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home:publications:proal_autoimmunity_2010 [06.15.2010]
marysue
home:publications:proal_autoimmunity_2010 [01.03.2012] (current)
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 ====#3 Molecular technologies allow microbes to be identified==== ​ ====#3 Molecular technologies allow microbes to be identified==== ​
  
-So, how are these bacteria detected? Well, instead of just using cultivation techniques, standard cultivation methods, to find the bacteria, the researchers used 16S RNA sequencing. They identified over 1,925 clones in the skin. +How are these bacteria detected? Well, instead of just using cultivation techniques, standard cultivation methods, to find the bacteria, the researchers used 16S RNA sequencing. They identified over 1,925 clones in the skin. 
    
 And similar techniques - these are techniques that also rely on identifying bacteria by characterizing their DNA - such as shotgun sequencing, pyrosequencing,​ and single cell sampling are revolutionizing the field of microbiology right now. And they'​re actually opening a door to a tremendous era of discovery. ​ And similar techniques - these are techniques that also rely on identifying bacteria by characterizing their DNA - such as shotgun sequencing, pyrosequencing,​ and single cell sampling are revolutionizing the field of microbiology right now. And they'​re actually opening a door to a tremendous era of discovery. ​
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 For example, in the psoriasis study, 84 of the clones likely represented novel species never before known to persist in the skin. And these tools allow us to study microbes in the tissues in which they persist. For example, in the psoriasis study, 84 of the clones likely represented novel species never before known to persist in the skin. And these tools allow us to study microbes in the tissues in which they persist.
  
-So, over the past few years, thanks to these molecular tools there have been so many novel microbes discovered in the human body. And in fact, there have been so many that we now realize that just a fraction of these microbes can be successfully cultured if we would only use standard laboratory methods.+Over the past few years, thanks to these molecular tools there have been so many novel microbes discovered in the human body. And in fact, there have been so many that we now realize that just a fraction of these microbes can be successfully cultured if we would only use standard laboratory methods.
  
 ====#4 Pathogens a.k.a. "​rascals"​==== ​ ====#4 Pathogens a.k.a. "​rascals"​==== ​
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 ====#5 Human Microbiome Project==== ====#5 Human Microbiome Project====
  
-Well, that's why the NIH is currently running the Human Microbiome Project, and it's a correlate to the Human Genome Project, where they are funding essentially the top genomic centers in the country to continue studying the differences in populations between bacteria and other microbes in health and disease. +That's why the NIH is currently running the Human Microbiome Project, and it's a correlate to the Human Genome Project, where they are funding essentially the top genomic centers in the country to continue studying the differences in populations between bacteria and other microbes in health and disease.
  
-Well, with this in mind, it's entirely possible that in autoimmune disease the antibodies are not being created in response to self but are instead being produced in response to these pathogens.+With this in mind, it's entirely possible that in autoimmune disease the antibodies are not being created in response to self but are instead being produced in response to these pathogens.
 ====#6 Gestational age at delivery as a function of bacterial rDNA concentrates in the amniotic fluid==== ====#6 Gestational age at delivery as a function of bacterial rDNA concentrates in the amniotic fluid====
  
-Well, even tissues with the highest reputation for sterility such as, let's say, the amniotic fluid, are actually filled with a diversity of bacteria. In 2008 DiGullio and Relman at Stanford published a paper showing the presence of 18 different bacterial taxa in the amniotic fluid.(({{pubmed>​long:​18725970}})) You can see here, on the x-axis, that the number of bacteria was inversely correlated with length of pregnancy. The positive predictive value of PCR for preterm delivery was 100%, which is a number not even heard of in science. So clearly, we're not just dealing anymore with HHV-6 or chamydia pneumonia, but hundreds and hundreds of other microbes. And, these microbes, they can persist in the blood and inside the cells of the immune system. For example, in patients with gastic ulcer disease, h.pylori doesn'​t just persist in the cells of the gastric mucosa, it also persists in peripheral blood.+Even tissues with the highest reputation for sterility such as, let's say, the amniotic fluid, are actually filled with a diversity of bacteria. In 2008 DiGullio and Relman at Stanford published a paper showing the presence of 18 different bacterial taxa in the amniotic fluid.(({{pubmed>​long:​18725970}})) You can see here, on the x-axis, that the number of bacteria was inversely correlated with length of pregnancy. The positive predictive value of PCR for preterm delivery was 100%, which is a number not even heard of in science. So clearly, we're not just dealing anymore with HHV-6 or chamydia pneumonia, but hundreds and hundreds of other microbes. And, these microbes, they can persist in the blood and inside the cells of the immune system. For example, in patients with gastic ulcer disease, h.pylori doesn'​t just persist in the cells of the gastric mucosa, it also persists in peripheral blood.
  
 ====#7 How does chronic disease develop?​==== ====#7 How does chronic disease develop?​====
  
-Well, in this context, how does chronic inflammatory disease appear to develop? ​Well, we can examine this question at the molecular level. And, key to the process is that chronic bacteria and viruses can alter expression of the body's metabolites. ​+In this context, how does chronic inflammatory disease appear to develop? ​We can examine this question at the molecular level. And, key to the process is that chronic bacteria and viruses can alter expression of the body's metabolites. ​
 ====#8 Nuclear receptors down regulated upon infection==== ====#8 Nuclear receptors down regulated upon infection====
  
-Take, for example, the Vitamin D Receptor or VDR - it's a type 1 nuclear receptor. ​Well, it turns out that viruses like Epstein-Barr Virus and bacteria like //​Mycobacterium tuberculosis//​ have evolved to survive in the same fashion - and that's by slowing activity of the VDR.(({{pubmed>​long:​19550398}})) ​ For example, MTb downregulates VDR activity by about a factor of 3.3.  And, this slide shows VDR activity being downregulated actually, by almost a factor of 30 in the longer lasting cell lines of B cells infected with EBV. +Take, for example, the Vitamin D Receptor or VDR - it's a type 1 nuclear receptor. ​It turns out that viruses like Epstein-Barr Virus and bacteria like //​Mycobacterium tuberculosis//​ have evolved to survive in the same fashion - and that's by slowing activity of the VDR.(({{pubmed>​long:​19550398}})) ​ For example, MTb downregulates VDR activity by about a factor of 3.3.  And, this slide shows VDR activity being downregulated actually, by almost a factor of 30 in the longer lasting cell lines of B cells infected with EBV. 
 ====#9 The Vitamin D Receptor (VDR)==== ====#9 The Vitamin D Receptor (VDR)====
  
-So, basically - you might ask, why the VDR? Well, colloquially ​speaking, the VDR serves as a "​gatekeeper"​ to the innate immune response - So, it expresses Cathelecidin,​ it expresses these key endogenous antimicrobials,​ that the body needs in order to target intracellular pathogens. ​ Cathelecidin - the beta-Defensins - it also expresses Toll-like receptor 2. In addition to that, it expresses at least 913 genes, many connected to autoimmune diseases and cancers. ​So, by dysregulating and slowing the VDR, Epstein-Barr Virus and Mycobacterium tuberculosis have actually evolved to slow the body's very defense mechanisms that would otherwise be actively working to render them dead.+You might ask, why the VDR? Colloquially ​speaking, the VDR serves as a "​gatekeeper"​ to the innate immune response -  it expresses Cathelecidin,​ it expresses these key endogenous antimicrobials,​ that the body needs in order to target intracellular pathogens. ​ Cathelecidin - the beta-Defensins - it also expresses Toll-like receptor 2. In addition to that, it expresses at least 913 genes, many connected to autoimmune diseases and cancers. ​By dysregulating and slowing the VDR, Epstein-Barr Virus and //Mycobacterium tuberculosis// have actually evolved to slow the body's very defense mechanisms that would otherwise be actively working to render them dead.
 ====#10 HIV and Borrelia burgdorferi==== ====#10 HIV and Borrelia burgdorferi====
  
 And note that HIV persists in the same fashion. It completely overtakes the VDR in order to transcribe its own genome.(({{pubmed>​long:​17556530}})) And, //​Borrelia//​ (Bb) does as well.  Live Borrelia downregulates the receptor by about a factor of 50, lysed by about a factor of 8.(({{pubmed>​long:​19461888}})) And note that HIV persists in the same fashion. It completely overtakes the VDR in order to transcribe its own genome.(({{pubmed>​long:​17556530}})) And, //​Borrelia//​ (Bb) does as well.  Live Borrelia downregulates the receptor by about a factor of 50, lysed by about a factor of 8.(({{pubmed>​long:​19461888}}))
  
-So - this is such a logical survival mechanism on the part of these microbes that it's almost certain that other less well-studied microbes have also evolved to slow VDR activity, or the activity of other receptors involved in controlling the immune response.+This is such a logical survival mechanism on the part of these microbes that it's almost certain that other less well-studied microbes have also evolved to slow VDR activity, or the activity of other receptors involved in controlling the immune response.
 ====#11 Successive infection==== ====#11 Successive infection====
  
-Well, these persistence mechanisms result in a snowball effect. When the immune system slows, and a person acquires one pathogen, then it becomes easier for them to acquire yet another pathogen. ​ And the immune system then acquires yet another pathogen. ​ And these pathogens each slow the immune system in turn. And the pathogens - they can be viral, fungal, bacterial... and so on and so on. And this process is referred to as successive infection.+These persistence mechanisms result in a snowball effect. When the immune system slows, and a person acquires one pathogen, then it becomes easier for them to acquire yet another pathogen. ​ And the immune system then acquires yet another pathogen. ​ And these pathogens each slow the immune system in turn. And the pathogens - they can be viral, fungal, bacterial... and so on and so on. And this process is referred to as successive infection.
  
 In the context of successive infection, an inflammatory disease state appears to result from the combined pathogenicity of the sum of microbes that any one person accumulates over the course of a lifetime. As human genes are upregulated or downregulated by components of these microbes, the human body shifts further and further away from its natural state of homeostasis. In the context of successive infection, an inflammatory disease state appears to result from the combined pathogenicity of the sum of microbes that any one person accumulates over the course of a lifetime. As human genes are upregulated or downregulated by components of these microbes, the human body shifts further and further away from its natural state of homeostasis.
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 ====#12 Epstein-Barr Virus (EBV)==== ====#12 Epstein-Barr Virus (EBV)====
  
-So, for example, over the past years, Epstein-Barr Virus has been detected in so many different proportions in so many disease states. ​ Here's just a sample of different diseases that'​ve been associated with EBV. And for almost the last century, these results have served as the source of confusion. ​ But, if we view them through the lens of metagenomics and in the context of successive infection they make sense! Epstein-Barr Virus is just one component of a mix. In some cases it could be a precipitating factor for an autoimmune disease condition. Or, in other cases, it's just a pathogen that's acquired later on in the disease process, when the body's already dealing with the widespread immunsuppression that can be caused by any of the hundreds of bacterial pathogens that accumulate in the body. And we now understand that by altering nuclear receptor activity, viruses can aid the survival of bacteria and vice versa. ​+For example, over the past years, Epstein-Barr Virus has been detected in so many different proportions in so many disease states. ​ Here's just a sample of different diseases that'​ve been associated with EBV. And for almost the last century, these results have served as the source of confusion. ​ But, if we view them through the lens of metagenomics and in the context of successive infection they make sense! Epstein-Barr Virus is just one component of a mix. In some cases it could be a precipitating factor for an autoimmune disease condition. Or, in other cases, it's just a pathogen that's acquired later on in the disease process, when the body's already dealing with the widespread immunsuppression that can be caused by any of the hundreds of bacterial pathogens that accumulate in the body. And we now understand that by altering nuclear receptor activity, viruses can aid the survival of bacteria and vice versa. ​
 ====#13 Pathogens, aka "​rascals"​==== ====#13 Pathogens, aka "​rascals"​====
  
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 ====#14 Co-morbidities among inflammatory diagnoses==== ====#14 Co-morbidities among inflammatory diagnoses====
  
-Well, it may also not be by accident that the uniqueness with which a patients'​ autoimmune symptoms develop parallels the incredible diversity of the pathogens that can persist in the human body. The following wheel shows how truly related chronic diseases are. Each “spoke” on the wheel represents a published study that's shown a significant statistical relationship between patients suffering from one disease and the next. And that is a lot of comorbidity and a lot of symptom overlap.+It may also not be by accident that the uniqueness with which a patients'​ autoimmune symptoms develop parallels the incredible diversity of the pathogens that can persist in the human body. The following wheel shows how truly related chronic diseases are. Each “spoke” on the wheel represents a published study that's shown a significant statistical relationship between patients suffering from one disease and the next. And that is a lot of comorbidity and a lot of symptom overlap.
 ====#15 Select bacterial genera detected in commonly smoked cigarettes==== ====#15 Select bacterial genera detected in commonly smoked cigarettes====
  
-So, where do we pick up these pathogens? They'​re everywhere! They'​re passed from mother to child during pregnancy, from father to child in the sperm, obviously through familial contact, they'​re in injectable medicines, they'​re in donated blood. There are many vectors. Consider for interest though, I thought this was interesting,​ a study came out recently - this is a group that tested for total bacterial diversity in four brands of cigarettes.(({{pubmed>​long:​20064769}})) And they found fifteen different classes of bacteria and a wide range of pathogenic microorganisms in every single cigarette tested – even the Kools! ​+Where do we pick up these pathogens? They'​re everywhere! They'​re passed from mother to child during pregnancy, from father to child in the sperm, obviously through familial contact, they'​re in injectable medicines, they'​re in donated blood. There are many vectors. Consider for interest though, I thought this was interesting,​ a study came out recently - this is a group that tested for total bacterial diversity in four brands of cigarettes.(({{pubmed>​long:​20064769}})) And they found fifteen different classes of bacteria and a wide range of pathogenic microorganisms in every single cigarette tested – even the Kools! ​
  
 Finally, and I want to stress this, the model of successive infection has great implications for the way autoimmune disease should be treated. If microbes - both bacterial and viral - are driving the autoimmune disease state, then treatments that suppress the immune response can at best succeed in achieving short-term palliation. They offer temporary relief by slowing the inflammation that would otherwise be generated if the immune system were actually targeting the pathogens. But instead the pathogens remain alive and they'​re able to proliferate - and they cause the person to become sicker over the long term. Finally, and I want to stress this, the model of successive infection has great implications for the way autoimmune disease should be treated. If microbes - both bacterial and viral - are driving the autoimmune disease state, then treatments that suppress the immune response can at best succeed in achieving short-term palliation. They offer temporary relief by slowing the inflammation that would otherwise be generated if the immune system were actually targeting the pathogens. But instead the pathogens remain alive and they'​re able to proliferate - and they cause the person to become sicker over the long term.
  
-Well, this being said, I work with the non-profit Autoimmunity Research Foundation and we, over the last six years have been working with a treatment for autoimmune disease that stimulates rather than suppresses the immune response in autoimmune disease. And, key to the treatment is the use of a VDR agonist which turns on - returns on - those components of the innate immune system that I described before that were so important. ​ And, the results of the treatment thus far are really interesting,​ at least in my opinion, because we have patients who are not only feeling better, but presenting with objective markers indicating significant improvement. ​ My colleagues will be talking more about the treatment in the vitamin D session and translational medicine session in hall C, I think, at two - and I really, highly encourage you to attend!+This being said, I work with the non-profit Autoimmunity Research Foundation and we, over the last six years have been working with a treatment for autoimmune disease that stimulates rather than suppresses the immune response in autoimmune disease. And, key to the treatment is the use of a VDR agonist which turns on - returns on - those components of the innate immune system that I described before that were so important. ​ And, the results of the treatment thus far are really interesting,​ at least in my opinion, because we have patients who are not only feeling better, but presenting with objective markers indicating significant improvement. ​ My colleagues will be talking more about the treatment in the vitamin D session and translational medicine session in hall C, I think, at two - and I really, highly encourage you to attend!
  
 ====#16 "​Don'​t palliate, stimulate!"​==== ====#16 "​Don'​t palliate, stimulate!"​====
  
-So, even when you leave this conference I hope you keep one important consideration - and honestly, this is a potential paradigm shift that we're dealing with here - in mind.  When it comes to the immune responses in autoimmune disease: Don't palliate, stimulate!!+Even when you leave this conference I hope you keep one important consideration - and honestly, this is a potential paradigm shift that we're dealing with here - in mind.  When it comes to the immune responses in autoimmune disease: Don't palliate, stimulate!!
  
 {{tag>​presentations videos Amy_Proal 2010}} {{tag>​presentations videos Amy_Proal 2010}}
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