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Friday 17 March 2017

T helper cells in Autism - TH1 TH2 & TH17


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:-

  

   


  
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.  DCs produce different cytokines.

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

IL-10 suppresses Th1 cells differentiation and function of dendritic cells.  

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. 

Effector Th cells secrete cytokines. 

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.  


  



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. 




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. 



 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]. Alzheimers 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

Table 2 -human diseases being treated with anti-p40, anti-p19, anti-IL-17, and anti-IL-17RA 

Conclusions and perspectives

Since the discovery of the IL-23-Th17 immune pathway a decade ago, immunologists and clinicians have worked diligently to bring this novel therapeutic strategy to the clinic, which is now showing encouraging results for psoriasis, Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. However, this treatment strategy is complex. It was initially assumed that IL-23 controls the production of pathogenic IL-17 and that these cytokines are ‘duplicate’ targets. Recent clinical results suggest that is not the case at all. We are now beginning to appreciate that anti-IL-23p19 versus anti-IL-17 treatments each has its own beneficial effects as well as unique challenges in different disease settings. For example, anti-IL-17 showed good therapeutic efficacy for the treatment of psoriasis—even surpassing anti-TNF therapy, but failed in Crohn’s disease. The search for better clinical efficacy biomarkers is critically needed to improve patient stratification and disease indication selection. In addition, better understanding of Th17 biology and cellular mechanisms would allow discovery of additional targets for inflammatory diseases. 


Blog post conclusion

There are so many known ways to modify the immune system; you would think that this aspect of many people’s autism really should be widely treated.

Very slowly in the literature we are moving towards defining inflammatory subtypes, which is a first step.

Modifying the immune system can have a profound effect on some types of autism.

We had the case of Stewart Johnson, who pioneered the TSO helminth therapy for his son with severe autism.  He teamed up with his son’s doctor Dr. Eric Hollander, Director of the Seaver York Autism Center at Mount Sinai Medical Center in New York, to try and make this a wider used therapy.  Ultimately the clinical trial was terminated and a company that was trying to commercialize the therapy gave up.

He documented his story here:

          http://autismtso.com/about/the_story/

We have our reader Alli from Switzerland, whose investigated the science and found that the Swedish variants of Lactobacillus reuteri should help; and they did.  In addition she uses 500mg sodium butyrate which will be converted into butyric acid.  Via its HDAC inhibiting properties it will further tune the immune system.  Sodium butyrate and butyrate-producing bacteria are widely used to improve immune health in animals.

What is clear is that there is no “cure-all” for autism, but that is hardly surprising.  There is no cure-all for cancer, which is equally heterogeneous.

The solution looks obvious to me and it is not hundreds of millions of dollars of research, it is to gather together all the existing knowledge and examine it fully.  This is how the world outside medicine generally operates.




31 comments:

  1. Here is a paper that is somewhat related to the current topic, but obviously much more related to RASopathies which you have covered extensively in past blog postings:

    Press Release:

    https://www.sciencedaily.com/releases/2017/03/170316112145.htm

    Paper:

    https://www.sciencedaily.com/releases/2017/03/170316112145.htm

    What the researchers found was that they believe that OCD symptoms have more to do with the amygdala than the basal ganglia, even though the mutated protein they did their research on (in mice) affected both structures.

    Now with respect to the current topic, I believe Biogaia Gastrus has helped my son quite a bit, likely from its indirect improvements in oxytocin which studies have shown helps put the brakes on a hyperactive and dysfunctional amygdala (the anti-inflammatory action may help as well as the amygdala and hippocampus are more vulnerable to oxidative stress and inflammatory cytokines from the blood stream than many other areas of the brain).

    They rescued the mice from the OCD behavior using good old-fashioned Fluoxetine (AKA Prozac). SSRI's of course are seriously potent drugs not to mess with even though they are liberally prescribed here in the United States for just about everything short of a scrape on the knee (who knows maybe that too), so trying to fix your kid's autism OCD symptoms with some Prozac would probably be an unwise move, nevertheless this paper does give some more hints as to where efforts should be concentrated in reducing one of the core features of autism (stereotypies and repetitive behaviors).

    ReplyDelete
  2. Here are a couple more important papers very relevant to discussions on this blog.

    The first one which will probably be widely reported on pretty soon:

    Press Release:

    https://www.sciencedaily.com/releases/2017/03/170316141101.htm

    Paper:

    http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005385

    This paper claims a blood screening test for autism based on one carbon folate metabolism using data that seems like it is straight from Mr. Fryes efforts. He is not listed on the paper, but the data set used was from Arkansas Children's Hospital where he bases his efforts and obviously has written several recent high-profile peer-reviewed papers. I am sure this paper and its data will be thoroughly debated, but if this research holds up to the scrutiny it will probably be getting, then this would be a pretty big thing in my opinion.


    The other paper discusses sulphoraphane and a novel effect it seems to have on long non-coding RNA's which if my memory serves me correctly seem to be one of the more affected areas of the genome in autism genomic research:

    Press Release:

    https://www.sciencedaily.com/releases/2017/03/170316141117.htm

    Paper:

    http://www.jnutbio.com/article/S0955-2863(16)30565-4/abstract

    Generally speaking, many brain proteins depend on these regulatory areas of the genome for orchestrating a diverse array of genetic expression, especially with regards to development (don't hold me to this comment though).

    Though this paper is on cancer research, it might be an alternative possible reason for suphoraphane's research benefits with respect to autism, rather than just NRF2 stimulation.

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  3. Hello Peter,

    What do you think is the relevance of a recent claim that Prof. Jeurgen Hahn, Renessalaer Polytechnic Institute makes of developing a blood test using 24 metabolites that may a accurately confirm an autism diagnosis...do you see any therapeutic potential of this test? He even suggests that these biomarkers may predict or identify to a certain degree where on the severity index are these individuals positioned.

    ReplyDelete
    Replies
    1. Dear Kritika, take a look at Table 1 of his paper:-

      http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005385#pcbi-1005385-t001

      These are all quite well known measures of oxidative stress and DNA methylation.

      So he is saying that if a toddler has oxidative stress and odd things going with epigenetics (methylation is one way you get epigenetic changes)then he very likely will be given an autism diagnosis.

      He has done an excellent job to model these biomarkers. Given how many types of autism there are, if can capture almost all of them this is very clever.

      The therapeutic potential does not lie in the test, but it lies in understanding all the things that lie behind these 24 markers and ratios. This deeper understanding and making of connections is something that is lacking among autism researchers/clinicians.


      Delete
    2. Yes Peter, this was extremely clever. In any case, 24 biomarkers, even if they are those good old friends, oxidative stress, methylation issues et al., if one starts investigating medical therapies around them, it is hell lot manageable and practical then those some hundred genes and then 18 more, which seem to be involved in autism. Sometimes I have serious doubts about the IQ and or/intentions of the so-called serious autism researchers. Connect the dots, find the pattern Doctors and Professors..the truth is out there.

      Delete
  4. Came across some very interesting research today concerning uridine metabolism:

    Press Release:

    https://www.sciencedaily.com/releases/2017/03/170317131617.htm

    Paper:

    http://science.sciencemag.org/content/355/6330/eaaf5375

    A couple years ago I recall we had a discussion about "to uridine or not to uridine, that is the question" on this blog post of yours:

    https://epiphanyasd.blogspot.com/2015/11/the-hyperuricosuric-subtype-of-autism.html

    Now what is interesting about this research and how it may related to autism are several things that came to me off the top of my head.

    First off, the researchers' primary finding was that the liver is not the only major producer of uridine in the body. Instead, the liver produces uridine while in the fed state, while fat cells produce uridine for the body in the fasted state.

    Acute fasting seems to have many positive benefits in some with autism which has generated many different hypotheses as to what could be the mechanism. Well, this research maybe suggests another mechanism if for some reason the liver is having problems producing adequate levels of uridine or else if there is a hiccup in uridine being delivered to the gut via bile or last but not least certain species of gut bacteria consume all of the available uridine in the gut, leaving the body famished of uridine. If any of these scenarios happen, then the fat cells producing uridine during the fasted state may improve symptoms as the fat cells make up for the deficiency in uridine production by the liver itself. Maybe daily intermittent fasting could help normalize uridine levels by letting the fat cells do more of the heavy lifting and giving the liver a rest so that it can keep producing glucose, rather than trying to produce uridine and glucose at the same time.

    So back in our previous discussion the question was more along the lines of whether higher than average levels of urate are desirable and whether uridine supplementation would lower urate levels. Perhaps, uridine supplementation immediately prior or else during meals might help normalize low blood plasma levels of uridine in those with autism (here is one study):

    https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/1743-7075-8-34

    while intermittent fasting might also help with uridine issues via the mechanisms mentioned in the paper above. Since uridine seems to affect body temperature as fasting lowers body temperature, it might be best to not supplement uridine during a fasted state, however, to the best of my knowledge I have not read any study that looked at a large pool of people with autism and looked at their average core body temperature relative to the general population, so I could be wrong on this.

    Has anyone out there supplemented uridine in significant amounts with their child and what if any were the results?

    ReplyDelete
  5. I reread the study I cited about in uridine and it had an error in the abstract and the discussion area in that it suggested in a copy/pasted sentence for both sections that there were low levels of uridine in the blood of those with autism relative to controls, while the actual results and charts show higher than normal levels of plasma uridine. I guess that is an error in the review process unless I am reading something wrong.

    ReplyDelete
  6. Peter, do you know if N-sativa binds to the benzodiazepine binding site of Gaba?
    I have some but I don't want to risk excitatory effect instead of inhibitory, my son worsens with benzodiazepines.

    I think that cholinergic therapies have adverse effect so I am thinking of anticholinergic or things that modulate/raising cholesterol in the brain.

    Ivermectin regulates metabolism and affects Gaba. It has ben shown to regulate glucose and cholesterol. If I wanted to trial it how much would be an initial dose?

    My son has been without Bumetanide for 5 days and I noticed I/E imbalances. I had some luck with intranasal insulin, but not with Diamox, phosphatidyl serine and choline. Inositol and 5htp can sometimes help but I think Gaba is to be regulated in the first place.

    ReplyDelete
    Replies
    1. Petra, I think you should look into something called P50 gating. This has long been known to be a measureable feature of schizophrenia, but has been shown to be present in Asperger's.

      You measure P50 by EEG. You could ask your research doctor about this, he might find it very interesting.

      http://onlinelibrary.wiley.com/doi/10.1002/aur.1452/abstract

      α7 nicotinic acetylcholine receptor (α7 nAChR) agonists correct P50 gating in schizophrenia and improve cognitive function.

      Nicotine from cigarettes will affect α7nAChR for about 30 minutes.

      There have been trials of an α7nAChR agonist.

      A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia.
      https://www.ncbi.nlm.nih.gov/pubmed/20573264


      Regarding N.sativa, I found this :

      "Exploration on the role of receptors suggests that picrotoxin and bicuculline-sensitive GABA receptors, most probably GABAA receptors, mediate an increase in GABAergic response (caused by N.sativa)."

      Ivermectin can only be used for short periods, so it may not be a good choice.

      I would follow the cholinergic line of thinking and have P50 measured by EEG.

      Delete
    2. I'll try to find tropisetron, I think there are no generics, it's very expensive and may not be available.
      Are there any other possible antiemetic drugs that have the same mechanism of action, agonists to a7 nicotinic receptors and antagonists to 5HT3?
      Sensory overload is a major challenge for Aspergers and it really comes with nausia and food/drink avoidance.

      Delete
    3. Petra, it has been suggested in the literature,

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306875/

      that a drug approved to help people stop smoking varenicline, although marketed as an α4β2 nAChR partial agonist, also has full agonist properties at α7 nAChRs.

      So you might expect varenicline to improve P50 gating and improve cognition. You might also expect it to help people with fibromyalgia and indeed some other people with chronic inflammation, as shown by elevated inflammatory cytokines.

      Anything that stimulates the vagus nerve should help, because this is what mediates the cholinergic system. There are posts in this blog on the vagus nerve.

      People with schizophrenia have been shown to have low amounts of α7 nAChRs in their brains. This is the root cause of their sensory gating problems.

      Delete
  7. Roger, the paper makes a hypothesis that folate-dependent one-carbon metabolism (FOCM) and trans-sulfuration (TS) are key underlying features of most autism.

    The authors then show that using 24 biomarkers, which they say are linked to FOCM/TS, that they can predict autism. The 24 biomarkers they used are well known to be disturbed in autism. I am not sure that they are really related to just FOCM/TS.

    ReplyDelete
  8. Hi Peter,
    As you may or may not recall, my 24 yr old son with autism was a "double tap" kid . We never recouped from that early second blow.
    In his early 20's he went from being a loud stimmy kid to a raging self-injurious young adult. Only some of the things recommended on this blog have helped at all with his mood , his blistery skin, and the stimminess.
    But beyond that (and we have tried so many things and seen so many autism docs over the years) nothing has improved anything.

    We recently started seeing a functional neurologist who moved his practice close to us in the past couple years. He quickly deduced that my son's parasympathetic system is pretty weak. We ordered immunology labs. His approach is that identification of inflammatory subtype that you wrote about.
    While waiting for the labs, we began transcutaneous vagus nerve stimulation. Within 24 hrs the raging was gone. My son's flexibility (and tolerance for noise, abrupt changes in schedule, and anything else that previous triggered him) was visibly increased. it has been almost 3 weeks and there has been one rage in that first week. Previously we were seeing at least one raging event and self-injury daily and sometimes more than one.
    His mood is smiley almost all the time.
    I also had begun Pharmepa and Alka Seltzer Gold but I am 100% convinced it is the tVNS that is the key. He is like a different kid.
    He had not cried in 10 years and had been a sobbing mess at times previously (with no anger). This had been replaced with hitting his head and raging uncontrollaby.
    Early last week he started crying. it was out of the blue and short-lived. Then back to his happy self. But it seemed odd and possibly somehow related to this new intervention?
    We also began butyric acid starting last week. This has increased the noise and stimming for sure but no negative effects on the mood.
    The labs came back recently. The stand out result (we have not met to discuss it yet) was the anti-phospholipid antibodies.
    This is concerning obviously. I am wondering your thoughts about the approach of overall lowering of inflammation and gut biome balancing as possibly effective in this autoimmune issue regarding phospholipids.
    Nancy

    ReplyDelete
    Replies
    1. Nancy, I am glad your son had a positive response to tVNS. I am surprised you actually have this therapy available. Was it done via his ear?

      Butyric acid seems to have an effect that is dose dependent, and less can be better. I would only use it if it gives positive effects, he may have enough already, depending on his fiber intake and his gut bacteria.

      I would double check which of your new interventions is the one that is helping, to be 100% sure. You just experiment by stopping and starting them.

      How often are you using tVNS and how long does the effect last?

      I am no expert on anti-phospholipid antibodies. You can have them and yet not have Antiphospholipid Antibody Syndrome, it is all about whether there are signs of abnormal blood clotting. You need to ask a specialist. As you damp down your son's immune system you may well reduce the anti-phospholipid antibodies.

      I would focus on confirming your "silver bullet" is tVNS. Things that do not help, I would stop using.

      Very different things seem to rebalance the over-activated immune system that is so troubling in some autism. It really is a case of trial and error. Once you have found what works, just be happy you have found it. Adding further therapies that may help some others, is not necessarily going to help your son.

      Delete
    2. Yes it is done via his left ear. The device is relatively cheap as it appears you just need a way to transmit an electrical impulse. Our Dr programmed it specific to my son.
      We started at 5 min 2x a day. Up to 10 min one if those 2 times each day. We saw positive effects with just the 5 min twice daily.
      Everything else he was on he had been on for at least a few weeks. There's no doubt in my mind it's the tVNS that is making the difference. Perhaps the onega 3s are required for this strong effectbut by themselves were not providing the effective we are seeing.

      Delete
    3. Very interesting Nancy. Can you share the name of the device, I expect other people may want to try it.

      Delete
    4. it is a TENS 7000 unit.
      nothing too high tech about it. A relative of mine is a nurse in a hospital and they use it in that setting for purposes other than autism.
      It is programmable in terms of hertz and pulsing. Our dr programmed it for my son. I am not sure I would have ventured to do it without guidance and oversight. I am told if you use the wrong ear, you can actually affect the heart so I would think physician involvement would make sense to avoid harm.
      I have to say I am astounded that something we are doing is actually dramatically positively affecting things over several weeks. Almost nothing ever has been this noticeable and sustained.

      Delete
    5. Nancy, you are a pioneer. I wrote a post a while back about tVNS, because I thought it should help some people, but I did not think anyone with autism has actually used it.

      https://epiphanyasd.blogspot.com/2018/04/transcutaneous-vagal-nerve-stimulation.html

      It was suggested that the mechanism for baking soda damping down the immune system is very similar to using VNS.

      I think most people will struggle to find a doctor willing to help with VNS for autism.

      Delete
    6. Nancy. I just looked up your machine. It is a Transcutaneous Electrical Nerve Stimulation (TENS) device with electrodes in pads. Do you use these standard pads or do you have a special electrode for his ear?

      Your doctor is re-purposing a very cheap TENS device, instead of using a very expensive tVNS device, which anyway do not seem to approved for sale in the US/Canada. Good for him.

      Delete
    7. Nancy, just for completeness, what settings do you use? I think for $25 some readers will want to follow your example.

      It looks like you have various settings:

      Pulse Amplitude: Adjustable, 0-100 mA in 10mA increments, which is controlled by the respective knobs located at the top of the device, for both channels

      - Pulse Rate: 2 - 150 Hz (adjustable), 1Hz per step

      - Pulse Width: 50 - 300 µs (adjustable), 10µs per step

      - Timer: Adjustable in 5-minute increments from 5 - 60 minutes, or (C) continuous

      5 Program Modes:
      • Burst Mode
      • Normal Mode
      • Modulation Mode
      • Strength-Duration Mode 1
      • Strength-Duration Mode 2

      Delete
  9. Peter, i think the way you use the TENS unit depends on the kind of problem you want to adress, epilepsy, depression or immunemodulation.I would like to use it but i dont think i can get a doctor who wants to help.
    Valentina

    ReplyDelete
    Replies
    1. I tend to agree. I am away at a work conference so can't look at the unit but I think I could only confirm the pulse and hertz.
      I have seen Patrick Nemechek using a similar unit on youtube in his discussion of autism treatment. He is in the midwest I believe. I think Derrick McFabe, out of Canada, also proposes such treatment.
      The physician we are seeing is Dr. Vreeland who used to be in St. Maarten then moved his practice to the US. I am thinking he could inform us who else is using this in the US. I don't think he came up with the idea of the TENS unit for tVNS.

      Delete
    2. Valentina, purpose built tVNS units are made and sold for example in Germany (www.cerbomed.de) and they have different versions, one for epilepsy one for pain/depression. There is research to support it, but they are not FDA approved.

      If you look on the web lots of people, for example with ME/CFS are buying a cheap TENS unit and an ear electrode and so making their own tVNS unit.

      Some people are being irresponsible, for example connecting it to the tragus of both the left and right ear. Only the left ear has the nerve you want to stimulate. So you do need to know what you are doing, and only some people in studies are responders.

      Your typical doctor is not going to approve of this.

      Delete
    3. Peter, you had asked earlier about how we are using the TENS 7000, which I think is the newer version. I ordered it from amazon.
      it comes with 2 sets of clips, not sure why. There are 2 channels, only one of which we use, along with one set of 2 ear clips. Yes it coms with pads but we don't use them. Just 2 clips on the left ear. I think the unit is set on 10 hertz and 200 pulse width. I am not home so I can't confirm that. The other settings are not displayed in the window so I don't see them easily and I didn't program it, my son's dr did. It is set for 5 min, after which there is a beep and it shuts off. I have started doing an additional 5 minutes with him to make a 10 min session occasionaly but not sure I need to.
      We have another appointment mid-July and he has advised me to just go slow and keep doing what we're doing.
      When we began (the first couple days), his urine upon peeing smelled horrific. I wondered if it was my imagination but I don't think so.

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    4. Peter, in rereading your posts, it appears to me that the knobs (one on each channel) possibly coontrol the amplitude?
      I thought the knobs went 1-10 but not sure as I am not looking at it.
      I move it slowly from 0. Anything past 2 as you turn it up starts to be noticeable in your ear. It feels good in a way. Beyond just past 2 and it starts to hurt. So 2ish seems to be sweet spot or at least what is tolerable .
      Nancy

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    5. Nancy, that is interesting.

      In page 2 of the linked paper below, they have a photo with 2 ear electrodes attached, but they are grounded by electrodes on the shoulder. So they used both channels.

      https://www.researchgate.net/profile/Rustin_Berlow/publication/304400345_Transcutaneous_Vagus_Nerve_Stimulation_for_Anxiety_A_Retrospective_Study_of_Clinical_and_EEG_Variables/links/576e897408ae842225a8802f/Transcutaneous-Vagus-Nerve-Stimulation-for-Anxiety-A-Retrospective-Study-of-Clinical-and-EEG-Variables.pdf

      In your case you have both electrodes (anode and cathode) on the left ear. This will produce a different effect to the shoulder pad method.

      Your method is very similar to the expensive German NEMOS tVNS device, shown here, where you can see 2 little silver electrodes on the white plastic part that attaches to the ear.

      https://www.researchgate.net/figure/Non-implantable-VNS-systems-a-NEMOS-tVNS_fig3_271220522

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    6. Peter,acute fronto temporal delta asimmetry was what my son´s EEGG showed when he was first diagnosed, which was correcting over time, I suspect that by stailizing his electrical activity. It says in the conclusion of the paper you linked,tVNS for anxiety, that there is a strong negative correlation between increased frontal delta asimmetry at the beginning of the treatment and greater improvement in anxiety at the end of it. Also it is suggested an EEGG analysis of frontal asimmetry as a predictive tool for tVNS treatment in anxious patients. I think that my son would be a responder due to his underlying problem. I can order the unit but I would need a very clear explanation with pictures and details showing how to use it.
      Valentina

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  10. When looking at Sjögrens syndrome, I stumbled across this article.
    https://sjogrenssyndromenews.com/2020/09/30/signaling-molecule-il-38-can-reduce-sjogrens-syndrome-inflammation-may-be-therapy-target-study-finds/
    Which references
    https://www.sciencedirect.com/science/article/pii/S016158902030482X

    It talks about that IL38 can block the Th17 response.

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  11. PTA 6475 uses L-histidine so its effect can be strengthened if supplemented together with l-carnosine? Or would it cause issues?

    Besides apple pectin has been mentioned to be good at promoting probiotics that produces butyrate.

    https://www.nature.com/articles/s12276-020-0449-2

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  12. Hi Peter,

    Here is another random fact about omalizumab. It might be able to increase your CD4 levels. In the case of my ASD son that is always sick that probably could help 1/2 of his ASD problem (the other half is FRAA).

    Successful Omalizumab treatment in HIV positive
    patient with chronic spontaneous urticaria: a case report

    https://scholar.google.com/scholar?hl=en&as_sdt=0%2C23&q=Successful+Omalizumab+treatment+in+HIV+positive+patient+with+chronic+spontaneous+urticaria%3A+a+case+report&btnG=

    Effects of Omalizumab on Rhinovirus Infections, Illnesses, and Exacerbations of Asthma

    https://www.atsjournals.org/doi/full/10.1164/rccm.201701-0120OC

    -Stephen

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    Replies
    1. I guess Dupilumab increases your CD4 levels too.

      Early and Long-Term Effects of Dupilumab Treatment on Circulating T-Cell Functions in Patients with Moderate-to-Severe Atopic Dermatitis

      https://www.sciencedirect.com/science/article/pii/S0022202X21001524#:~:text=The%20percentage%20of%20CD4%2B%20regulatory,effect%20on%20skin%2Dhoming%20cells.

      -Stephen

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