Giannotta Girolamo, Giannotta Nicola
Originally published: January 2022
Background: The relationship between vaccines
and neuroinflammation have consistent molecular biology bases. In a
recent paper we have already analyzed this kind of relationship.
Hypothesis: In this paper, we have gained
additional evidence to support the link between vaccines and
neuroinflammation. Furthermore, we found the molecular bases that
support the link between HPV vaccines and certain adverse events (AEs).
The peripheral proinflammatory cytokines (IL-1β, IL-6, and TNF-α),
expressed after the injection of the vaccines can reach the brain and
can cause neuroinflammation after microglia activation. After vaccine
injection significant systemic immune activation may occur with signs
suggesting reactive brain inflammation, such as acute crying, fever,
restlessness and failure to eat. It is a warning of danger to the brain
in front of which we should reflect before causing irreversible damage.
We also hypothesized the existence of a post-vaccination inflammatory
syndrome caused by the proinflammatory cytokines strongly expressed
after HPV vaccine injections. In addition, the molecular explanation of
the chronic pain that has affected many girls in the world, including
the complex regional pain syndrome (CRPS) in Japanese girls.
Conclusion: All vaccines can cause
neuroinflammation. HPV vaccines can cause a post-vaccination
inflammatory syndrome characterized by chronic pain and
neuroinflammation. In this case, the phenomena of central sensitization
is responsible for all the symptoms associated with chronic pain. The
strong expression of proinflammatory cytokines, secreted after HPV
vaccinations, brings to process that can produce irreversible
neurological results in HPV vaccinated girls.
Post-vaccination inflammatory syndrome,
Neuroinflammation, Microglia activation, vaccines and autism, ASD,
Autism Spectrum Disorders, HPV Vaccines, HPV vaccines adverse events,
HPV vaccines AEs, complex regional pain syndrome (CRPS) in Japanese
girls, CRPS type I, Chronic pain, Central sensitization.
Vaccines are an important health policy tool and have
changed the history of infectious diseases. In recent years, the number
of vaccines injected to infants have increased, and many doses are
administered during the first year of life, when the immune system and
the central nervous system have yet to complete their development.
Moreover, the immune system and the brain are bonded for life, dependent
upon each other in sickness and in health [1]. In addition, at the same
time, each immunological challenge is a challenge for the brain, and
each vaccination is a challenge for both. Each injection of vaccine,
regardless of the type, is followed by the production of variable
amounts of pro-inflammatory cytokines, which exert both local effects
and at a distance from the production site.
Since the peripheral cytokines, produced after the
injection of the vaccines, are able to reach the central nervous system,
we have hypothesized, in our recent paper [2], that these cytokines can
have effects on the microglia (macrophages of the central nervous
system). Microglia are the primary responders to an immune challenge and
the primary producers of cytokines and chemokines within the brain.
Microglial activation is the initial cellular event that occurs during
acute neuroinflammation [3]. Furthmore, timing of a developmental immune
challenge can be critical in determining the long-term outcomes on
brain and behavior [4], since cognitive function and immune function are
inextricably linked [1].
Since the post-vaccination adverse events (AEs) are related
to the different period of life (childhood or adolescence), and to the
different nervous area involved (brain or spinal cord); in this article
we will deal with the regressive form of ASDs and present our hypothesis
of a new post-vaccination inflammatory syndrome triggered by HPV
vaccines. In our discussion we will only manage with molecular biology
and our work is not suitable for improbable comparisons with
epidemiological studies on vaccines. In this case, our task will be to
describe the biological plausibility that links vaccine injections to
these two clinical entities. Therefore, we will also proceed with a
review of the specific scientific literature published on the two topics
to find the evidence that supports our scientific hypothesis.
In our previous paper [2], we discussed the immunological
aspects in ASD and in this paper we report additional findings. ASD is a
pervasive neurodevelopmental condition characterized by variable
impairments in communication and social interaction as well as
restricted interests and repetitive behaviors. In the case of regressive
autism, children are born healthy, have apparently normal development,
and have been reaching their developmental milestones (as clearly
documented in their medical records) and suddenly develop autism-like
symptoms shortly after receiving a schedule vaccine [5].
There is a growing body of work to support the role of
inflammatory cytokines in ASD. An emerging focus of research into the
etiology of ASD has suggested neuroinflammation as one of the major
candidates underlying the biologica model [5]. Plasma levels of IL-1β,
IL-6 and IL-8 were increased in children with ASD and correlated with
regressive autism, as well as impaired communication and aberrant
behavior [6,7,8]. Vargas [9] showed an active neuroinflammatory process
in the cerebral cortex, white matter, and in the cerebellum of autistic
patients. Immunocytochemichal studies showed marked activation of
microglia [5].
Since brain and immune system are inextricably woven
together, immune-activating events can influence the long-term
trajectory and function of developmental processes [10]. At birth, the
neonatal immune system faced the critical challenge of transferring from
a sterile environment to a world filled whit pathogens, microbes, and
toxins where it must effectively defend the newborn. Early life
infection is not the only challenge that can activate the immune system
and impact the developing brain and behavior [1], and vaccinations are
important immune challenges.
1.1 Genes and Environment
Gene networks are involved in immune processes are
overexpressed in the brain of individuals with ASD [11,12]. Human
communication and patterns of behavior are governed by a large number of
genes and by a complex orchestra-like communication between these genes
which are formed and organized during the early stage of human fetal
development [13].
There is an extreme vulnerability of the developing human
brain to toxic exposure in the environment [14]. Moreover, the fetal
brain can be a major target for some synthetic chemicals that can cause
mutations and/or interrupt the well-orchestrated pattern of fetal brain
development. Any environmental agents that interfere with fetal brain
development can cause major adverse effects even after birth. Indeed,
pollutants can induce genetic mutations in fetal brain cells [13]. These
effects then depend on the time of exposure, on the composition of the
contaminating chemical mixture and on the specific vulnerability of the
fetus in that specific phase of development. For example, damage to a
cellular progenitor can lead to a greater loss of a cellular component
since the cell population, dependent on that ancestral progenitor, is
missing. In addition, epigenetic modifications can make one type of
brain progenitor neuron change to another type [15]. Epigenetic changes
produce a change in phenotype without a change in genotype. Toxins, such
as diesel exhaust, drugs such as morphine, amphetamines and alcohol can
trigger TLR signaling [16]. Different environmental stimuli can trigger
TLR signaling, either directly or indirectly via an alarmin pathway.
HMGB1 is a ubiquitous component of chromatin which can be released by
necrotic cells, and is actively secreted by cells undergoing an
inflammatory challenge or biological stress. HMGB1 activates microglia
in the brain via TLR4 [16].
1.2 Peripheral cytokines in ASD
Pro-inflammatory cytokines, including IL-1β, IL-6, and
TNF-α, appear to be at the forefront in the communication between the
immune and the nervous system, playing dual roles in mediating
physiological and neuroprotective roles in normal brain function or
being detrimental and associated with brain diseases, especially when
present at elevated concentrations [17]. Altered cytokine profiles have
been consistently linked to ASD in children in the postnatal period
[18]. Cytokines may influence behavior through effects on
neurotransmitter function, neuroendocrine activity, neurogenesis, and
alterations to brain circuitry [19]. Peripheral cytokine signals are
thought to access the brain through three pathways: humoral, neural, and
cellular [19,20]. The blood-brain barrier (BBB) has an
energy-dependent, saturable, carrier-mediated transport system for
cytokines, primarily IL-1, IL-6, and TNF-α [21,22]. When endothelial
cells making up the BBB come into contact with these peripheral
cytokines, they secrete various immune molecules into the brain
parenchyma, including NO, prostaglandin E2, IL-1, and IL-6, all
proinflammatory cytokines known to affect neurological function [23].
The entry of peripheral cytokines into the brain determines
different effects. The brain recognizes cytokines such as the
pro-inflammatory cytokines IL-1α, IL-1β, TNF-α, and IL-6 as molecular
signals of sickness [24]. Elevated IL-1β and IL-6 have been associated
with increased stereotypical behaviors. Normal levels of IL-1β and its
IL-1ra receptor antagonist are necessary to achieve normal development
and normal brain function. TNF-α is a central regulator of inflammation
and is elevated in the cerebrospinal fluid of children with ASD [25].
1.3 Microglia
Microglia is associated with neurons, synapses and blood
vessels. Microglia are multifunctional immune cells of the brain and are
involved in the defense of neural parenchima, and in immune response in
the brain. Microglia are also concentrated in sites of
incomplete BBB function, such as the circumventricular organs (CVOs),
or the organum vasculosum of the lamina terminalis, subcommissural
organ, subfornical organ, area postrema, posterior pituitary, median
eminence, pineal, and choroid plexus [26]. Amoeboid microglia remove
inappropriate superflous axons and cellular debris. A recent study by
[27] demonstrated a central role of microglia in synaptic pruning and
circuit development in the developing embryonic brain.
Neuroglial activation and its innate immune responses have
been reported to contribute to autism [28]. Microglial activation is
reported to be present in autistic patients throughout their life
(including the early period of development) and play a critical role in
the development of autism [29]. Autopsy studies performed on autistic
brains revealed marked activation of microglia [28] and sustained
neurological inflammatory response due to microglial activation in
cortical and subcortical white matter as well as in the cerebellum.
Autistic brains expressed a wide array of pro-inflammatory cytokines.
On activation, microglial cells are known to secrete
proinflammatory cytokines/chemokines and the presence of proinflammatory
chemokines such as MCP-1 is attributed to the pathogenesis of autism by
activated microglia or by recruiting monocyte/macrophages to the sites
of cortical neuronal abnormalities [28]. Furthemore, excitotoxin
glutamate released by activated microglia is also of prime concern as
excess glutamate in the brain is deleterious to neurons and synaptic
connections [30]. Microglia also exert cytotoxic effects through
secretion of toxic factors such as nitric oxide (NO), reactive oxygen
species (ROS) and cytokines [31].
1.4 Microglia primed
Microglial activation is quite rapid following systemic
immune activation, usually within minutes and results in
immunoexcitotoxicity. Upon stimulation, microglia produces also a vast
array of cytokines, some of which are know to have neurotrophic and
neuroprotective functions [31]. Indeed, IL-10 and TGF-β are known to
have anti-inflammatory activities, IL-6 has also neurtrophic activity
and pro-inflammatory activity [31].
Microglia can switch from a resting phenotype to a primed
state by an initial immune stimulus that is not excessively intense. For
example, a mild head injury or episode of hypoxia can switch microglia
from its resting state to a functional condition in which the enzymes
and genetic activation is upregulated, but the active immune molecules,
primarily proinflammatory cytokines and chemokines, are not released
[32]. With a second immune stimulus, these primed microglia began to
release proinflammatory cytokines and chemokines in much higher
concentrations than that of not primed microglia [32].
Systemic immune stimulation can prime brain microglia,
which means that either subsequent brain disturbances or systemic immune
activation would trigger a magnified immune response within the brain
[32]. Immune events throughout life, exposure to neurotoxic metals,
exposure to pesticides/ herbicides and fungicides, head injury, and
other factors, can cause episodes associated with microglia priming and
activation, leading to a progressive loss of neurons in the most
vulnerable parts of the CNS, such as the hypothalamus, temporal lobes
(hippocampus, striatal area, amygdala, and entorhinal cortex) and
prefrontal cortex [32].
In the infant or small child, the priming event may come
from a number of sources, such as vaccination of the mother during
pregnancy or with intrauterine or early post birth infections [33,34].
In other instances, the priming event may occur with the first vaccine
inoculation, usually at birth (hepatitis B). Once primed, subsequent
vaccinations, especially within months of the previous inoculation, will
trigger full microglial activation and in the developing brain can
result in abnormal pathways development [35-38]. While natural
infections can also produce this neurodestructive response, vaccinations
produce higher levels of immune activation and the immune response can
persist longer than natural infections – sometimes lasting years [32].
It is well-established that inflammation in the periphery
can prompt immune responses in the brain [39]. Contrary to the long held
assumption that immunological memory exists only in cells of the
adaptive immune system, recent evidence has indicated that also myeloid
cells display memory effects [40,41]. For example, certain immune
stimuli training blood monocytes to generate enhanced immune responses
to subsequent immune insults [42,43]. By contrast, other stimuli induce
immune tolerance/suppression of inflammatory responses to subsequent
stimuli [43,44].
Innate immune memory lasts for several days in vitro and
for up to three months in circulating monocytes in vivo and is mediated
by epigenetic reprogramming in cultured cells, with chromatin changes
also apparent in vivo [43,45,46]. However, while training may be
beneficial in the periphery, owing to enhanced pathogen elimination
[47,48], and tolerance may be detrimental owing to higher rates of
infection resulting from immune suppression [44], training promotes,
while tolerance alleviates neuropathology [49].
In summary, innate immune memory is a vital mechanism of
myeloid cell plasticity that occurs in response to environmental stimuli
and alters subsequent immune responses [49]. Two types of immunological
imprinting can be distinguished, training and tolerance. These are
epigenetically mediated and enhance or suppress subsequent inflammation,
respectively [49]. Peripherally applied inflammatory stimuli induce
acute immune training and tolerance in the brain and lead to the
differential epigenetic reprogramming of microglia that persists for at
least six months [49]. Individual cytokines applied peripherally may
also elicit immune memory effects in the brain [49].
1.5 Dangerous Oxidative Species
Many of the toxic substances secreted by microglia are
reactive oxygen and nitrogen species (RONS) which include superoxide
anion radical, hydrogen peroxide, nitric oxide, peroxynitrite, and
nitrogen dioxide (Blaylock, 2004). Superoxide is produced by the enzyme
NADPH oxidase. The RONS produced by microglia are capable of not only
killing healthy neurons but they are also capable to cause oxidative
stress and produce priming microglia for further activation (Kaur and
Eng-Ang, 2012). Reactive nitrogen species are produced by nitric oxide
synthase including the inducible isoform (iNOS) that is upregulated
during microglia activation [31]. The iNOS is expressed only during
inflammation by activated microglial cells under certain conditions such
as hypoxic injury and infections [31]. Reactive nitrogen species are
neurotoxic and are capable of damaging the vasculature and impairing the
mitochondrial respiratory chain. NO has multiple roles in the brain,
from regulation of blood flow to being a potent neurotoxin. These
effects depend on the cellular source and the amount generated [31]. A
simultaneous activation of iNOS and phagocyte NADPH oxidase in microglia
leads to the formation of peroxynitrite which is an extremely powerful
oxidizing agent [31].
In the field of post-vaccination adverse reactions (AEs or AEFI), there are two major problems:
- The unbundled report system that is present in the vaccines data sheets.
2.1 The first problem: WHO
In January 2018, the WHO produces a document on how to
catalog the adverse reactions that are indicated by the acronym AEFI.
The WHO states: “Causality assessment is the systematic review of
data about an AEFI case; it aims to determine the likelihood of a causal
association between the event and the vaccine(s) received” [50]. It also specifies: “At
the individual level it is usually not possible to establish a definite
causal relationship between a particular AEFI and a particular vaccine
on the basis of a single AEFI case report” [50]. Since all adverse
reactions are case reports (because they occur in a single vaccinated
individual), excluding them results in the consequent elimination of all
post-vaccine AEs. Furthermore, the report cases form the series of
reports that will never exist with this evaluation system that excludes
the individual case reports.
A practical example shows that the reports of AEs do not
end up on the reports of the regulatory agencies. These are two cases of
transient neutropenia from MMRV vaccines (Measles, Mumps, Rubeola and
Varicella) that have been published [51] after reporting to the Italian
Medicines Agency [52], but it do not appear in the Agency Report [53].
2.2 The second problem: Vaccines Data Sheets
Taking as an example a vaccine widely used in Europe [54],
we immediately notice that the adverse reactions are cataloged reporting
the frequency of the single symptom, but there are no data on the
combination of reactions in the same subject (GSK, 2018). Infanrix Hexa
is indicated for primary and booster vaccination of infants and toddlers
against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and
disease caused by Haemophilus influenzae type b. The following
drug-related reported adverse reactions in clinical studies (data from
more than 16,000 subjects) and during post-marketing surveillance (GSK,
2018).
Very Common Adverse Events (≥ 1/10 doses)
- Appetite lost.
- Crying abnormal and pain.
- Irritability.
- Fever ≥ 38°C.
The presence of all these symptoms in the same subject
suggests a post-vaccination reactive brain inflammation produced by
proinflammatory cytokines, secreted after vaccine injection.
2.3 Post-Vaccination Reactive Brain Inflammation
During the first two years of life, particularly in the
winter months, the immune system is often engaged with several
infectious challenges. These are immune stimulations added to the immune
challenges, linked to the adoption of the vaccination schedule.
After vaccine injection, especially if multiple doses are
given to a young child during a single office visit, significant
systemic immune activation may occur with signs suggesting reactive
brain inflammation, such as acute crying, fever, restlessness and
failure to eat [32,36]. When this reaction takes place, it is necessary
to suspend the vaccination schedule for at least 6 months to allow the
innate immune system to “forget that it has become so little tolerant in the brain”.
Otherwise, the neuroinflammation may produce serious damages especially
if the microglia continues to be stressed by peripheral cytokines
produced after each vaccination. It is a warning of danger to the brain
and you can choose to continue the vaccination schedule (putting at risk
the health of the small child) or, vice versa, stop with vaccinations
to respect the principle of “primum non nocere”.
Human papillomavirus vaccines (HPV Vaccines) are neither
safe nor effective as claimed by so much scientific literature. These
vaccines are anti-virus vaccines, but they are not anti-tumor vaccines
[2], In our previous publication, we addressed the issues of the alleged
safety and efficacy of these vaccines [2]. In this paper we will
discuss the molecular biology that supports our hypothesis of a new
post-vaccination inflammatory syndrome triggered by HPV vaccines.
Let us just remember that it was shown that vaccinated
young women have had a higher prevalence of any HPV type infection (type
with high and low risk for cancer), and a higher prevalence of virus
infection with high risk of non-vaccine types, despite having a lower
prevalence of vaccination types [55].
3.1 History of adverse reactions
In Japan, the period of HPV vaccination overlapped with the
development of HPV vaccine-related symptoms in the vaccinated patients,
including chronic regional pain syndrome (CRPS) and autonomic and
cognitive dysfunctions [56]. Brinth [57] reported the characteristics of
a number of patients with a syndrome of orthostatic intolerance,
headache, fatigue, cognitive dysfunction, and neuropathic pain starting
in close relation to HPV vaccination. The Lareb in the Netherlands, has
received a substantial number of reports concerning long-lasting AEs
after vaccination with Cervarix® [58,59].
3.2 HPV vaccines and pain
In the Cervarix Package insert [54] it is reported that:
20% of subjects were in pain, 20% of subjects had a sense of fatigue. In
the Gardasil 4 Package insert [60] it is reported that: headache,
fever, nausea, and dizziness; and local injection site reactions (pain,
swelling, erythema, pruritus, and bruising) occurred after the
administration of Gardasil. In the Gardasil 9 Package insert [61], pain
is reported to be present in almost 90% of vaccinated girls.
3.3 HPV vaccines and pain: the molecular bases
Vaccination produces always inflammation. During
inflammation, tissue resident and recruited immune cells secrete
molecular mediators that act on the peripheral nerve terminals of
nociceptor neurons to produce pain sensitization . Nociceptor peripheral
nerve terminals possess receptors and ion channels that detect
molecular mediators released during inflammation. Nociceptor neurons
express receptors for immune cell-derived cytokines, lipids, proteases,
and growth factors . High circulating plasma cytokine/chemokine levels
were observed after the first dose of Gardasil 4® vaccine and the
proinflammatory cytokines were elevated after the 1st and 3rd injection
of the Cervarix® vaccine [62,63,64].
In summary, proinflammatory cytokines produced after
vaccine injection are able to stimulate specific receptors that are
present on nociceptor neurons. Indeed, Nociceptor neurons are also
sensitized by TNF-α, IL-1β and IL-6 produced by mast cells, macrophages,
and neutrophils [63]. All these proinflammatory cytokines are produced
after vaccine injection.
3.4 Pain processing
Understanding pain processing is fundamental to identify
the roots of post-vaccination inflammatory syndrome caused by HPV
vaccines . This is a complicated path that begins with the expression of
proinflammatory cytokines on the vaccine injection site, and then
arrives at the somatosensory cortex.
3.5 Nociceptors
Physiological pain is initiated by specialized sensory
nociceptor fibers which innervate peripheral tissues and are only
activated by noxious stimuli [61]. The stimulation of nociceptors
determines the onset of an action potential that is propagated along the
axons of nociceptive Aδ and C fibres, through the dorsal root ganglion
(DRG) to the axon terminals in the spinal cord dorsal horn [63]. A brief
period of low frequency C-fibre stimulation, in the absence of nerve
damage, is sufficient to activate microglia resulting in behavioural
hyperalgesia [64].
Nociceptors by responding directly to cytokines can directly “sense”
the immune response in inflamed tissue; essentially they are,
therefore, not only noxious stimulus detectors, but also inflammation
sensors [65]. Moreover, TNF-α is a key regulator of the inflammatory
response and is involved in the increased production of proalgesic
agents [64].
3.6 The second order neurons
The second order dorsal horn neurons, involved in pain
circuitry, exist in two broadly characterised populations. After
synapsing at the spinal cord, the second neuron travels in the spinal
tracts, crosses the midline and runs up the spinothalamic tract to the
thalamus where they synapse again and the next neuron travels to the
somatosensory cortex. Here the impulses are processed in distinct areas,
known collectively as the “pain matrix” so the nature of the pain can be perceived.
3.7 Neurophatic and inflammatory pain
Peripheral nerve injury activates spinal microglia. This
leads to lasting changes in the properties of dorsal horn neurons that
initiate central sensitization and the onset of neuropathic pain [66].
Vice versa, inflammatory pain is initiated by tissue
damage/inflammation. Both are characterized by hypersensitivity at the
site of damage and in adjacent normal tissue [67].
3.8 Chronic pain
It is now well established that chronic pain, such as
inflammatory pain, neuropathic pain, and cancer pain, is an expression
of neural plasticity, both in the peripheral nervous system as
peripheral sensitization [68,69], and in the central nervous system
(CNS) as central sensitization [69,70].
The rules of perception and pain management change in
chronic pain. In fact, at peripheral level, nociceptors undergo
sensitization and hyper-excitability (peripheral sensitization); while
at the central level, excitatory synaptic transmission is increased in
spinal cord, brainstem, and cortical neurons (central sensitization),
caused by transcriptional, translational, and post-translational
regulation [71].
3.9 Peripheral sensitisation
The International Association for the Study of Pain (IASP) definition of peripheral sensitisation is: “Increased
responsiveness and reduced threshold of nociceptive neurons in the
periphery to the stimulation of their receptive fields” [72]. Then, Peripheral sensitisation induces a hyperexcitability of afferent nociceptive neurons [63].
3.10 Central Sensitization
The IASP definition of central sensitisation is: “Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input”
[73]. Then, central sensitization refers to the amplification of pain
by central nervous system mechanisms. On a cellular level, central
sensitization results from multiple processes altering the functional
status of nociceptive neurons [74]. Central sensitization increases
response to pain sensation. Heightened sensitivity results in the
perception of pain from non painful stimuli (allodynia) and greater pain than what one would be expected to get from normal painful stimuli (hyperalgesia).
3.11 Effects of Peripheral and central sensitization
While peripheral sensitization in nociceptors is essential
for the development of chronic pain [75], and transition from acute pain
to chronic pain [74], central sensitization regulates the chronicity of
pain, causes the spread of pain beyond the site of injury, and
influences the emotional and affective aspects of pain [62].
3.12 Spinal cord microglia
The spinal cord microglia, can respond to peripheral
injuries that are distant from the spinal cord to produce
neuroinflammation in the central nervous system [70]. Spinal glia
activation is necessary and sufficient to induce neuropathic pain [74].
Astrocytes perform numerous critical functions such as neurotransmitter
recycling, formation of the blood-brain barrier, regulation of
extracellular ion concentration, and modulation of synaptic
transmission, among many others [75].
3.13 Nociceptors activates microglia and astrocytes
In the case of strong and repetitive noxious stimuli,
larger quantities and additional signaling molecules are released from
the spinal terminals of nociceptive nerve fibers leading to the
activation of microglia and astrocytes [76], and in some cases, to the
degranulation of dural mast cells, to vasodilation, impairment of the
blood–spinal cord barrier, and to the recruitment of T-cells to the
spinal parenchyma [77]. This in turn causes the release of inflammatory
mediators in the spinal cord, including chemokines and cytokines [76].
Hathway [63] had shown that a brief period of low frequency C-fibre
stimulation, in the absence of nerve damage, is sufficient to activate
microglia resulting in behavioural hyperalgesia.
3.14 Neuroinflammation in chronic pain
Neuroinflammation (in the peripheral and central nervous system) drives and manteined widespread chronic pain via central
sensitization, which is a phenomenon of synaptic plasticity, and
increased neuronal responsiveness in central pain pathways after painful
insults [78]. A characteristic feature of neuroinflammation is the
activation of glial cells, such as microglia and astrocytes, in the
spinal cord and brain, leading to the release of proinflammatory
cytokines and chemokines [78]. Sustained increase of cytokines and
chemokines in the central nervous system also promotes chronic
widespread pain that affects multiple body sites [78].
3.15 CRPS type I
Individuals without a confirmed nerve injury are classified
as having CRPS type I, while in CRPS type II there is an associated and
confirmed nerve injury. When pain arises in the absence of a nerve
injury it is nociceptive pain. The term nociceptive pain is used to
describe pain occurring with a normally functioning somatosensory
nervous system to contrast with the abnormal function seen in
neuropathic pain [71]. CRPS describes an array of painful conditions
(nociceptive pain in CRPS type I) that are characterized by a continuing
(spontaneous and/or evoked) limb pain that is seemingly
disproportionate in time or degree to the usual course of any known
trauma or other lesion. The pain is regional (not in a specific nerve
territory or dermatome) and usually has a distal predominante [79].
Symptoms of CRPS-I include spontaneous pain (“burning” pain referred to
the skin, and “aching” pain referred to deep tissues), and a variety of
stimulus-evoked abnormal pain sensations, including
mechano-hyperalgesia, mechano-allodynia, cold-allodynia and sometimes
heat-hyperalgesia. Other symptoms include disorders of vasomotor and
sudomotor regulation; trophic changes in skin, hair, nails, and bone,
and dystonia and other motor abnormalities [80].
Thus, the most prominent mechanism appears to be the
inflammatory process because all the classic signs of inflammation
(oedema, redness, hyperthermia, and impaired function) are conspicuous
in the early stages of CRPS [81]. High levels of the proinflammatory
cytokines (TNF-α and IL-6) have been found in skin blister fluid of the
affected limbs versus the unaffected limbs of CRPS patients [82]. In
patients with CRPS, the levels of IL-1β and IL-6 were significantly
increased in cerebrospinal fluid (CSF), compared to other subjects
[83,84]. In the blood of subjects with painful neuropathy, TNF-α levels
were doubled, compared to healthy subjects and those with non-painful
neuropathy [85]. IL-1β can modulate the transmission of sensory neurons
because it increases the release of substance P [86,87]. Thus, CRPS type
I is associated with high levels of IL-1β and IL-6 in CSF, and high
levels of TNF-α in the blood. Furthermore, these proinflammatory
cytokines are strongly expressed after the injection of HPV vaccines.
Each vaccine injection determines the mandatory
intervention, at the injection site, of dendritic cells that are, at the
same time, antigen presenting cells (APC) and tissue macrophages.
Macrophages secrete pro-inflammatory cytokines such as IL-1β, IL-6, and
TNF-α, when activated. Furthemore, the immune competent cells are one of
the largest sources of cytokines, that being capable to migrate in
almost all tissues of the body, represent moving regulators of the local
microenvironment [88]. Cytokines, together with neurotransmitters and
hormones, are signaling molecules which have unique immunomodulatory
functions. Virtually, they can influence every physiological system
including neuroendocrine interactions, neurotransmitter metabolism and
neuroplasticity, thereby affecting behavioral and cognitive functioning
[89].
Each vaccine injection results in a strong expression of
proinflammatory cytokines. Cytokines take center stage in orchestrating
immune responses [90]. They act in most cases at shorter distances (with
exceptions such as IL-1, IL-6 and TNF).
In a previous paper [2], we had hypothesized a link between
vaccinations and neuroinflammation. The peripheral pro-inflammatory
cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of all
vaccines, can reach the brain and can cause neuroinflammation after
microglia activation. Elevated proinflammatory cytokines, particularly
TNF-α, have been described in studies regarding the cytokines profile in
autistic children. IL-1β represents a cytokine that controls the local
pro-inflammatory cascade and thereby affects the balance between
protective immunity and destructive inflammation. A subgroup of children
with ASD have developed neuroinflammation. Several postmortem studies
have confirmed the activation of microglia and neuroinflammation. A
recent study shows the presence of aluminium in brain tissue in ASD.
Aluminium was also found in microglia cells [91]. Aluminium from
vaccines is redistributed to numerous organs including the brain, where
it accumulates. Each vaccine adds to this tissue different levels of
aluminium. Aluminum, like mercury, activates microglia leading to
chronic brain inflammation and neurotoxicity.
Gardasil and Cervarix vaccines (Figure 1) contain aluminum,
which activates caspase-1 enzyme, via NLRP3 inflammasome. The caspase-1
enzyme converts the pro-interleukins 1β and 18 in their active forms.
IL-18 determines the production of IFN-γ. IL-1β represents a cytokine
that controls the local pro-inflammatory cascade and contributes to
activate the transcription factor NF-κB. The Cervarix adjuvant AS04
contains Aluminum Hydroxide and MPL. The second one stimulates the TLR4.
Gardasil 4 vaccine is contaminated with foreign DNA in non-B
conformation [92], which activates TLR9. TLRs act through the adapter
protein MyD88 which acts increasing the activity of NFκB, which then
increases the expression and secretion of IL-1β, IL-6 and TNF-α (for
references see [2]. Thus, there is a strong immune stimulation and a
strong production of pro-inflammatory cytokines, including IL-1β IL-6
and TNF-α, which are capable of exerting effects at a distance from the
production site.
Figure 1. Gardasil and Cervarix
vaccines contain aluminum, which activates caspase-1 enzyme, via NLRP3
inflammasome. The caspase-1 enzyme converts the pro-interleukins 1β
(IL-1β) and 18 in their active forms. TLRs act through the adapter
protein MyD88 that acts by increasing the activity of NF-κB. Both, the
IL-1β and the activation of the toll-like receptors (TLR) 4 and 9,
determines the activation of the transcription factor NF-κB, which then
increases the expression and secretion of IL-1β, IL-6 and TNF-α.
All adjuvants modulated a common set of 168 genes and
promoted antigen-presenting cell recruitment. Alum regulated 312 genes
[93]. A number of in vitro experiments [94] have shown that alum
activates the NLRP3 inflammasome in macrophages which, in turn,
activates caspase-1 and consequent production of interleukin- (IL-) 1β
(IL-1β). Upon activation, members of the Nod-Like Receptors (NLR)
family, such as NLRP3, form complexes with ASC and pro-caspase-1. The
complex formed by these molecules is referred to as the inflammasome.
The NLRP3 inflammasome is activated by a number of materials, including
alum. Whatever the cause of inflammasome activation, the consequences
include production of active caspase-1 thus conversion of inactive
precursor cytokines of the IL-1 family, including IL-1β, IL18 and IL-33,
to their active forms [95].
In summary, the aluminum salts injected as vaccine
adjuvants are taken by the innate immunity cells (especially from
dendritic cells), they engage a receptor called NLR (NLRP3), which
together with other proteins is organized into an intracellular
macromolecular complex that activates the enzyme caspase-1. This enzyme
converts pro-IL-1β and pro-IL-18 into their active forms (IL-1β, and
IL-18). The role of caspase-1 is not limited to the conversion of pro
IL-1β to IL-1β alone, but it strongly affects the secretion of
proinflammatory cytokines: IL1β, IL-1α, IL-6, TNF-α, IL-18 and IFN-γ.
IL-1 is a primary regulator of inflammatory and immune responses. Via
its type I receptor it activates specific protein kinases, including the
nuclear factor kappa-light-chainenhancer (NF-κB) inducing kinase (NIK)
and three distinct mitogenactivated protein (MAP) kinase cascades. These
modulate a number of transcription factors including NF-κB, AP1 and
CREB, each of which regulate a plethora of immediate early genes central
to the inflammatory response [96]. Therefore, each injection of the
vaccine produces a proinflammatory response. An immune response to the
vaccine antigens (to the quantities currently present in the vaccines),
is non-possible without a pro-inflammatory response, which is produced
by adjuvants.
In (Figure 2), the mechanism of action of the aluminum is
always represented, but a new anti-meningococcal B vaccine produces the
activation of the TLR- 2 and 4. The OMV vesicles contain lipoproteins
that activate the TLR2, and LPS that activate TLR4. The strong
production of peripheral pro-inflammatory cytokines is capable of
producing microglia activation and neuroinflammation.
Figure 2. The mechanism of action of
the aluminum is always represented, but a new anti-meningococcal B
vaccine produces the activation of the TLR- 2 and 4. The OMV vesicles
contain lipoproteins that activate the TLR2, and LPS that activate TLR4.
The strong production of peripheral pro-inflammatory cytokines is
capable of producing microglia activation and neuroinflammation.
On the right side of (Figure 3), you can see that the
peripheral proinflammatory cytokines, expressed after the injection of
vaccines, can reach the brain and, apart from neuroinflammation, can
cause a post-vaccination inflammatory syndrome [97], as in the case of
HPV vaccines. If a neuroinflammation is present, it could be followed by
autoimmune reactions and neurodegeneration. Peripheral cytokines can
produce primed microglia and the inflammatory phenotype M1 which
participates in the neuroinflammation. The neuroinflammation increases
production of pro-inflammatory cytokines and it activates astrocytes, it
produces an oxidative stress and increases the production of
prostaglandins in the brain. Oxidative stress and astrocytes activation
cause a rupture of the BBB that eases the entry of the T and B
lymphocytes in the brain. Oxidative stress also produces damage to
self-antigens and may help to produce autoimmunity and neurodegenerative
diseases for references see [2].
Figure 3. Peripheral pro-inflammatory
cytokines, expressed after the injection of vaccines, can reach the
brain and, apart from neuroinflammation, can cause a post-vaccination
inflammatory syndrome, as in the case of HPV vaccines.
As for the relationship between vaccines and pain, it is
now evident that the pro-inflammatory response to the injections of the
HPV vaccines is identical, under the common cytokines substrate, to the
inflammatory profile of the CRPS type I. Certainly, individual
predisposition and other possible interfering factors have determined
who should get sick and who does not, while expressing (both categories
of subjects) high levels of proinflammatory cytokines after injections
of HPV vaccines [2], As is evident, in the case of HPV vaccines, the
pain is initially caused by the strong production of proinflammatory
cytokines (such as IL-1β, IL-6, and TNF-α), which are followed by the
phenomena of peripheral and central sensitization associated with signs
of neuroinflammation in the CNS (elevated cytokines in CSF, such as
IL-1β and IL-6).
Figure 4 shows the two mechanisms (haematic and neural)
which can lead to neuroinflammation, in some girls, after the injection
of HPV vaccines.
Figure 4. Injections of HPV vaccines
can produce microglia activation and neuroinflammation. The strong
expression of pro-inflammatory cytokines (such as IL-1β, IL-6 and
TNF-α), can activate microglia via blood and/or through nociceptors
which activate microglia and astrocytes in the spinal cord. The double
activation pathway of microglia can produce neuroinflammation.
Finally, (Figure 5) demonstrates how an abnormal response
of nociceptors, to cytokines produced after injections of HPV vaccines,
can produce the peripheral and central sensitization phenomena, that are
present in chronic pain, including the signs and symptoms of CRPS type I
that in Japan was reported as an HPV vaccines AEs.
Figure 5. An abnormal nociceptor
response to cytokines produced after HPV vaccine injections can produce
peripheral and central sensitization phenomena. This new condition
explains the mechanisms of chronic pain and produces the symptoms
associated with it.
The existence of extensive lines of communication between
the nervous system and immune system represents a fundamental principle
underlying neuroinflammation. Immune memory in the brain is an important
modifier of neuropathology. Systemic inflammation generates signals
that communicate with the brain and lead to changes in metabolism and
behavior, with microglia assuming a pro-inflammatory phenotype. Two
types of immunological imprinting can be distinguished: Training and
tolerance. These are epigenetically mediated and enhance or suppress
subsequent inflammation respectively.
The molecular mechanisms presented here demonstrate how
peripheral cytokines, expressed after vaccination, can cause
neuroinflammation in some subjects, after microglia activation,
depending on the immunogenetic background and the innate immune memory.
The effects produced by the activation of the microglia, and the
subsequent neuroinflammation, are diversified according to age: before
the first two years of life they can contribute to producing ASD (in
some subjects with ASD there is neuroinflammation and aluminum
accumulation in the brain); while a different neurological
symptomatology can arise in girls vaccinated with HPV vaccines. Indeed,
the proinflammatory cytokines expressed after HPV vaccine injections can
cause neuroinflammation and chronic pain, and we hypothesize that the
aforementioned cytokines are capable of producing a post-vaccination
inflammatory syndrome in which chronic pain and neuroinflammation are
practically always present.
In all girls mentioned in the book “The HPV vaccine on trail”
[98], the chronic pain is always present and highly debilitating.
Furthermore, many girls present the signs and symptoms of central
sensitization with the associated psychic and motor symptoms (Table 1).
Finally, in Japanese girls, the period of human papillomavirus
vaccination considerably overlapped with that of unique post-vaccination
symptom development (symptoms including chronic regional pain syndrome
and autonomic and cognitive dysfunctions in the vaccinated patients).
Table 1. Symptoms and signs produced by Central Sensitization (Smith, 2010).
Central Sensitization. |
Malignant process of up-regulation, pain be getting more pain, becoming autonomous. |
Effects |
|
Secondary Hyperalgesia |
Reduced threshold, Hyperpathia, Paresthesia, Numbness. |
Modality Effects |
Allodynia. |
Sympathetic System |
Dysautonomia, Persistent hyperactivation, Paradoxical hyporeactivity to stress, Psychological problem. |
Autonomic effects |
Hyperhydrosis, Arousal/Non-arousal, Local Changes, Neurogenic
edema, Temperature changes, Hypoalgesia; onset of stress- induced
hyperalgesia, Vascular changes, Trophic changes, Hair and Nails
problems. |
Movement Effects |
Difficulty in initiation, maintenance, and precision of small
movements. Weakness, Dystonia, Decreased range of motion, Tremor, Spasm,
myclonic jerks, Neglect-like syndrome, Pathophysiology of complex
regional pain syndrome (CRPS). |
Systemic Effects |
Sleep disturbance, Fatigue, Circadian Rhythm disruption, Development of Additional Pain Syndromes, Sickness Behavior. |
Psychological effects |
Fear, Anger, Social login, Pain Behaviors, Motivation,
helplessness effects, Depressive effects, Preoccupation with pain, and
body self. |
In this paper, we have provided the explanation, in terms
of molecular biology, to the epidemiological observations published by
[99], and we have shown that the symptoms presented by girls with AEs
have a molecular basis and clinical entities well known to the
scientific world (CRPS type I, and central sensitization).
The reading of table 1 crash the alibi of the denialist
scientists, because the girls suffering from these HPV vaccines AEs have
all symptoms of the central sensitization [100] that is produced, by
these injections, with the molecular mechanisms described by us in
figure 4 and figure 5.
To further confirm the role of proinflammatory cytokines in
the neurological diseases, we list, in (Table 2), some neurological
syndromes with the associated proinflammatory cytokines, such as:
Pathological pain [100], Peripheral neuropatic pain [101], Hyperalgesia
[102], CRPS [103,104,105], Chronic fatigue [106,107], CFS/ME [108,109],
and POTS [110,111].
Table 2. Neurologic clinic syndromes and proinflammatory cytokines.
Syndrome |
Proinflammatory cytokines |
|
IL-1β |
TNF-α |
IL-6 |
IFN-γ |
IL-8 |
Pathological pain |
Yes |
Yes |
Yes |
Yes |
|
Peripheral neuropatic pain |
Yes |
Yes |
|
|
|
Hyperalgesia |
Yes |
|
|
|
|
CRPS |
Yes |
Yes |
Yes |
|
Yes |
Chronic fatigue |
Yes |
Yes |
Yes |
|
|
CFS/ME |
Yes |
Yes |
|
|
|
POTS |
|
|
Yes |
|
|
Funding Information
This work has not received any funding and publication costs are paid by the authors of this paper.
Author’s Contributions
Giannotta N., has conducted the bibliographic research and
prepared the part of the paper that deals with pain. Furthermore, he
prepared the figures included in the paper.
Giannotta G., has studied neuroinflammation and prepared
the part of molecular biology, in particular he studied the relationship
between vaccines and neuroinflammation.
Conflict of Interest
The authors declare that they have no conflict of interests.
Ethics
We believe that this paper provides a clear contribution in
understanding the molecular biology of vaccines, and for this reason we
believe it would not create any ethical problem after its publication.
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