Today’s post is about another complex and still emerging subject. It should really be earlier in this blog.
There are lots of papers highlighted for those who like the
details. The papers written by the autism researchers are generally much
simpler to read than those by the mainstream researchers.
First some biology:-
If DCs produce IL-12, naïve T cells polarise into the
Th1 subset
If DCS produce IL-4 into the Th2 subset
if DCs synthesise IL-6, naïve T helper cells will
become the Th17 cells.
Th2 helper cells are triggered by IL-4 and their effector
cytokines are IL-4, IL-5, IL-9, IL-10 and IL-13
Th2 over activation against autoantigen will cause Type1
IgE-mediated allergy and hypersensitivity. Allergic rhinitis, atopic
dermatitis, and asthma belong to this category of autoimmunity.
Memory Th cells retain the antigen affinity of the
originally activated T cell, and are used to act as later effector cells during
a second immune response (e.g. if there is re-infection of the host at a later
stage).
Regulatory T cells do not promote immune function, but
act to decrease it instead. Despite their low numbers during an infection,
these cells are believed to play an important role in the self-limitation of
the immune system; they have been shown to prevent the development of various autoimmune
diseases.
***
It has been pointed out by Paul Ashwood, and others, that people
with autism fit into sub-groups based on their immune profile and could be
treated as such. In the jargon that
becomes:-
“Children with ASD may be
phenotypically characterized based upon their immune profile. Those showing
either an innate proinflammatory response or increased T cell
activation/skewing display a more impaired behavioral profile than children
with noninflamed or non-T cell activated immune profiles. These data suggest
that there may be several possible immune subphenotypes within the ASD
population that correlate with more severe behavioral impairments.”
In my case I want more IL-10, less Th2, less Th17 (IL-17)
and less IL-6.
The idea of Th1/Th2 balance that appears on parent internet forums
no longer seems entirely valid, because in autism cytokines from both systems can
be found elevated. It used to be thought that someone’s immune system could be
skewed one way or the other.
Allergies have been thought of as generally Th2
driven and autoimmune disorders generally Th1 driven. Some people have both.
Under normal circumstances, the Th1 and Th2 systems
balance one another by inhibiting each other's activity. Each type of helper T
cell (Th) produces different kinds of cytokines, with the Th cell types defined
by the cytokines they produce. These cytokines are termed interferons and
interleukins. Within the Th1 system, the dominant cytokine is interferon gamma (IFN-gamma), which
is responsible primarily for reactions against viruses and intra-cellular
microbes, and is pro-inflammatory.
Th2 cells produce interleukins IL-4, IL-5, IL-9, (IL-10) and IL-13 among. These
interleukins are important for stimulating production of antibodies and often have
multiple functions. As part of the Th2 system, IL-4 and IL-13 are primarily
anti-inflammatory (by inhibiting Th1 cells), but they also promote the growth
and differentiation of other immune cells. IL-4 also has the very important
role of producing the regulatory cytokine IL-10, which helps maintain the
balance between the Th1- and Th2- produced cytokines.
Historically, the role of cytokines in the immune
system dysregulation observed in studies of individuals with autism has not
been conclusive, because different patterns of cytokine activation have been
found. It is necessary to great
subgroups with similar profiles.
Along
came Th17
The relative newcomer is Th17 which produce IL-17. Th17 is the
target of much research into Crohn’s disease, MS and now even autism. Inhibition of IL-17 is seen as having great
merit for numerous diseases. There is also the IL-23 - IL-17 immune axis; since most cells that produce
IL-17 cannot do so with IL-23 being present. In the research anti-IL-17 and
anti-IL-23 treatments are remarkably effective for many immune-mediated
inflammatory diseases.
The autism research has shown that IL-17 can
be inhibited in mouse models that show clear behavioral gains; but they use resveratrol doses of 20 and 40 mg/kg given by injection. We
already know that resveratrol given orally has very low bioavailability.
Th17 has been shown able to cause autism, via immune
activation of the pregnant mother, but it has also been shown to be an ongoing
issue, with elevated levels of IL-17 and IL-17a found in people with autism.
Not
to forget Tregs
T regulatory cells (Tregs) are another
component of the immune system that suppresses the immune responses of other
cells. Impaired function, or just lack of Treg cells, is associated with
various diseases including MS.
Some autism studies show increased IL-6,
increased IL-17 but a systemic deficit of Treg cells.
In the middle seesaw we have plenty of Th1, Th2, Th17, known collectively as Teff, but few Tregs. Things are not in equilibrium, but that is many people's autism.
The generation of both effector (Th1, Th2,
Th17) and regulatory T cells (Tregs) is profoundly influenced by gut microbiota.
You could see this as a lack of wide range of bacteria in the
mother and baby resulting in a maladjusted immune system, or you could just see
modifying the microbiota of an person with autism as a novel therapeutic
strategy.
Regular readers of this blog will be well aware that we have
already looked at three different ways to use the gut to modify the immune
system.
1.
Using the short chain fatty acid (SCFA) butyric acid you can
increase Tregs and affect Th1. Th2 and Th17.
We saw this added to animal feed to improve immune health and a least
one reader of this blog uses sodium butyrate. The mode of action is as an HDAC
inhibitor.
2.
The TSO helminth worms that are ingested every few weeks. In order to avoid being rejected by the body
these worms modify the host’s immune system. This seemed clever. Potassium channels, Kv1.3 and KCa3.1, have been
suggested to control T-cell activation, proliferation, and cytokine production.
Recall the clever researchers in Australia determined the worm’s mode of action
and are working to develop a pill.
3.
Various probiotic bacteria and not the ones that produce SCFAs
have been shown to affect Th1 Th2 and Th17 and increase Tregs. These are
various different forms of Lactobacillus reuteri
There is a lot of research on this subject, for those who are
interested, even as an anti-obesity therapy and an anti-asthma therapy.
Resetting microbiota by Lactobacillus
reuteri inhibits T reg deficiency–induced autoimmunity via
adenosine A2A receptors
A recent epidemiological study showed that eating ‘fast
food’ items such as potato chips increased likelihood of obesity, whereas
eating yogurt prevented age-associated weight gain in humans. It was demonstrated
previously in animal models of obesity that the immune system plays a critical
role in this process. Here we examined human subjects and mouse models
consuming Westernized ‘fast food’ diet, and found CD4+ T helper (Th)17-biased immunity
and changes in microbial communities and abdominal fat with obesity after
eating the Western chow. In striking contrast, eating probiotic yogurt
together with Western chow inhibited age-associated weight gain. We went on to
test whether a bacteria found in yogurt may serve to lessen fat pathology by
using purified Lactobacillus reuteri
ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone
was sufficient to change the pro-inflammatory immune cell profile and prevent
abdominal fat pathology and age-associated weight gain in mice
regardless of their baseline diet. These beneficial microbe effects were
transferable into naïve recipient animals by purified CD4+ T cells
alone. Specifically, bacterial effects depended upon active immune tolerance by
induction of Foxp3+ regulatory T cells (Treg) and interleukin
(Il)-10, without significantly changing the gut microbial ecology or reducing ad
libitum caloric intake. Our finding that microbial targeting restored CD4+
T cell balance and yielded significantly leaner animals regardless of their
dietary ‘fast food’ indiscretions suggests population-based approaches for
weight management and enhancing public health in industrialized societies.
Histamine
Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling
Beneficial microbes and probiotic species, such as Lactobacillus
reuteri, produce biologically active compounds that can modulate host
mucosal immunity. Previously, immunomodulatory factors secreted by L.
reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial
genetics strategy was utilized to identify small compound(s) produced by L.
reuteri that were TNF-inhibitory. Hydrophilic interaction liquid
chromatography-high performance liquid chromatography (HILIC-HPLC) separation
isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was
determined by NMR and mass spectrometry analyses. Histamine was identified and
quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from
L-histidine via histidine decarboxylase by some fermentative bacteria including
lactobacilli. Targeted mutagenesis of each gene present in the histidine
decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement
of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine
antiporter (hdcP), and hdcB in production of the TNF-inhibitory
factor. The mechanism of TNF inhibition by L. reuteri-derived histamine
was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid
cells. Bacterial histamine
suppressed TNF production via activation of the H2 receptor.
Histamine from L. reuteri 6475 stimulated increased levels of cAMP,
which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA)
and resulted in suppression of TNF production by transcriptional regulation. In
summary, a component of the gut microbiome, L. reuteri, is able to
convert a dietary component, L-histidine, into an immunoregulatory signal,
histamine, which suppresses pro-inflammatory TNF production. The identification
of bacterial bioactive metabolites and their corresponding mechanisms of action
with respect to immunomodulation may lead to improved anti-inflammatory
strategies for chronic immune-mediated diseases.
Lactobacillus reuteri–induced Regulatory T cells Protect against an Allergic Airway Response in Mice
Conclusions: These
results strongly support a role for nonantigen-specific CD4+CD25+Foxp3+
regulatory T cells in attenuating the allergic airway response following oral
treatment with L. reuteri. (ATCC #23272). This potent
immuno-regulatory action may have therapeutic potential in controlling the Th2
bias observed in atopic individuals.
There is a rather complex paper that shows how the different short
chained fatty acids (SCFAs) affect different element of the immune system. More
work needs to done to see if only butyric acid has therapeutic merit.
Microbial metabolites such as short chain fatty acids (SCFAs) are highly
produced in the intestine and potentially regulate the immune system. We
studied the function of SCFAs in regulation of T cell differentiation into
effector and regulatory T cells. We report that SCFAs can directly promote T
cell differentiation into T cells producing IL-17, IFN-γ, and/or IL-10
depending on cytokine milieu. This effect of SCFAs on T cells is independent of
GPR41- or GPR43 but dependent on direct histone deacetylase (HDAC) inhibitor
activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of
p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for
generation of Th17, Th1, and IL-10+ T cells. Acetate (C2)
administration enhanced the induction of Th1 and Th17 cells during C.
rodentium infection but decreased anti-CD3-induced inflammation in an
IL-10-dependent manner. Our results indicate that SCFAs promote T cell
differentiation into both effector and regulatory T cells to promote either
immunity or immune tolerance depending on immunological milieu.
acetate (C2), propionate (C3), and butyrate (C4), are highly produced from
dietary fibers and other undigested carbohydrates in the colon
Effector T cells, such as Th1
and Th17 cells, fight pathogens and can cause tissue inflammation.12-15 Regulatory T
cells, such as IL-10+ T cells and FoxP3+ T cells,
counter-balance the activities of effector immune cells. Importantly, the
generation of both effector and regulatory T cells is profoundly influenced by
gut microbiota
Once entered into T cells undergoing activation, SCFAs effectively suppress
HDACs as demonstrated in this study. Acetylation of proteins including
histones, transcription factors and various signaling molecules by HDACs can
alter the functions of modified proteins
A pathway, important for T cell differentiation and affected by HDAC
inhibition demonstrated in this study, is the mTOR-S6K pathway. The mTOR
pathway promotes the expression of key effector and regulatory cytokines such
as IL-10, IFN-γ and IL-17.27, 39-41 In this
regard, the sustained high mTOR-S6K activity in T cells cultured with SCFAs
reveals a regulatory point for SCFAs in regulation of T cell differentiation.
Consistently, metformin, an anti-diabetic drug that activates AMPK and
negatively regulates the mTOR pathway, was effective in suppressing the SCFA
effect on T cells. Along with the mTOR pathway, STAT3 activation was enhanced
as well by SCFAs, which is involved in expression of the cytokines (IL-10,
IFN-γ and IL-17) in T cells.
Our results indicate that the C2 function in regulation of T cells is
modulated by cytokine milieu and immunological context. We observed that IL-10+ T cells were
increased by SCFAs in the steady condition in vivo, whereas effector T cells
were increased by C2 only during active immune responses. Moreover,
IL-10 expression was promoted in all T cell polarization conditions tested in
this study, whereas the expression of IL-17 and IFN-γ was promoted specifically
in respective polarization conditions. IL-10 production by effector T cells is an important
negative feedback mechanism to rein in the inflammatory activities of effector
T cells.42, 43 This
selective enhancement of effector versus IL-10+ T cells would be beneficial
to the host in promoting immunity with the built-in negative feedback function
of IL-10. An interesting observation made in this study in this regard was that
induction of FoxP3+ T cells by SCFAs can occur in a low TCR
activation condition. Taken together, SCFAs can induce both effector and
regulatory T cells including IL-10+ T cells and FoxP3+ T
cells in appropriate conditions.
Our study provides an example how the host immune system harnesses
commensal bacterial metabolites for promotion of specialized effector and
regulatory T cells. The
results identified SCFAs as key gut metabolites important for T cell
differentiation into effector and regulatory cells in the body depending on
SCFA levels and immunological context. The results have many practical
ramifications in regulation of tissue inflammation and immunity.
What
to do?
It would make sense to group people with autism together by their
immune profile and then develop practical therapies for each sub-group. When
will this happen? Not soon, nobody seems to be in a hurry to translate their
findings into therapies.
There is no point treating imaginary dysfunctions.
Numerous studies suggest that
abnormal activation of the immune system plays a role in causing autism. Some
behavioral problems in children have been traced back to viral infections in
their mothers during pregnancy. Studies in experimental mice have shown that
revving up the mother’s immune system during pregnancy results in offspring
with altered gene expression in the brain and problems with behavioral
development. More specifically, immune system changes and autoimmune disorders,
such as inflammatory bowel disease, have been found in individuals with autism.
Dan Littman and his colleagues at
New York University School of Medicine suspect that the link between immune
function and autism lies in a newly discovered subset of immune cells called
Th17 cells.
Th17 cells are so named because
they produce the inflammation-inducing signaling molecule interleukin-17. Their
normal role is thought to be in fighting bacterial and fungal infections, but
if this defense mechanism goes awry, Th17 cells can cause inflammatory tissue
damage that eventually leads to rheumatoid arthritis, multiple sclerosis,
Crohn’s disease, psoriasis and other autoimmune and inflammatory diseases.
Viral infection during pregnancy has been correlated with
increased frequency of autism spectrum disorder (ASD) in offspring. This
observation has been modeled in rodents subjected to maternal immune activation
(MIA). The immune cell populations critical in the MIA model have not been
identified. Using both genetic mutants and blocking antibodies in mice, we show
that retinoic acid receptor–related orphan nuclear receptor gamma t
(RORγt)–dependent effector T lymphocytes [for example, T helper 17 (TH17)
cells] and the effector cytokine interleukin-17a (IL-17a) are required in
mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA
induces an abnormal cortical phenotype, which is also dependent on maternal
IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17
cells in susceptible pregnant mothers may reduce the likelihood of bearing
children with inflammation-induced ASD-like phenotypes
Highlights
·
We examined cytokine production and co-morbid conditions in
children with autism.
·
Increased prevalence of asthma was observed in children with
autism.
·
Children with autism produced increased levels of IL-17.
·
Increased production of IL-17 and IL-13 was associated with ASD
cases with asthma.
·
Typically developing children with food allergies produced
increased levels of IL-13.
Inflammation and asthma have both
been reported in some children with autism spectrum disorder (ASD). To further
assess this connection, peripheral immune cells isolated from young children
with ASD and typically developing (TD) controls and the production of cytokines
IL-17, -13, and -4 assessed following ex vivo mitogen stimulation. Notably,
IL-17 production was significantly higher following stimulation in ASD children
compared to controls. Moreover, IL-17 was increased in ASD children with
co-morbid asthma compared to controls with the same condition. In conclusion, children with ASD
exhibited a differential response to T cell stimulation with elevated IL-17
production compared to controls.
Background:
Autism spectrum disorder (ASD) is
characterized by social communication deficits and restricted, repetitive
patterns of behavior. Varied immunological findings have been reported in
children with ASD. To address the question of heterogeneity in immune
responses, we sought to examine the diversity of immune profiles within a
representative cohort of boys with ASD.
Methods:
Peripheral blood mononuclear cells
from male children with ASD (n = 50) and from typically developing age-matched
male control subjects (n = 16) were stimulated with either lipopolysaccharide
or phytohemagglutinin. Cytokine production was assessed after stimulation. The
ASD study population was clustered into subgroups based on immune responses and
assessed for behavioral outcomes.
Results:
Children with ASD who had a
proinflammatory profile based on lipopolysaccharide stimulation were more
developmentally impaired as assessed by the Mullen Scales of Early Learning.
They also had greater impairments in social affect as measured by the Autism
Diagnostic Observation Schedule. These children also displayed more frequent
sleep disturbances and episodes of aggression. Similarly, children with ASD and
a more activated T cell cytokine profile after phytohemagglutinin stimulation
were more developmentally impaired as measured by the Mullen Scales of Early
Learning.
Conclusions:
Children with ASD may be phenotypically characterized based upon their
immune profile. Those showing either an innate proinflammatory response or
increased T cell activation/skewing display a more impaired behavioral profile
than children with noninflamed or non-T cell activated immune profiles. These data suggest that there may be several possible
immune subphenotypes within the ASD population that correlate with more severe
behavioral impairments.
With support from Cure Autism Now, a study recently
published in the Journal of Neuroimmunology has found that children with
autism have a more active immune system. The research, led by Cynthia Molloy,
MD, also identified a potential mechanism for this immune dysregulation. The
authors suggest that a cytokine called interleukin-10 (IL-10) could be a key
part of the mechanism that leads to alterations in the adaptive immune response
in individuals with autism. This new finding about the role of IL-10 provides
another piece of the puzzle in understanding the complex nature of immune
dysfunction in autism.
As early as the 1970's, immunological factors were
identified in autism. Over time, a growing body of evidence has indicated a
role of immune dysfunction in individuals with autism, but the exact nature is
not fully clear, and no causal function has been established. One potent area
of research has been the study of cytokines, chemicals in the body that serve
as signaling molecules and play a crucial role in mediating specific types of
immune responses. Cytokines are essential components of both the innate immune
system (immune defense mechanisms that are the first line of defense against
any kind of invading substance, and present from birth) and the adaptive immune
system (immune defense mechanisms that develop in response to specific invading
substances, built up as immunities to infection from diseases we have been
exposed to over our lifetimes.) These important messengers control the
strength, length, and direction of immune responses, and are essential in
regulating the repair of tissue after injury. The many individual cytokines
play different roles; some act as stimulators of immune system activation,
while others provide inhibitory functions. Together, the various cytokines work
in an intricately coordinated system, the success of which is dependent on
their well-timed production by the various cell types of the immune system.
Interested in the impact of immune regulation on the
development of autism, in 2003 Dr. Molloy received a pilot project grant from
CAN. Dr. Molloy is an Assistant Professor of Pediatrics at the Center for
Epidemiology and Biostatistics at Cincinnati Children's Hospital Medical
Center, and is also the mother of a 13 year-old daughter with autism. While she
began her career in pediatric emergency medicine, the emphasis of her work
changed in 1999, when Dr. Molloy started a research fellowship in developmental
disabilities at Cincinnati Children's Hospital Medical Center. She joined the
faculty in 2003, where her research currently focuses on immune phenotypes and
the contribution of genes on chromosome 21 to autism. Dr. Molloy highlights the
benefits of teamwork at Cincinnati Children's Hospital, where she works closely
with Marsha Wills-Karp, Ph.D. "I have been fortunate to collaborate with
an exceptional immunobiologist to work on understanding the extent to which the
immune system contributes to the pathogenesis of autism."
In this study, Dr. Molloy and her colleagues were
interested in the levels of certain cytokines that are produced by a specific
type of immune cell in the adaptive immune system, called helper T cells (T
cells are a type of white blood cell). Helper T cells contribute to the immune
response by promoting the production of other types of T and immune cells. The
research team studied two types of helper T cells that work as a system: Th1
and Th2. Under normal circumstances, the Th1 and Th2 systems balance one
another by inhibiting each other's activity. Each type of helper T cell
produces different kinds of cytokines, with the T cell types defined by the
cytokines they produce. These cytokines are termed interferons and
interleukins, and the research group concentrated on a certain subset. Within
the Th1 system, the dominant cytokine is interferon gamma (IFN-gamma),
which is responsible primarily for reactions against viruses and intra-cellular
microbes, and is pro-inflammatory. Among others, Th2 cells produce interleukins
IL-4, IL-5, and IL-13. These interleukins are important for stimulating
production of antibodies (immune proteins that identify specific foreign
substances for destruction) and often have multiple functions. As part of the
Th2 system, IL-4 and IL-13 are primarily anti-inflammatory (by inhibiting Th1
cells), but they also promote the growth and differentiation of other immune
cells. IL-4 also has the very important role of producing the regulatory
cytokine IL-10, which helps maintain the balance between the Th1- and Th2-
produced cytokines.
Historically, the role of cytokines in the immune
system dysregulation observed in studies of individuals with autism has not
been conclusive, because different patterns of cytokine activation have been
found. Some studies of the
adaptive immune system in autistic individuals have shown that the cytokines of
the Th1 cells are elevated, while other studies have found elevations in the
cytokines of the Th2 system. Interestingly, a study of patient registries in Europe found that many
individuals suffered from both allergies (generally Th2 driven) and autoimmune
disorders (generally Th1 driven). Typically, autoimmune diseases and allergies are not seen
together in an individual, because both Th systems are not usually overactive
at the same time. One goal of Dr. Molloy's study was to determine if
direct measures of the cytokine levels themselves (as opposed to measures of
the allergic/autoimmune disorders produced by imbalances in these systems)
would show the same simultaneous hyper-activation in individuals with autism.
To examine the adaptive immune system, Dr. Molloy's
team measured cytokine production of children's immune cells in a cell culture,
both at a baseline level and after stimulation by an allergen and a toxin. The
team compared individual cytokine levels in blood samples from twenty children
with autism and twenty unaffected controls matched on the basis of age, race,
gender and date of study visit; this careful one-to-one matching was important
for controlling some of the variability that has made previous studies of
immune function in autism hard to interpret.
At baseline,
the researchers found that immune cells of children with autism produced higher
levels of both the Th1 and Th2 cytokines, including
IFN-gamma and IL-4, -5, -13, than the cells cultured from the control group. In
contrast, in the experiment using stimulation by an allergen or toxin, there
was no difference between cases and controls, indicating that the cells in both
groups were equally capable of producing the cytokines and generating an immune
response.
These
findings demonstrate that, in children with autism, both the Th1 and Th2
cytokines are more highly activated in the immune system's resting state,
indicating potential underlying hypersensitivity to exposures in the general environment. Dr. Molloy's study shows that immune dysregulation is found in
the adaptive immune system, as has been previously shown for the innate immune
system, confirming that children with autism exhibit hyper-sensitivity in both
innate and adaptive systems. Dr. Molloy's research has found increases in both
pro- and anti- inflammatory cytokines in the Th1 and Th2 system which is
indicative of dysregulation in the two systems. Instead of focusing on the
exact role of the anti- or pro- inflammatory cytokines, the study highlights
the importance of balanced regulation between these two systems in the adaptive
immune system.
In an intriguing twist, although baseline levels of
almost all the cytokines measured were higher in children with autism than in
control individuals, Dr. Molloy found an exception in the relatively lower levels of the critical
regulatory cytokine, IL-10, in individuals with autism. If both Th1 and
Th2 cells are just generally overactive in individuals with autism, elevated
IL-10 production would have been predicted as well. Dr. Molloy explains that
"it is unusual to see both the Th1 and Th2 arms of the adaptive immune
response so active at the same time; it is even more unusual to see this
increased activation without a proportional increase in the regulatory cytokine
IL-10, which is involved in Th1 and Th2 system regulation." Although previous research has
shown that IL-10 regulates the Th1 and Th2 systems, the exact mechanisms
contributing to the balance within the two systems is currently not known.
Dr. Molloy proposes that "many of the paradoxical findings that have been
reported about immune responses in autism could possibly be explained by the general dysfunction of IL-10."
The finding that IL-10 levels were not elevated in individuals with autism,
even when the levels of both Th1 and Th2 cytokines were elevated, suggests that
the immune response dysfunction seen in autism may be a problem with regulating
the cytokine system. Dr. Molloy hypothesizes that "children with autism
may not be able to down-regulate their Th1 and Th2 systems" either because
of a dysfunction in the production of IL-10 or because of a dysfunction with
the activity of IL-10 itself.
Dr. Molloy's research contributes a crucial piece of
information to the ability to determine how these cytokines function within the
complex interactions of an adaptive immune system response. Further study of
IL-10 is needed to determine how it contributes to the balance between the Th1
and Th2 systems.
Role of Regulatory T Cells in Pathogenesis and Biological Therapy of Multiple Sclerosis
Figure 1: Differentiation
of naïve T helper cells into particular subsets. T helper lymphocytes leaving
the thymus (naïve or TH0) are not yet fully differentiated to perform their specific
functions in peripheral lymphoid tissues. They are endowed of these properties
in the process of their interactions with dendritic cells (DCs) that engulf,
process, and present antigens to them. Moreover, DCs in dependence of the
processed antigens produce different cytokines. If DCs produce IL-12, naïve T cells polarise into the TH1
subset, if IL-4 into the TH2 subset and eventually, if DCs
synthesise IL-6, naïve T helper cells will become the TH17
cells.
Autism appears to be the middle seesaw
Figure 2: Causes of impaired Treg cells
function in autoimmunity development. Failures of regulatory T (Treg)
cell-mediated regulation can include: inadequate numbers of Treg cells owing to
their inadequate development in the thymus, for example, due to a shortage of
principal cytokines (IL-2, TGF-β)
or costimulatory signals (CD28), and so forth. Further, the number of Treg
cells can be in a physiological range; however, there are some defects in Treg-cell function
that are intrinsic to Treg cells, for example, they do not synthesise
sufficient quantity of immunosuppressive cytokines (IL-10, IL-35, and TGF-β), or there is a breakdown of their
interaction with effector T cells. Ultimately, pathogenic effector T cells
(Teff) are resistant to suppression by Treg cells owing to factors that are
intrinsic to the effector cells or factors that are present in the inflammatory
milieu that supports effector T cells resistance.
Regulatory T cells play a
vital role in the regulation of immune processes. Based on the induction of
autoimmune processes caused by the FOXP3 gene mutation, it was supposed that
defective Treg cells might also contribute to the development of
immunopathological processes in “more common” autoimmune disorders. This
supposition has been confirmed.
Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism.
Abstract
Autism is a neurodevelopmental
disorder characterized by stereotypic repetitive behaviors, impaired social
interactions, and communication deficits. Numerous immune system abnormalities
have been described in individuals with autism including abnormalities in the
ratio of Th1/Th2/Th17 cells; however, the expression of the transcription
factors responsible for the regulation and differentiation of Th1/Th2/Th17/Treg
cells has not previously been evaluated. Peripheral blood mononuclear cells
(PBMCs) from children with autism (AU) or typically developing (TD) control
children were stimulated with phorbol-12-myristate 13-acetate (PMA) and
ionomycin in the presence of brefeldin A. The expressions of Foxp3, RORγt,
STAT-3, T-bet, and GATA-3 mRNAs and proteins were then assessed. Our study
shows that children with AU displayed altered immune profiles and function,
characterized by a systemic deficit of Foxp3+ T regulatory (Treg)
cells and increased RORγt+, T-bet+, GATA-3+,
and production by CD4+ T cells as compared to TD. This was confirmed
by real-time PCR (RT-PCR) and western blot analyses. Our results suggest that autism impacts
transcription factor signaling, which results in an immunological imbalance.
Therefore, the restoration of transcription factor signaling may have a great
therapeutic potential in the treatment of autistic disorders.
Autism spectrum disorder (ASD) is a
neurodevelopmental disorder. It is characterized by impaired social
communication, abnormal social interactions, and repetitive behaviors and/or
restricted interests. BTBR T + tf/J (BTBR) inbred mice are commonly
used as a model for ASD. Resveratrol is used widely as a beneficial therapeutic
in the treatment of an extensive array of pathologies, including neurodegenerative
diseases. In the present study, the effect of resveratrol administration (20
and 40 mg/kg) was evaluated in both BTBR and C57BL/6 (B6) mice. Behavioral
(self-grooming), Foxp3, T-bet, GATA-3, RORγt, and IL-17A in CD4+ T
cells were assessed. Our study showed that BTBR control mice exhibited a
distinct immune profile from that of the B6 control mice. BTBR mice were
characterized by lower levels of Foxp3+ and higher levels of RORγt+,
T-bet+, and GATA-3+ production in CD4+ T cells
when compared with B6 control. Resveratrol (20 and 40 mg/kg) treatment to
B6 and BTBR mice showed substantial induction of Foxp3+ and
reduction of T-bet+, GATA-3+, and IL-17A+
expression in CD4+ cells when compared with the respective control
groups. Moreover, resveratrol treatment resulted in upregulated expression of
Foxp3 mRNA and decreased expression levels of T-bet, GATA-3, RORγt, and IL-17A
in the spleen and brain tissues. Western blot analysis confirmed that
resveratrol treatment decreased the protein expression of T-bet, GATA-3, RORγ,
and IL-17 and that it increased Foxp3 in B6 and BTBR mice. Our results suggest that autism
is associated with dysregulation of transcription factor signaling that can be
corrected by resveratrol treatment.
Recent studies have demonstrated that Th17, Th1, Th2, and Treg
cells have a dominant central role in the progress and development of
neurological disorders through a composite system of contacts among cells and
their cytokines.
Previous investigation demonstrated that patients with autism
had a significantly lower number of Treg cells than did healthy children
Because Tregs play an important role in preventing immune
activation and inhibiting self-reactivity, a deficiency in their numbers could
underlie a link between autism and the immune system
RORγt has been identified as a Th17-specific transcription
factor [17]. Because RORγt is a critical regulator of the IL-17A pathway,
its role in contributing to ASD-like behaviors in mouse offspring has been
investigated [18]. Several recent studies have reported an increased production
of IL-17A in children with ASD [19, 20].
Th17 cells are intricately associated with the development of a variety of and
inflammatory autoimmune diseases. Initiation and propagation of Th17 cells are
linked to the suppression of Treg cells
Resveratrol Regulates Immunological Imbalance through
Decreasing IL-17A Cytokine
Treatment of B6 mice with resveratrol also caused a
marked decrease in IL-17A mRNA expression levels (Fig. 6b). Correspondingly, IL-17 protein expression levels
were significantly higher in BTBR control mice when compared with that of B6
control mice. Resveratrol treatment of BTBR mice also significantly reduced
IL-17 protein expression when compared with that of BTBR control mice (Fig. 6c). These results indicated that resveratrol could
reverse the appearance of inflammatory cytokines and signal transducers related
with differentiation and production of Th17 cells.
Elucidating the mechanisms and pathways associated with
n eurodevelopmental disorders such as autism is essential.
This will provide an understanding of the etiology
of these disorders and also help to discover early diagnostic markers and
prophylactic therapies. Resveratrol prevents social deficits in an animal model
of autism [26] and improves
hippocampal atrophy in chronic fatigue syndrome by enhancing neurogenesis [39]. Resveratrol is widely recognized as an anti-oxidant
and as an anti-inflammatory, anticancer, cardioprotective, and neuroprotective
compound [40, 41]. It has been shown to inhibit increases in levels
of proinflammatory factors [42]. Resveratrol has also been found to provide a neuroprotective
effect on dopaminergic neurons [43]. The mechanism of action of resveratrol against neuroinflammation
appears to involve targeting activated microglia.
This results in a decrease in levels of
pro-inflammatory factors through the modulation of key signal transduction
pathways [43]. In addition, it
has been reported that resveratrol inhibits the activation of NF-κB, decreases
levels of IL-6 and TNF-α cytokines [42], and prevents suppression of Treg cells [9]. In the current study, we explored the effects of
resveratrol on Th1, Th2, Th17, and Treg cell-related transcription factors.
Our results demonstrated that resveratrol was
effective in reducing a prominent repetitive behavior in the BTBR mouse model
of autism. Doses of 20 and 40 mg/kg i.p. reduced repetitive self-grooming. The
efficacy of resveratrol in reducing repetitive behavior is a novel finding and
adds to the potential therapeutic indications of resveratrol for the treatment
of autism. BTBR is an inbred strain of mice which displays social deficits,
reduced ultrasonic vocalizations in social settings, and high levels of
repetitive self-grooming [44]. Learning and memory defects have been reported for BTBR mice
when they are assessed in fear conditioning, water maze reversal, discrimination
flexibility, and probabilistic reversal learning tests [45, 46]. Stereotypy and behavior rigidity are widely known as core and
defining features of ASD [47].
In the present study, we explored the effect of
resveratrol on Foxp3 expression in BTBR mice. We found a significant
upregulation of Foxp3 expression on CD4+ T cells following resveratrol administration
to BTBR mice. The expression of Foxp3 plays an important role in regulating the
development and function of Treg. Our results suggest that immune dysfunction, specifically
in Treg cells, is associated with the modulation of behaviors and core features
of autism. Treg cells have been identified as important mediators of peripheral
immune tolerance. A functional defect caused by Foxp3 dysregulation has been
demonstrated to lead to several autoimmune diseases [48, 49]. Autoimmune neuroinflammation is considered to result from a
disrupted immune balance between effector T cells such as Th1/Th2/Th17 and
suppressive T cells such as Treg [50]. Several attempts have been made to elevate the numbers of
Treg cells to suppress ongoing autoimmunity in experimental autoimmune
disorders [51].
In the present study, we observed that the high
T-bet expression in CD4+ T cells of control BTBR mice could be reversed by
resveratrol treatment. This may suggest that resveratrol can downregulate
expression of T-bet in autistic individuals. Several studies suggest that
expression of T-bet plays an important role in disease initiation and
progression of experimental autoimmune disorders [52]. T-bet enhances IL-17 production by central
nervous system (CNS)-infiltrating T cells and this may be linked to
neuroinflammation [53].
Our study also demonstrated that the high GATA-3 expression
levels in CD4+ T cells and spleen of BTBR mice could be reversed by treatment
with resveratrol. This suggests that resveratrol may correct neurodevelopment
dysregulation in autism through regulation of Foxp3 expression. GATA-3 is
involved in the development of serotonergic neurons in the caudal raphe nuclei
[15] and regulates
several processes in the body including cell differentiation and immune
response [54]. The GATA-3
transcript is detected in the pretectal region, mid-brain, and most of the
raphe nuclei [55]. Intriguingly, disturbances
in these processes are considered involved in the etiology of ASD in human or
autism-like behaviors in animals [56]. Targeted disruption of the GATA3 gene causes severe
abnormalities in the nervous system [57]. A recent study reported higher GATA-3 levels in lymphoblastic
cell lines derived from the lymphocytes of autistic children as when compared
to that of their non-autistic siblings [58], suggesting the importance of GATA-3 in this
neurodevelopmental disorder. Valproate- and thalidomide-use may also be linked to autism through
induction of GATA-3 expression [16].
Another key transcription factor associated with the
Th17 lineage is RORγt [59]. Suppression of
RORγt ameliorates CNS autoimmunity [33]. Alzheimer’s disease patients
have increased expression levels of RORγt in the brain, cortex, and hippocampus
[60]. Th17 cell
signature cytokines have a confirmed role in ASD. For example, IL-17A
administration promotes abnormal cortical development and ASD-like behavioral phenotypes
[18]. Elevated levels
of IL-17A have been detected in autistic children [61]. In line with these observations, our data showed
that resveratrol treatment inhibits RORγt and IL-17A expression in CD4+ T cells
and spleen in BTBR mice, suggesting their importance in regulation of autistic behavior.
Recent data also suggest that therapeutic targeting of Th17 cell, or its
transcription factor, in susceptible pregnant mothers may reduce the likelihood
of children being born with SD-like phenotypes [18].
Conclusions
Our results indicate that resveratrol treatment can
improve social behaviors in a BTBR mouse model of autism through suppression of
Th17, Th2, and Th1 cell-related transcription factors and induction of Treg
cell-related transcription factor. Our data also suggest that resveratrol may
be a promising candidate for the treatment of ASD and other immune mediated neurological
disorders.
A heavyweight mainstream study:-
IL-23-IL-17 immune axis: Discovery, Mechanistic Understanding, and Clinical Testing
With the discovery of Th17 cells, the past
decade has witnessed a major revision of the T helper subset paradigm and
significant progress has been made deciphering the molecular mechanisms for T
cell lineage commitment and function. In this review, we focus on the recent
advances on the transcriptional control of Th17 cell plasticity and stability
as well as the effector functions of Th17 cells—highlighting IL-17 signaling
mechanisms in mesenchymal and barrier epithelial tissues. We also discuss the
emerging clinical data showing anti-IL-17 and anti-IL-23 treatments are
remarkably effective for many immune-mediated inflammatory diseases.
“Type 17”
subsets of cells ubiquitously express RORγt and IL-23R. Their development is Thymic dependent with the
exception of Group 3 ILCs. Adaptive
CD4+ IL-17-producing cells require IL-6 signaling during initial TCR-mediated
activation. All other
subsets do not require IL-6 activation and are capable of responding to IL-1
and IL-23 signaling upon emigrating from the thymus. These “innate” immune
cells are poised to produce IL-17 upon sensing inflammatory cytokines as well
as stress and injury signals. While the adaptive Th17 cells reside
primarily in secondary lymphoid organs, the “innate” Type 17 cells are situated
in a broad range of peripheral tissues, where they directly survey the
interface between the host and the environment.
Company
|
Agent
|
Target
|
Indications
|
Stage
|
Clin Trial ID
|
Eli
Lilly
|
Ixekizumab
(Ly2439821) |
IL-17A
|
Psoriasis
Rheumatoid arthritis |
Phase
3
Ph 2 complete |
|
Novartis
|
Secukinmab
(AIN457) |
IL-17A
|
Psoriasis
Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Asthma Multiple sclerosis Type 1 Diabetes Crohn’s disease |
Phase
3
Ph 3 Ph 3 Phase 3 Ph 2 Ph 2 Ph 2 Ph 2terminated |
|
Amgen/
MedImmun e |
Brodalumab
(AMG 827) |
IL-17
Receptor A |
Psoriasis
Psoriatic arthritis Asthma Crohn’s disease |
Phase
3
Ph 3 Ph 2 Ph 2suspended |
|
Abbott
AbbVie |
ABT-122
|
IL-17A/
TNFa |
Rheumatoid
arthritis
|
Phase
1
|
|
Johnson
&
Johnson Janssen Biotech |
Stelara
(Ustekinumab) (CNTO 1275) |
p40
subunit
of IL-12 and IL-23 |
Psoriasis
Crohn’s disease Ankylosing spondylitis Rheumatoid arthritis Psoriatic arthritis Multiple sclerosis GvHD Atopic dermatitis |
Approved
2009
Phase 3 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 |
|
Abbott
|
Briakinumab
ABT-874 |
p40
subunit
of IL-12 and IL-23 |
Crohn’s
disease
Psoriasis Multiple Sclerosis |
Ph
2terminated Phase 3 Phase 2 |
|
Merck
|
Tildrakizumab
(MK 3222) (SCH 900222) |
IL-23p19
|
Psoriasis
|
Phase
3
|
|
Johnson
&
Johnson Janssen Biotech |
Guselkumab
CNTO 1959 |
IL-23p19
|
Psoriasis
Rheumatoid arthritis |
Phase
2
Phase 2 |
|
Amgen/
MedImmun e |
AMG
139
|
IL-23p19
|
Psoriasis
Crohn’s disease |
Phase
1
Phase 1 |
|
Eli
Lilly
|
LY3074828
|
IL-23p19
|
Psoriasis
|
Phase
1
|
|
Boehringer
Ingelheim |
BI
655066
|
IL-23p19
|
Ankylosing
spondylitis Crohn’s disease Psoriasis (single rising dose) |
Phase
2
Phase 2 Phase 2 |
