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Transcription of ‘The Role of the Immune System in ME/CFS’: a presentation given by Dr. Mady Hornig at the NIH Pathways to Prevention workshop, ‘Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome’, on December 9, 2014.
I’ll speak about immune factors in chronic fatigue syndrome.
We have been thinking about immune-mediated brain disorders as a wide range of disorders that are due to interaction between the brain and the immune system.
We're very interested in the microbiome in this story and [we’re] thinking about the intestinal microbes that condition the immune system and create metabolites that are neuroactive and that may play an important role in the development of chronic fatigue syndrome.
We have an enormous number of neuropsychiatric disorders that we consider to be due to brain-immune interactions, at least in a subset, ranging from autism to depression and schizophrenia as well as ME/CFS.
There is a wide range of infectious factors we have thought of as triggers for this process.
And so not only gut microbes but also implicated are herpes viruses, including Epstein Barr virus, HHV-6 and a wide range of other viruses.
Microbes of course are important for normal brain function as well. We know that germ-free mice have abnormal cognition. They don't have normal anxiety responses.
And so microbes are really critical, so we don’t only think of them as offending agents, but in the context of the symptom complex that we see in chronic fatigue syndrome, we're trying to understand what goes awry.
The brain-gut axis has many aspects in which it interacts. If I were able to show you my slides, I would be able to show you how dietary products are acted upon by bacteria that are in the gut, and these can create tryptophan, which is the building block for the neurotransmitter serotonin, which is so important in a variety of key functions including sleep, sex drive, your vigilance factors and your ability to maintain your emotional tone.
Tryptophan can be also broken down further by a variety of agents, including immune factors like interferon gamma. And so tryptophan — which normally will be a building block for serotonin synthesis and also for the circadian rhythm regulator melatonin — tryptophan can be degraded by activation of the immune system or by activation of the stress-response system in the hypothalamic-pituitary-adrenal axis like glucocorticoids.
And that takes tryptophan down a pathway that has neuroactive and sometimes neurotoxic compounds that are regulating mood, regulating thought processes as well as regulating memory, and we believe that the tryptophan degradation that is activated by both stress factors — glucocorticoid stress hormones — but also by immune factors and pro-inflammatory cytokines may play a very important role in the activation of the biochemical changes that we see in ME/CFS.
The lining of the intestines is flooded and studded with bacteria that condition our immune system.
In animal models we know there are certain bacteria, called segmented filamentous bacteria or SFB bacteria, that are pro-inflammatory and increase cells called TH-17 cells that are involved in autoimmune and inflammatory disorders like rheumatoid arthritis as well as other...and probably implicated in other pain syndromes such as fibromyalgia, which of course we know overlaps with chronic fatigue syndrome.
Similarly, other bacteria — the absence of these bacteria — seems to allow the increase of the types of t-cells that quiet down the inflammatory process, the t-regulatory cells that are beneficial and are able to reduce autoimmune and inflammatory responses.
So here [indicates slide] we are able to see the segmented filamentous bacteria that increase the TH-17 cells, increase IL-17 production.
So we have been thinking about a model wherein the microbes condition a wide range of factors that include oxidative stress factors, cystine production that is related to your mitochondrial pathways. In these pathways, one alters the redox status. If you have a severe shift in redox status you will cause oxidative stress.
And this will alter your genetic regulation, turn certain genes on and off and lead to the production of inflammatory molecules and reduce t-reg cells that may lead to the alteration in the production of autoantibodies.
Some of these autoantibodies, when we're looking at this process in the intestine, the autoantibodies that are produced may be to receptors that are present in the intestine that are there for your absorption of dietary products such as folate, as well as vitamin D receptors.
We know that auto-immunity is altered by intestinal microbes in association with genetic factors, and these can be both beneficial in protection against autoimmune disease, such as in the SJL mouse in the EAE models — encephalomyelitis model — as well as causing suppression in autoimmune disease models with use of a particular probiotic agent.
We also know that microbes may play a different role in the induction of autoantibodies that may mimic brain proteins, and there are many studies now that have suggested there may be an autoimmune process that contributes at least to a subset of ME/CFS.
An example would be with H1N1 haemoglutenin; one sees that there are conserved parts in the sequence of the virus itself that are shared by certain brain proteins, and so this is a model for the possible production of autoantibodies that may be involved in regulation of fatigue, particularly mental fatigue and cognitive processes.
We know that certain microbes are producers of short-chain fatty acids that are anti-inflammatory like the butyrate producers here [indicates slide], and when you have a reduction in butyrate producers one often will see classical autoimmune diseases being increased, like Type 1 diabetes, whereas you have an autoimmune scenario that may be induced by other short-chain fatty acids such as acetate and propionate that lead to a leaky gut and a greater production of TH-17 cells and autoimmune phenomena.
Probiotics can influence this scenario; we have seen it in animal models, where giving Lactobacillus johnsonii will increase tryptophan production both in the intestine and the ileum — the small intestine — as well as in the peripheral blood and the serum.
And one can also see this even in human studies where probiotics can prevent encephalopathic reactions in individuals with cirrhosis, and you can reduce the probability of development of this brain dysfunction by the use of probiotics that alter the commensal bacteria and alter the serotinergic and tryptophan metabolites in the blood.
Our studies have been wide-ranging. We have many collaborators in the audience here today, working with the Chronic Fatigue Initiative, which is five centers of excellence for chronic-fatigue care with 200 cases, 200 controls with a follow-up study that has just been completed in sample collection with some microbiome samples as well as plasma and PBMC samples for a variety of gene expression studies as well as longitudinal immune studies in 50 cases and 50 controls who had participated in the initial cohort study.
The earlier NIH study — 150 cases and controls — we are currently planning a follow-up and hoping to follow up and we have other studies that we have been doing, including a spinal fluid study, an immune analysis which I will show you some data for.
Our approach has been to take a wide look at all of the triggers of immune dysfunction through a staged strategy that includes molecular analyses, looking at the bacterium as well as doing classical pathogen-discovery with high-throughput sequencing but also screening results.
We also look carefully at host responses and try to integrate what pathogens we might find, and looking at immune markers, doing RNA seq and gene expression, also looking at autoantibodies that may tell us something about autoimmune diseases that may be triggered by shared conserved sequences, as I showed with the H1N1 scenario; also anti-pathogen antibodies as well as proteomics and metabalomics.
Our studies for looking for pathogens that may be a trigger started with those agents that clinicians in our working group for ME/CFS had identified as being ones that may be involved, and so we created multi-presentation techniques looking at these agents, and we found very little in serum but it may be that these agents are cell-associated.
So we are now looking at peripheral blood mononuclear cells but here we see that there area only two free in serum: two HHV-6 and one parvovirus B19.
Similarly, in a study using Dr. Jose Montoya’s samples, we found very little to suggest that there’s a specific pathogen involved in chronic fatigue syndrome, although we did find some increase in annelloviruses, which are very small and very ubiquitous viruses but you can see it was actually a much higher rate in controls than in cases.
Again, sort of like the commensal bacteria which may play an important role in calming down our immune systems, perhaps certain viruses are important as commensal agents that are controlling the immune response and that perhaps their presence is a healthy presence, keeping other pathogens from leading to a strong inflammatory response.
Also, we're also pursuing HHV-6 studies using peripheral blood mononuclear cells.
What we have really been seeking, though, are aspects of host response that may be more generic and more general, that may be independent of a specific infectious trigger or may occur with certain classes of triggers, and we are looking at a wide range of cytokines and chemokines that we know have a role in brain function and that interact with our stress response — the hypothalamic-pituitary-adrenal axis.
...[have removed reference to results that have been submitted for publication]
So we're trying to understand the nature of these differences, and the central nervous system and the peripheral regulation.
-------------------------------------------------------------------------
Here is the video. Dr Hornig's presentation starts at 146 minutes into the video.
http://videocast.nih.gov/summary.asp?Live=14727&bhcp=1
Transcription of ‘The Role of the Immune System in ME/CFS’: a presentation given by Dr. Mady Hornig at the NIH Pathways to Prevention workshop, ‘Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome’, on December 9, 2014.
I’ll speak about immune factors in chronic fatigue syndrome.
We have been thinking about immune-mediated brain disorders as a wide range of disorders that are due to interaction between the brain and the immune system.
We're very interested in the microbiome in this story and [we’re] thinking about the intestinal microbes that condition the immune system and create metabolites that are neuroactive and that may play an important role in the development of chronic fatigue syndrome.
We have an enormous number of neuropsychiatric disorders that we consider to be due to brain-immune interactions, at least in a subset, ranging from autism to depression and schizophrenia as well as ME/CFS.
There is a wide range of infectious factors we have thought of as triggers for this process.
And so not only gut microbes but also implicated are herpes viruses, including Epstein Barr virus, HHV-6 and a wide range of other viruses.
Microbes of course are important for normal brain function as well. We know that germ-free mice have abnormal cognition. They don't have normal anxiety responses.
And so microbes are really critical, so we don’t only think of them as offending agents, but in the context of the symptom complex that we see in chronic fatigue syndrome, we're trying to understand what goes awry.
The brain-gut axis has many aspects in which it interacts. If I were able to show you my slides, I would be able to show you how dietary products are acted upon by bacteria that are in the gut, and these can create tryptophan, which is the building block for the neurotransmitter serotonin, which is so important in a variety of key functions including sleep, sex drive, your vigilance factors and your ability to maintain your emotional tone.
Tryptophan can be also broken down further by a variety of agents, including immune factors like interferon gamma. And so tryptophan — which normally will be a building block for serotonin synthesis and also for the circadian rhythm regulator melatonin — tryptophan can be degraded by activation of the immune system or by activation of the stress-response system in the hypothalamic-pituitary-adrenal axis like glucocorticoids.
And that takes tryptophan down a pathway that has neuroactive and sometimes neurotoxic compounds that are regulating mood, regulating thought processes as well as regulating memory, and we believe that the tryptophan degradation that is activated by both stress factors — glucocorticoid stress hormones — but also by immune factors and pro-inflammatory cytokines may play a very important role in the activation of the biochemical changes that we see in ME/CFS.
The lining of the intestines is flooded and studded with bacteria that condition our immune system.
In animal models we know there are certain bacteria, called segmented filamentous bacteria or SFB bacteria, that are pro-inflammatory and increase cells called TH-17 cells that are involved in autoimmune and inflammatory disorders like rheumatoid arthritis as well as other...and probably implicated in other pain syndromes such as fibromyalgia, which of course we know overlaps with chronic fatigue syndrome.
Similarly, other bacteria — the absence of these bacteria — seems to allow the increase of the types of t-cells that quiet down the inflammatory process, the t-regulatory cells that are beneficial and are able to reduce autoimmune and inflammatory responses.
So here [indicates slide] we are able to see the segmented filamentous bacteria that increase the TH-17 cells, increase IL-17 production.
So we have been thinking about a model wherein the microbes condition a wide range of factors that include oxidative stress factors, cystine production that is related to your mitochondrial pathways. In these pathways, one alters the redox status. If you have a severe shift in redox status you will cause oxidative stress.
And this will alter your genetic regulation, turn certain genes on and off and lead to the production of inflammatory molecules and reduce t-reg cells that may lead to the alteration in the production of autoantibodies.
Some of these autoantibodies, when we're looking at this process in the intestine, the autoantibodies that are produced may be to receptors that are present in the intestine that are there for your absorption of dietary products such as folate, as well as vitamin D receptors.
We know that auto-immunity is altered by intestinal microbes in association with genetic factors, and these can be both beneficial in protection against autoimmune disease, such as in the SJL mouse in the EAE models — encephalomyelitis model — as well as causing suppression in autoimmune disease models with use of a particular probiotic agent.
We also know that microbes may play a different role in the induction of autoantibodies that may mimic brain proteins, and there are many studies now that have suggested there may be an autoimmune process that contributes at least to a subset of ME/CFS.
An example would be with H1N1 haemoglutenin; one sees that there are conserved parts in the sequence of the virus itself that are shared by certain brain proteins, and so this is a model for the possible production of autoantibodies that may be involved in regulation of fatigue, particularly mental fatigue and cognitive processes.
We know that certain microbes are producers of short-chain fatty acids that are anti-inflammatory like the butyrate producers here [indicates slide], and when you have a reduction in butyrate producers one often will see classical autoimmune diseases being increased, like Type 1 diabetes, whereas you have an autoimmune scenario that may be induced by other short-chain fatty acids such as acetate and propionate that lead to a leaky gut and a greater production of TH-17 cells and autoimmune phenomena.
Probiotics can influence this scenario; we have seen it in animal models, where giving Lactobacillus johnsonii will increase tryptophan production both in the intestine and the ileum — the small intestine — as well as in the peripheral blood and the serum.
And one can also see this even in human studies where probiotics can prevent encephalopathic reactions in individuals with cirrhosis, and you can reduce the probability of development of this brain dysfunction by the use of probiotics that alter the commensal bacteria and alter the serotinergic and tryptophan metabolites in the blood.
Our studies have been wide-ranging. We have many collaborators in the audience here today, working with the Chronic Fatigue Initiative, which is five centers of excellence for chronic-fatigue care with 200 cases, 200 controls with a follow-up study that has just been completed in sample collection with some microbiome samples as well as plasma and PBMC samples for a variety of gene expression studies as well as longitudinal immune studies in 50 cases and 50 controls who had participated in the initial cohort study.
The earlier NIH study — 150 cases and controls — we are currently planning a follow-up and hoping to follow up and we have other studies that we have been doing, including a spinal fluid study, an immune analysis which I will show you some data for.
Our approach has been to take a wide look at all of the triggers of immune dysfunction through a staged strategy that includes molecular analyses, looking at the bacterium as well as doing classical pathogen-discovery with high-throughput sequencing but also screening results.
We also look carefully at host responses and try to integrate what pathogens we might find, and looking at immune markers, doing RNA seq and gene expression, also looking at autoantibodies that may tell us something about autoimmune diseases that may be triggered by shared conserved sequences, as I showed with the H1N1 scenario; also anti-pathogen antibodies as well as proteomics and metabalomics.
Our studies for looking for pathogens that may be a trigger started with those agents that clinicians in our working group for ME/CFS had identified as being ones that may be involved, and so we created multi-presentation techniques looking at these agents, and we found very little in serum but it may be that these agents are cell-associated.
So we are now looking at peripheral blood mononuclear cells but here we see that there area only two free in serum: two HHV-6 and one parvovirus B19.
Similarly, in a study using Dr. Jose Montoya’s samples, we found very little to suggest that there’s a specific pathogen involved in chronic fatigue syndrome, although we did find some increase in annelloviruses, which are very small and very ubiquitous viruses but you can see it was actually a much higher rate in controls than in cases.
Again, sort of like the commensal bacteria which may play an important role in calming down our immune systems, perhaps certain viruses are important as commensal agents that are controlling the immune response and that perhaps their presence is a healthy presence, keeping other pathogens from leading to a strong inflammatory response.
Also, we're also pursuing HHV-6 studies using peripheral blood mononuclear cells.
What we have really been seeking, though, are aspects of host response that may be more generic and more general, that may be independent of a specific infectious trigger or may occur with certain classes of triggers, and we are looking at a wide range of cytokines and chemokines that we know have a role in brain function and that interact with our stress response — the hypothalamic-pituitary-adrenal axis.
...[have removed reference to results that have been submitted for publication]
So we're trying to understand the nature of these differences, and the central nervous system and the peripheral regulation.
-------------------------------------------------------------------------
Here is the video. Dr Hornig's presentation starts at 146 minutes into the video.
http://videocast.nih.gov/summary.asp?Live=14727&bhcp=1
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