Infection, Autoimmunity and PANDA's: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas' NSU Conference
Quite the Resume
Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).
An MD and immunologist with a background in neuropsychiatry, Dr. Hornig's been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA's, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She's currently a lead investigator for the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in....
Chronic Fatigue Syndrome Studies at Dr. Hornig's Laboratory
- 200/200 Cases and controls with Chronic Fatigue Initiative - 18 pathogens identified, then unbiased high throughput sequencing - pretty much tell us anything that is in there
- 150/150 cases/controls in XMRV study
- 400/400 cases/controls in huge Montoya Stanford study
- 60 cases/60 controls Simmaron Spinal Fluid Study
Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it 'really intriguing', calling the number of well-characterized spinal fluid samples 'unparalleled', and stating the study was a 'unique opportunity'.We'll get another chance to see her at the 2013 Invest In ME Conference in May.
The Talk - Infection, Autoimmunity and Illnesses
Placing chronic fatigue syndrome into the category of 'neuropsychiatric disorders' (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she's studying a group of insane people, but demonstrating how infections can generate symptoms we don't generally associate with them.
Mom???
Dr. Hornig believes three factors, timing - a window of opportunity, a genetic predisposition, and an environmental insult probably come together to cause chronic fatigue syndrome. That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy: a time, it appears, when many chronic disorders are set into motion.
She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or 40 or 50 years until another window of vulnerability opens up - perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases). Indeed, that model of disease, she said, could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson's and Alzheimer's disease in later life.Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating disease. It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia. Basically smoking pot when you're an adolescent increases your risk of schizophrenia (it happened to one of the my best friends) but smoking it when you're an adult - even if you have this particular form of this gene- doesn't increase your risk at all.She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping forward they found that women whose mothers had high cytokine levels during pregnancy tended to be depressed and have reduced brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus's brain enough to make those women more vulnerable to depression later on. She noted that some of the same stress-circuitry showing up in those women is implicated in ME/CFS as well.
The Immune Side of Neuopsychiatric Disorders
Hornig is an immunologist and she explained that many 'neuropsychiatric disorders' may be explained by immune problems; the list she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette's syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).There are several groups in here; the heavy psychiatric disorders - depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.
The Infection Autoimmune Connection
The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections...but..(there's always a but :)) she noted that other autoimmune disorders can take years to show up making it difficult to determine the trigger. If it was a pathogen, it could've and may very well have done it's damage and then disappeared, leaving a chronically disrupted immune system in its wake.
PANDAS - A Possible Model for ME/CFS
"Several studies suggest autoimmunity may play a role…"
Hornig then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS. Children with PANDAS don't eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind of ' vigilance' and arousal that shows up in some people with chronic fatigue syndrome.Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it's believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting antibodies to streptococcus into mice caused problems with learning and memory, coordination, and social interactions. Then, in a nice Koch-like test, they found that removing the antibodies from the mice resulted in the return of normal behavior.
General Stress Response Affected
That made it pretty clear it’s the antibodies; eg. the immune response that's the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie target for destruction) two important parts of the immune system; C4 complement and heat shock proteins.Why would we, with ME/CFS, be interested in these factors? Because both appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to infection, trauma, etc.).Dr. Hornig didn't mention it both C4 and heat shock proteins have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other
- Heat Shock Proteins - Declines in heat shock protein levels after exercise in ME/CFS have been seen in three studies. Dr. Hornig believes HSP's have the ability to disrupt 'many, many organs'.
- Complement C4 - Two CDC studies have found increased activation of C4a in chronic fatigue syndrome after exercise. This is different than in PANDA's where the C4 levels are decreased but suggests C4 plays a role in both disorders.
Dr Hornig noted that children with PANDAS can respond to IVIG, antibiotics and other immune agents. That's a bit controversial (no surprise there) with the American Heart Association (AHA) recommending that strep not be tested for in children with PANDAS or that they attempt IVIG treatment despite the fact that one preliminary study has found IVIG effective.It's more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH's priority list.
Key Partners - The Stress Hormone-Immune System Interactions
Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having balanced immune and stress responses; throw those responses in just one part of the system- tryptophan degredation - into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain - the enteric nervous system or gut....
Getting Down With The Gut
Hornig then directed us out of the brain and downwards into the gut. On a very, very basic level this makes sense since everything that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress, pro-inflammatory cytokines and auto-antibodies (autoimmune reactions).Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an autoantibody attack of folate receptors could show up in problems with metabolism, methylation and B-12.Then she shifted upwards - back to the brain. So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines, and high levels of autoantibodies in our blood. Send all that stuff up to the precious (and fragile) blood-brain barrier protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.
More Floral Than Viral?
Lest we think this is some researcher's fantasy, Hornig described her work with autistic kids. Hornig's group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn't break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn't have gotten the milk protein into their bodies even they could have broken it down.Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls. Sutterella was not just present, it was flourishing, accounting for up to 7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids. That really raised some eyebrows.
Still, it's not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but we do know that Sutterella thrives in low oxygen environments and has been linked to inflammatory bowel disorder, Crohn's disease and ulcerative colitis. (It can also, though, sometimes be found in healthy individuals.) Hornig's ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.
Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis. (Check out a horrifying and fascinating New York Times story of young child's battle with rheumatoid arthritis.) Cesareans appear to put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal. Bacterial imbalances in the gut appear to be associated with increased obesity in people with type two diabetes .
- Check out Bacteria in Your Body
Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate inflammation. Fecal transplants may actually be more effective because they contain more of the bacteria that's actually populating our guts.Hornig noted how important the small intestine is for so many different type of phenomena - for cognition, anxiety and even for sleep. Did you know that if you're not getting peristalsis (small gut movements pushing the food along) during the night then you're missing some sleep enhancing molecules.
Major Chronic Fatigue Syndrome Gut Study Out This Year
The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire gut microbriome before and after exercise in people with ME/CFS.
By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009
- Xafaxan: Gut Rebalancer Extraordinaire - Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan...
Q & A Period
Is Chronic Fatigue Syndrome Infectious?She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was infectious in later stages of the illness. Hornig is following the same model as Klimas in her research; she's looking for an infectious agent but finding immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be throwing it into a tizzy. If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus. With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.One reason for Hornig's interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system - the early immune response system involving NK cells, dendritic cells and others - is getting more and more attention in ME/CFS. Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult. Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.
_________________________________________________________Clin Invest Med. 2008 Dec 1;31(6):E319-27. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndromepatients and matched healthy controls. Thambirajah AA, Sleigh K, Stiver HG, Chow AW.J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Jammes Y, Steinberg JG, Delliaux S, Brégeon F.Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. Jammes Y, Steinberg JG, Delliaux S. J Intern Med. 2012 Jul;272(1):74-84. doi: 10.1111/j.1365-2796.2011.02488.x. Epub 2012 Jan 4.Mol Psychiatry. 2010 Jul;15(7):712-26. doi: 10.1038/mp.2009.77. Epub 2009 Aug 11. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.J Allergy Clin Immunol. 2003 Aug;112(2):397-403. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF.Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Sorensen B, Jones JF, Vernon SD, Rajeevan MS.