainly expressed by glial, neuronal, and vascular endothelial
cells (Le Thuc et al., 2015). Moreover, chemokine concentrations
significantly vary following several pathological conditions (Milenkovic
et al., 2019; Jaerve and Muller, 2012; Biber et al., 2002). In the attempt
to identify potential therapeutic targets, their role in neuroinflammation
and immunomodulation has been investigated in different neurological
diseases, including ischemic and hemorrhagic stroke, demyelinating
disorders, and progressive neurodegenerative pathologies such as Alz­
heimer’s disease and Parkinson’s diseases (Ramesh et al., 2013; Gual­
tierotti et al., 2017; De Luca et al., 2018; Minami et al., 2006; DiSano
et al., 2019; Mracsko and Veltkamp, 2014; Zuena et al., 2019; Guedes
et al., 2018; Bagheri et al., 2018; Lee et al., 2019). Studies have shown
that chemokines are not only involved in neuroinflammation but also
directly interact with neuropeptides and neurotransmitters, thus
modulating neuronal activity (Le Thuc et al., 2015; Rostene et al., 2011;
Adler and Rogers, 2005; Cardona et al., 2008).
Different murine models have highlighted the molecular mecha­
nisms in which chemokines contribute to epileptogenesis. CCL2
expression is enhanced after seizure induction with pilocarpine or
kainite (Foresti et al., 2009; Manley et al., 2007). In mice with
kainate-induced seizures, the activation of the CCL2-receptor (CCR2)
resulted in an induction of the STAT3 signaling pathway, implicated in
neuronal cell death, and the production of IL-1β (Tian and Peng, 2017).
CCL2 also triggers seizures by altering intracellular calcium signaling
and enhancing postsynaptic currents in the hippocampus (Zhou et al.,
2011; Banisadr et al., 2005).
Differently, the interaction between CXCL12 and CXCL4 can induce
TNF-α secretion by microglial cells, influencing the synaptic function,
and enhancing glutamate release (Lee et al., 2007). In the brain of epi­
lepsy animal models, high levels of CCR5 (which binds CCL3, CCL4, and
CCL5) have been reported, suggesting a potential pathogenic role in the
complex history of epileptogenesis (Cerri et al., 2017; van Gassen et al.,
2008). Finally, the chemokine CX3CL1/fractalkine can influence and
modulate GABAergic inhibitory functions in patients with mesial tem­
poral lobe epilepsy through its receptor CX3CR1, expressed by micro­
glial cells (Roseti et al., 2013), suggesting that CX3CL1 may have
anti-seizure activity and a protective role in epileptogenesis.
Studies on humans have shown promising results and further
stressed the role of chemokines in epileptogenesis (Fabene et al., 2010).
It is now well known that CCL2, CCL3 and CXCR4 (the
CXCL12-receptor), which are fundamental in driving the leukocyte
trafficking towards inflamed areas, are highly expressed in the surgically
4
Epilepsy Research 172 (2021) 106588
resected brain tissue of patients with epilepsy (mainly temporal lobe
epilepsy) (Choi et al., 2009a; Lee et al., 2007; van Gassen et al., 2008;
Wu et al., 2008; Arisi et al., 2015).
4. Understanding the link between neuroinflammation and
developmental epileptic encephalopathies
4.1. The paradigm of West syndrome
West syndrome is an infantile form of epileptic encephalopathy. WS
is clinically defined by a triad of a) electroencephalographic abnor­
malities, b) epileptic spasms, c) neurodevelopmental arrest and regres­
sion (Kato, 2006). Although clinically homogeneous, WS has different
causing factors that are either hereditary or acquired (Baram, 1993;
Tekgul et al., 1999). Still, in the majority of patients, the exact etiology
remains unknown (Frost and Hrachovy, 2005) and the overall mecha­
nisms underlying the progression to severe epilepsy and cognitive
regression are not fully understood. The use of ACTH and glucocorti­
coids (GC) has proven its efficacy in WS by reducing epileptic spasms
and improving background EEG activity (Shumiloff et al., 2013; Tsuji
et al., 2007). Several authors have long speculated on the possible role of
the hypothalamic-pituitary-adrenal axis in the pathogenesis of WS. As
evidenced in infant animal models, the Corticotropin-Releasing Hor­
mone (CRH) may induce epileptogenic activity and cause brain damage
leading to cognitive impairment (Baram and Schultz, 1991). This effect
is thought to be partly dependent on a reduction of circulating IGF-1
levels, which causes synaptic dysfunction (Vitaliti et al., 2019). ACTH
is thought to influence epileptic activity by binding the melanocortin
receptors in the amygdala and reducing the secretion of CRH (Brunson
et al., 2001, 2002). Other proposed mechanisms for the action of ACTH
are represented by its influence on IGF-1 production (Vitaliti et al.,
2019) and GABA homeostasis. Indeed, studies have demonstrated that
ACTH can positively influence GABAA receptor functioning, mainly
through the stimulation of the secretion of adrenal glucocorticoids and
mineralocorticoids (Rogawski and Reddy, 2002). Of note, GABA-ergic
function and hypothalamus-pituitary-adrenal axis are linked in a bidi­
rectional way, as GABA has been shown to inhibit the axis at both hy­
pothalamic and pituitary levels (Giordano et al., 2006). Also, since
ACTH induces the synthesis and release of GC, several studies have
focused on its steroid-related immunomodulatory properties, following
the hypothesis that WS develops within an inflammatory process. It is
unclear whether inflammation in WS is the result of the same
tissue-damaging events that determine the disease or may represent it­
self as the key trigger of the condition. Therefore, several studies have
attempted to verify whether the therapeutic effects of ACTH in WS are
mainly determined by its anti-inflammatory activity.
ACTH exerts anti-inflammatory processes through its influence on
cytokines and immune cell activity, especially on lymphocytes (Talaber
et al., 2015). Table 1 resumes the main clinical studies that investigated
the effects of ACTH on the immune system homeostasis and activation in
patients with WS, focusing on a) the alteration in the baseline cytokines
homeostasis in WS patients compared to controls (Liu et al., 2001;
Montelli et al., 2003; Tekgul et al., 2006; Haginoya et al., 2009; Ture
et al., 2016); b) the variation of composition and concentration of
circulating and CSF cytokines after treatment with ACTH (Ohya et al.,
2009; Shiihara et al., 2010; Yamanaka et al., 2010, 2018; Dias De Sousa
et al., 2012).
Liu et al. evidenced higher serum levels of IL-2, TNF-α, and IFN-α in
WS children when compared to controls. Likewise, Türe et al. demon­
strated that serum levels of IL-6 and IL-17 were higher than controls in a
small cohort of WS patients (Ture et al., 2016), while others evidenced
reduced CSF baseline levels of IL-6 in a group of WS patients compared
to controls (Tekgul et al., 2006). The role of IL-6, IL-17, and other cy­
tokines in WS still needs to be clarified, but the fact that many circu­
lating cytokines (including IL-17) decrease after the administration of
ACTH in patients with WS may prompt research toward new therapeutic
A. Orsini et al. Epilepsy Research 172 (2021) 106588

Table 1
Available studies on serum cytokines and lymphocyte subsets in West syndrome at baseline (a) and their variation before/after ACTH treatment (b).

N. of N. of Results
Authors Year Main parameters studied
patients controls Increased Decreased

Liu et al. 2001 23 15 Serum cytokines IL-2, TNF-α, IFN-α

Peripheral lymphocyte subsets; CD1+, CD3+ cells, CD4+ cells and
Montelli et al. 2003 33 20 CD8+ cells
CD4+/CD8+ ratio CD4+/CD8+ ratio
a) Tekgul et al. 2006 12 12 IL-6 in CSF IL-6
Haginoya et al. 2009 24 13 Serum IL-1β, IL-1RA, IL-6 and TNF-α IL-1RA
Serum IL-1β, IL-2, IL-6, IL-17a, IL-23 and
Türe et al.* 2016 20 20 IL-6, IL-17a
TNF-α
Peripheral lymphocyte subsets; CD4+/
Ohya et al. 2008 18 0 CD4+ cells, CD4+/CD8+ ratio
CD8+ ratio
Pre ACTH, WS group vs.
controls: CD3+ CD25+ cells,
Pre ACTH, WS group vs. controls:
Peripheral lymphocyte subsets; serum CD19+ CD95+ cells;
Shiihara et al. 2010 76 26 IL-1RA, IL-5, IL-6, IL-15,
cytokines, chemokines, growth factors. Post ACTH, WS group: CD3+
eotaxin, bFGF, IP-10
b) cells, CD4+ cells, CD4+/
CD8+ ratio
Yamanaka et al. 2011 13 0 IL-1RA, IL-1β IL-1RA
Dias de Sousa et al. 2012 4 0 IL-1β, IL-5, IL-10, TNF-β and INF-γ in CSF IL-1β, INF-γ
IL-5, IL-9, IL-17, PDGF, bFGF,
Serum cytokines, chemokines, growth
Yamanaka et al. 2018 5 0 INF-γ, IP-10, CCL2, CCL3 and
factors and TNF-α.
CCL4
*
= this study compared inflammatory features before and after ACTH treatment, but found no significant differences. Therefore, only baseline WS parameters,
compared to controls, were considered (a). ACTH: adrenocorticotropic hormone; CSF: cerebrospinal fluid; IL-1RA: interleukin-1 receptor antagonist; INF: interferon;
TNF: tumor necrosis factor; WS: West syndrome.

targets (Yamanaka et al., 2018). Some studies suggested that peripheral
lymphocytes can be a parameter for evaluating the perturbation in the
immune asset of patients with WS (Montelli et al., 2003) and to identify
a possible immunomodulatory role of ACTH (Ohya et al., 2009; Shiihara
et al., 2010) (Table 1). In these studies, baseline levels of CD3+ CD25+
cells and CD19+ CD95+ cells were reduced in patients with WS
compared to controls. After ACTH administration, there was a signifi­
cant reduction of CD3+ cells, CD4+ cells, and CD4+/CD8+ ratio in WS
patients (Ohya et al., 2009). These data may suggest a decreased
T-regulatory activity with reduced B-cells apoptosis in WS patients and a
T cell inactivation as a result of ACTH administration.
The hypothesis that inflammation could play a role in the patho­
genesis of WS is intriguing both for its neuropathological implications in
epileptogenesis, and for its obvious therapeutic prospective. Still, it is
not to exclude that all the mentioned inflammatory alterations may be
concomitant, rather than causal, and be the expression of an underlying
brain-damaging process. The role of ACTH would, therefore, be more
likely related to its direct, steroid-independent neurotropic effects
(Rogawski and Reddy, 2002). Further researches will better clarify the
actual role of inflammation in the genesis of WS and the precise thera­
peutic mechanism of ACTH and steroids in the treatment of DEE.
4.2. Neuroinflammation in other epileptic encephalopathies
4.2.1. The response to antinflammatory therapies
Although many efforts have been carried out to investigate the as­
sociation between neuroinflammation and WS or epilepsy in general,
little has been done to assess whether this could apply to other severe
forms of DEE (non-WS-DEE). After the first reports on steroids and ACTH
employed as anti-epileptic drugs (Mcquarrie and Ziegler, 1942; Klein
and Livingston, 1950; Lacy and Penry, 1976), and following the clinical
evidence of their anticonvulsant activity in drug-resistant epilepsies
(Vezzani et al., 2011), the use of corticosteroids has been progressively
extended from WS to non-WS-DEE and other forms of severe, often
drug-resistant epilepsy characterized by the involvement of the immune
and inflammatory response.
Patients with Landau-Kleffner Syndrome (Sinclair and Snyder,
2005), encephalopathy related to ESES (Buzatu et al., 2009),
Lennox-Gastaut Syndrome (Kurokawa et al., 1980; Charuvanij et al.,
1992), protocadherin-19 female epilepsy (PCDH19-FE) (Higurashi et al.,
2015), have shown good clinical responses to corticosteroids, in terms of
reduction in seizure frequency and seizure freedom rate in different
case-reports and case-series. On the other hand, the efficacy of cortico­
steroids was less clear in other forms of epilepsy, such as
Myoclonic-Atonic Epilepsy (Doose Syndrome) (Oguni et al., 2002;
Bakker et al., 2015) and Dravet syndrome. In a cohort of 6 patients with
Dravet syndrome treated with prednisone by Sinclair, only two patients
became seizure-free, two relapsed after an initial improvement (one
showing a 50 % decrease in seizure frequency after relapse), while the
other two showed no change in the course of their disease (Sinclair,
2003). O’Regan and colleagues treated one patient with ACTH, with no
significant changes in seizure frequency or in the EEG pattern (O’Regan
and DCH, 2008).
The variability in the response to the therapy, may be partially
explained by a lack of a consensus on the medication regimens (Gupta
and Appleton, 2005). Pulse intravenous methylprednisolone
(10− 30 mg/kg/day for 3 days) or oral prednisone (1− 2 mg/kg/day for
6 weeks) are often used for the induction regimen, followed by a
maintenance with oral prednisone (0.5− 2 mg/kg/day tapered over 2–6
weeks) (Bakker et al., 2015; Sinclair, 2003; Bast et al., 2014; Sevilla-­
Castillo et al., 2009; You et al., 2008). However, the variable therapeutic
outcomes experienced in non-WS-DEE patients may underlie the exis­
tence of different therapeutic effects of steroids, for which a
dose-dependence is been less investigated (Riikonen, 1987; Dontin et al.,
2015). A recent Cochraine review stated that there is lack of evidence for
the efficacy and safety of corticosteroids in non-WS-DEE (Mehta et al.,
2015).
Among other immunomodulatory treatment options, intravenous
immunoglobulins (IVIG) were introduced in the treatment of epilepsy
after the first empirical observations made by Pechadre and colleagues
in 1977 (Péchadre et al., 1977). IVIG are widely used for the treatment
of several immune-mediated diseases of the CNS, in which they act as a
powerful modulator of both humoral and cell-mediated responses
(Lünemann et al., 2015). Nevertheless, there is still uncertainty about
their role in DEE. Studies focusing on both WS and non-WS-DEE re­
ported a variable rate of therapeutic response (Billiau et al., 2007).
Particular interest grew on Landau-Kleffner syndrome, in which an
immune pathogenesis was strengthened by the detection of

5
A. Orsini et al.
autoantibodies against myelin and brain endothelial cells in a propor­
tion of patients (Nevšímalová et al., 1992). However, even if several
patients showed a good response to IVIG, prospective studies failed to
confirm clear efficacy (Fayad et al., 1997; Lagae et al., 1998; Mikati and
Saab, 2000; Arts et al., 2009; Geva-Dayan et al., 2012; Geng et al., 2019)
and further randomized trials are needed to assess whether IVIG may be
a valuable treatment option in DEE.
4.2.2. The role of cytokines
The involvement of cytokines in non-WS-DEE has been less exten­
sively studied compared to WS. Some authors found elevated IL-6 serum
levels in patients with LGS, ESES, and Dravet syndrome, indicating that
recurrent seizures may activate inflammatory pathways leading to po­
tential neurotoxic effects and aggravating intellectual disabilities (Leh­
timäki et al., 2011). Patients with Dravet syndrome, in particular, also
show a proinflammatory vaccine-responsiveness profile, with increased
production of IL-1β, IL-6, TNF-α after in vitro stimulation of peripheral
blood mononuclear cells (Auvin et al., 2018).
To conclude, the liaison between epilepsy and neuroinflammation
has been validated through studies on animal models (Vezzani et al.,
2013) and assumed in DEE (Auvin et al., 2016) but the prognostic role of
neuroinflammation have been poorly investigated in non-WS-DEE.
There is experimental evidence that neuroinflammation could influ­
ence brain excitability and induce long-term neurological sequelae,
affecting crucial areas of the immature brain in a particular moment of
the development, or creating immune priming that would, thereby,
exacerbate a second inflammatory response and affect processes rele­
vant for the development of cognitive impairment (Auvin et al., 2016).
Major limitations, compared to WS, are the substantial lack of adequate
animal disease models and the difficulty to provide large cohorts of
patients due to their relative rarity and the heterogeneous pathogenetic
background of non-WS-DEE.
4.3. Inflammation in other severe epilepsies
The experience with non-DEE epilepsies featured by immune and
inflammatory involvement helped to better characterize the mecha­
nisms underlying neuroinflammation and contributed to the knowledge
on the effects of immune agents in the treatment of epilepsy.
Rasmussen encephalitis (RE) is a progressive DEE with unilateral
hemispherical involvement characterized by a chronic and progressive
process with histopathological features of inflammation (Pardo et al.,
2014; Orsini et al., 2020). A role of humoral immunity was initially
supposed (Rogers et al., 1994), even if later reconsidered (Mantegazza
et al., 2002), and recent evidence suggests rather a cell-mediated im­
mune response pathogenesis, with a major role of CD8+ cytotoxic cells
(Bien et al., 2002) and a brain tissue cytokine and chemokine profile
skewed towards a Th1 response (Owens et al., 2013). Different immu­
nomodulatory drugs, including steroids, IVIG, and immunosuppressive
therapies, have been proposed for the treatment of RE (Orsini et al.,
2020, 2019). Recently, the pathogenic role of the CXR3/CXCL10 axis
has been demonstrated, suggesting it as a possible therapeutic target
(Mirones et al., 2013).
The role of neuroinflammation and its potential therapeutic impli­
cations have been studied also in PCDH19-FE. Higurashi and colleagues
reported a reduction of acute clusters in five patients with PCDH19-FE
after corticosteroid administration. Authors did not find significant
brain inflammation in their patients, suggesting that the action of cor­
ticosteroids would rather consist in amelioration of the BBB dysfunction,
resulting -in turn- from a systemic inflammation (Higurashi et al., 2015).
Furthermore, an emerging role of neurosteroids as neuromodulators in
PCDH19-FE has been recently investigated, supporting the use of ACTH
to restore steroidogenesis, improve adrenal response and raise levels of
allopregnanolone, a positive modulator of GABAA receptor (Tan et al.,
2015; Trivisano et al., 2017).
Finally, the evidence of these links between inflammatory pathways
6
Epilepsy Research 172 (2021) 106588
and epilepsy has led to a growing clinical interest in new immuno­
modulatory agents for the treatment of severe forms of epilepsy. The
adoption of Anakinra, a monoclonal IL-1 receptor antagonist, for the
treatment of Febrile infection-related epilepsy syndrome (FIRES) (Ken­
ney-Jung et al., 2016) is an interesting example of how targeted
anti-inflammatory drugs may be used in the future to treat drug-resistant
epilepsies.
5. Implications for future treatments
5.1. The anti-inflammatory role of ketogenic diet in drug-resistant
epilepsy
The anti-inflammatory effects of well-known antiepileptic therapies
such as the ketogenic diet (KD) have been largely investigated. KD is a
high-fat, low-carbohydrate, normal protein diet known since the very
first years of the ninetieth century. In the last decade, several studies
reported the high efficacy of KD for the treatment of various causes of
drug-resistant epilepsy beyond GLUT-1, such as infantile spasms, in
which KD can reduce seizure burden and improve the intellectual
outcome (Sakuma et al., 2020; Nosadini et al., 2017; Dupuis et al., 2015;
Pardo, 2020; Dressler et al., 2019; Hussain, 2018; Caraballo et al., 2013;
Goldberg et al., 2019; Wells et al., 2020; Yu et al., 2013; Arsyad et al.,
2020; Wang et al., 2020; Dressler and Trimmel-Schwahofer, 2020). The
antiepileptic mechanisms of KD are still not completely clear and
include multiple effects of reduced cortical hyperexcitability due to
changes in neuronal metabolisms, synaptic function, mitochondrial ac­
tivity, neurotransmitters production, but also changes in the gut
microbiota and neuroinflammation. Recent evidence has demonstrated
the high efficacy of KD in FIRES and in new-onset refractory status
epilepticus (NORSE) supporting the hypothesis that a major contribu­
tion to the anti-epileptic properties of KD may be directly linked to its
immunomodulatory effects (Sakuma et al., 2020). Multiple hypotheses
regarding the effect of ketosis on inflammation have been formulated in
recent years. (Sakuma et al., 2020; Nosadini et al., 2017; Dupuis et al.,
2015; Pardo, 2020; Dressler et al., 2019; Hussain, 2018; Caraballo et al.,
2013) KD can modulate fever and seems to decrease peripheral
inflammation and brain IL-1β expression. In KD-fed rats, decreased
circulating amino acids result in a reduced ability to synthesize
proinflammatory-6 derivatives, with the dual effect of impairing both
body temperature and IL-1β increase (Dupuis et al., 2015). Other au­
thors reported a direct effect of KD on T-cells in KD-fed mice, that was
not observed in non-ketogenic high caloric density diet-fed mice. In
particular, KD increased γδT cell proliferation via fatty acid oxidation
(Goldberg et al., 2019). Moreover, KD seems to inhibit
nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3)
inflammasome function and activate the hydroxycarboxylic acid 2
(HCA2) receptor, which acts on monocytes and macrophages via
β-hydroxybutyrate (Wells et al., 2020). Finally, recent studies have
shown that KD also protects against excitotoxicity-mediated neuronal
cell death by decreasing the cellular oxidative stress in the Krebs cycle
(Yu et al., 2013).
5.2. Anti-cytokines and anti-chemokines treatments
The evidence on the contribution of neuroinflammation in the gen­
esis and perpetuation of epilepsy in DEE has led to an increased interest
in potential therapeutic targets, as summarized in Table 2. In particular,
the emerging role of cytokines and chemokines in the pathogenesis of
epilepsy has been extensively studied as a target for therapy (Vitaliti
et al., 2014). Treatments targeting the IL-1β /TLR4 axis are of extreme
clinical interest, given the role of this molecular pathway in epilepto­
genesis and the increased levels of IL-1β found in patients with WS. As
expected, agents interfering with the IL-1β synthesis (Ravizza et al.,
2008; Maroso et al., 2011b) (such as the caspase-1 inhibitors (Vezzani
et al., 2010)) and signaling (including the anti-IL-1 receptor monoclonal
A. Orsini et al. Epilepsy Research 172 (2021) 106588

Table 2 seizure frequency (Zhao et al., 2017). The TLR4 pathway is another
Potential therapeutic targets in drug-resistant epilepsy and DEE: clinical and promising target for the reduction of neuroinflammation (Rahimifard
preclinical experience. et al., 2017), although there are no drugs available directed against
Target Role in Targeted- Clinical/ TLR4. Moreover, the inhibition of TGF-beta signaling prevented epi­
epileptogenesis therapy preclinical leptogenesis in animal models of BBB disruption (Shandra et al., 2017;
experience Bar-Klein et al., 2014). Clinical studies on cytokine-directed therapies
Influence on NMDA Case reports - inhuman subjects with DEE are lacking. However, biologic drugs
receptor; reduction of FIRES ( directed against IL-1, IL-6, and TNF-α have been used in patients with
glutamate uptake; Anakinra (IL-1 Kenney-Jung
epilepsy with promising results. As previously discussed, the first reports
IL-1 β increase of glutamate receptor et al., 2016;
release; enhanced antagonist) Dilena et al., of patients affected by FIRES successfully treated with anakinra have
glutamatergic effect 2019; Sa et al., shed light on a new and promising therapeutic field (Dilena et al., 2019;
with excitotoxicity 2019) Sa et al., 2019). Likewise, the administration of the anti-IL-6 monoclonal
Case series - antibody tocilizumab was effective to treat patients with refractory
Pro-inflammatory
Tocilizumab refractory
a) cytokines release
(anti-IL-6 status
status epilepticus (Jun and Lee, 2018; Gaspard, 2019). In patients with
IL-6 promotion and RE, the administration of the anti-TNF-α antibody adalimumab resulted
monoclonal epilepticus (Jun
maintenance of
antibody) and Lee, 2018; in a clinical response on seizures and, in 3/11 patients, also in an arrest
neuroinflammation
Gaspard, 2019) of the disease progression. (Lagarde et al., 2016) Interestingly, a recent
Case series -
Reduced expression of Adalimumab trial investigating the efficacy of the anti-α4-integrin antibody natali­
Rasmussen
TNF-α
GABA-A; influence on (anti-TNF-α
Encephalitis ( zumab in patients with refractory epilepsy showed a reduction of the
glutamatergic monoclonal seizure frequency, although the study did not reach its primary endpoint
Lagarde et al.,
transmission antibody)
2016) (Rizzo et al., 2020).
microRNA- Targeted-therapies directed against chemokines are currently avail­
Activation of the Experimental
146a analogue
inflammasome, and model of able for the treatment of HIV infection (Gilliam et al., 2011) and the
TLR4 (interference
release of IL-1β and epilepsy (Iori mobilization of human hematopoietic stem cells from the bone marrow
with IL-1/
HMGB1 et al., 2017)
TLR4 axis) (Yang et al., 2019), while their use in epilepsy has not been considered
Activation of NF-ĸB,
Anti-HMGB1
Experimental yet. Animal studies showed that interference with CCL2 signaling or
chemoattractant model of
HMGB1 monoclonal transcription can abrogate lipopolysaccharide-induced seizures in mice
action; interference epilepsy (Zhao
with NMDA function
antibodies
et al., 2017) (Cerri et al., 2016; Wu et al., 2019; Xu et al., 2017). In rats with
Experimental kainate-induced epilepsy, lowering the expression of CCR5 through RNA
Component of the
inflammasome, Inhibitors of
model of interfering agents reduced neuroinflammation while improving the ef­
Caspase-1 epilepsy ( ficiency of neuronal proliferation and repair (Louboutin and Strayer,
central for the IL-1 caspase 1
Vezzani et al.,
synthesis 2013). CX3CL1/fractalkine and its receptor and the CXCL12/CXCL4
2010)
Maintenance of Experimental interaction represent other potential targets for future antiepileptic ap­
Losartan
neuroinflammation; model of proaches (Roseti et al., 2013; Fabene et al., 2010).
(interference
TGF-β influence on epilepsy (
with TGF
glutamatergic Bar-Klein et al.,
b) signaling) 6. Conclusion
transmission 2014)
Promotion of Experimental
leukocyte recruitment, CCR5-RNA model of The path to understanding the role of neuroinflammation in epilepsy
integrin-mediated interfering epilepsy ( is still long. In the last few years, there has been increasing evidence of
endothelial adhesion, agents Louboutin and the involvement of inflammatory processes in the pathophysiology of
and tissue repairing; Strayer, 2013)
seizures and different forms of epilepsy, including DEE. Notably, the role
alteration of calcium miR-206
Chemokines
signaling; activation of (interference
Experimental of the innate immune system has been investigated both in vitro and in
model of
pro-inflammatory with CCL2 vivo, mainly in animal models. Yet, there are some intrinsic difficulties
epilepsy (Cerri
pathways (STAT3), signaling);
et al., 2016; Wu in studying the neuroimmune activation in patients with epilepsy,
modulation of CXCR2
et al., 2021; Xu because, in the majority of the cases, scientists only get access to the
neurotransmitters selective
activity antagonists;
et al., 2017) cerebrospinal fluid, or need to relay over non-invasive investigations
Experimental that must be further implemented in the future. Furthermore, we still
Neuroinflammatory
model of need to explore the role played by the adaptive immune system in this
Complement C5ar1 inhibitor epilepsy ( complex scenario.
enhancement
Benson et al.,
Even considering their etiopathogenic heterogeneity, taken as a
2015)
whole, DEEs constitute a unique opportunity to study the role of
FIRES: Febrile infection-related epilepsy syndrome; GABA: Gamma- inflammation in epilepsy (and vice-versa). Clinical practice has taught
aminobutyric acid; HMGB1: High mobility group box 1; IL: Interleukin; IL- us that different DEEs may share a similar clinical evolution and
1RA: Interleukin-1 receptor antagonist; NF-κB: Nuclear factor κB; NMDA: N-
response to immunomodulatory treatments (including steroids), which
methyl-D-aspartate, STAT3: Signal transducer and activator of transcription 3;
can be as effective as antiepileptic drugs in reducing seizure frequency or
TGF: Transforming growth factor; TLR4: Toll-like receptor 4; TNF: Tumor ne­
crosis factor.
aborting seizure clusters. Although the underlying molecular mecha­
nisms remain largely unknown, common clinical features may suggest
the presence of a vicious circle involving inflammation and epilepto­
antibody anakinra) are effective in reducing seizures (Vezzani et al.,
genesis within different stages (from childhood to adulthood) of brain
2013, 2000; van Vliet et al., 2018) in animal models of epilepsy. The
maturation (Striano et al., 2011).
administration of a microRNA-146a analog, which down-regulates the
Future studies on DEE should finally clarify whether targeted ther­
IL-1β /TLR4 pathway, is effective in reducing seizures and preventing
apies against neuroinflammation may be helpful in the prevention or
the progression of epileptogenesis in mice (van Vliet et al., 2018; Iori
control of seizures and developmental regression. Finally, from bedside
et al., 2017). Other strategies targeting the IL-1β/TLR axis include the
to bench, this would provide indirect insight into the physiopathological
use of HMGB1 antagonists (Musumeci et al., 2014): in animal models of
processes that promote seizures and regression in DEEs.
epilepsy, anti-HMGB1 monoclonal antibodies can significantly reduce

7
A. Orsini et al.
Funding details
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Disclosure statement
The Authors declare no conflict of interest. P.S. received speaker fees
and participated at advisory boards for Biomarin, Zogenyx, GW Phar­
maceuticals, and has received research funding by ENECTA srl, GW
Pharmaceuticals, Kolfarma srl., Eisai.
Author’s contribution
AO and TF conceived and designed the original study; AM, GC and
FV performed a systematic literature review and implemented the text
with the tables; RC gave substantial scientific contribution for the
immunological implications; DP, SS and PS critically revised the
manuscript for intellectual content. PS developed this work within the
framework of the DINOGMI Department of Excellence of MIUR
2018–2022 (legge 232 del 2016).
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