TNF alpha and Chronic Disease.

TNF alpha is critical to most chronic illnesses.  Regulating its overexpression is critical – but we are designed to have some TNF alpha all the time, and a whole lot when we need it.  So we will need to find ways to determine its proper balance. I think we have that available to us in our proper use of biomarkers of inflammation.

In this graphic the researchers bring our attention to the important subject of sensitizing cells to the TNF effect.  I believe this is at the heart of the downward spiral of chronic illnesses.




This link is to an important presentation by the researcher working on the Enbrel® protocol for and therapy for Alzheimer’s. TBI and Stroke.  It may be equally important in autism.  Please go to the link and click on the video and then listen to his talk. It is important to what I will be talking about in the next series of blogs

And this literature points to the very complex regulatory role of NF- kappa B.  It is influenced by TNF and also regulates TNF.



“TNF-α is one of the most prominent pro-inflammatory cytokines significantly increased in AD and it plays a central role in initiating and regulating the cytokine cascade during inflammatory responses. For example, TNF-α increases the expression of adhesion
molecules on the vascular endothelium, which allows leukocytes and immune cells to infiltrate areas of tissue damage and infection.” (I. Granic et al. / NF-κB in Alzheimer’s Disease and Diabetes).


This quote from Blood Journal illustrates the complexity of the immune regulation of vascular disease. “Atherosclerosis is an inflammatory disease of the arterial wall that carries an important socioeconomic burden. The severe clinical manifestations of atherosclerosis (myocardial infarction, stroke) are mainly due to the abrupt obstruction of the vessel lumen by a thrombus formed on the contact of a ruptured or eroded atherosclerotic plaque. The available data strongly suggest that immunoinflammatory–related mechanisms are the major determinants of plaque complications. Therefore, most of the important advances in the comprehension of the mechanisms of atherosclerosis have come from studies aimed at elucidating the critical components involved in the modulation of the immunoinflammatory balance within the plaque. However, despite the increasing knowledge regarding the role of inflammation in atherogenesis, the precise intracellular transduction pathways involved in this process remain largely unexplored.”  (


Over the next weeks I will be pulling the facts together so you can make better health decisions about all these chronic illnesses including Cancer and HIV and most neurological problems. 

Does HIV Cognitive Impairment Tell Us Anything About Autism?

The answer is likely.  Although the specifics will no doubt be different, if there is a subset of persistent CNS viral infection related autism (as suggested by Persico and others), then the mechanism of impairment may be similar.



The net effect is still that TNF alpha is elevated and with that both direct and indirect harm to neurons will take place.  Keeping a lid on TNF and ultimately removing the virus is the target we need to try to shoot for in ASD in the viral-mediated subset.

But can we identify the subset of children affected this way?  I think that we can – without performing brain biopsies of course.

Linking TNF-alpha to Glutathione Deficiency and Various Brain Symptoms

I’ve had the pleasure to publish with Dr James onm some very important findings regarding the loss of protection from both toxins and oxidative stress in fairly large cohort of children with autism.  The findings, apart from the genetics data more typical of autism, would likely be the same for ALL neurological chronic illnesses including schizophrenia, Parkinsonism, Alzheimer’s and other conditions.  ALL of these have been associated with low glutathione levels in the brain. I will explain why this is so important.  



Recall Dr Chez’ very important data and observations that even after intervention with anti-inflammatory medications (IVIG, Steroids etc) children with ASD had elevated spinal fluid TNF-alpha (the master inflammatory regulatory messenger of the immune system).  He compared CSF TNF-alpha to blood.  It should always be less than 1.0(CSF/Blood) and as you can see it never was.


Study this and tonight I will finish the discussion.  Right now I have to catch a plane to lecture in South Carolina. 

More Evidence TNF-alpha Allows Viral Persistence

This comment came on one of my think tank blogs from researcher and professor Dick Deth:

“Viruses such as XMRV are suppressed by methylation, and the enzyme methionine synthase is a master controller of methylation. We observed very powerful and rapid inhibition of methionine synthase (MS) transcription by TNF-alpha (>90% decrease of  MS mRNA). An examination of the promoter region of methionine synthase revealed a consensus site for NF-kappa-B binding which overlaps the normally promotional AP-1 site. Thus we can hypothesize that TNF-alpha decreases methylation activity via NF-kappa-B. This decrease will augment viral persistence and replication. Notably, MS is very sensitive to oxidative stress, implying that oxidative stress, initiated by any number of provocations, would increase susceptibility to viral infection. Persistent viral infection could in turn prolong/delay recovery from oxidative stress, leading to a persistent oxidative stress and persistent v (a self-reinforcing relationship). In other words we normally recover from an oxidative stress-producing event, but the presence of a viral infection can turn this into a chronic condition…”

This is exactly what we are observing in numerous conditions including XMRV, Autism and ME/CFS.  The good news is these conditions can be treated. 

Why I Am More Hopeful Now Than Ever About Autism, ME/CFS, HIV, Alzheimer’s and other Chronic Illnesses: the Stem Cell, TNF-alpha, Viral/Pathogen connection.

On this blog I have been writing about stem cells, hyperbaric oxygen (HBOT), and some incredible new observations related to reversing brain inflammation.  All of the diseases I listed above and a whole bunch more are tied to persistent inflammation.  Inflammation itself is very important to the body.  In a healthy person it doesn’t persist. It comes in response injury or infection – cleans that up – then stem cells communicate the need to stop the inflammation and heal.  To that extent, these chronic – persistent inflammatory conditions are the result of a failure of stem cells to do their job to counter inflammation. I will explain what is keeping them out of the process below and in future posts.

As this following picture demonstrates, the balance of inflammation regulation in the brain is complicated, intricate and precarious. But science has reached a point where we understand a large portion of the regulatory pathways.


[Frontiers in Bioscience 14, 5291-5338, June 1, 2009]

Caption: Microglia are the primary recipients of peripheral inflammatory signals as they reach the brain. Activated microglia initiate an inflammatory cascade by releasing cytokines, chemokines, prostaglandins and reactive nitrogen and oxygen species (RNS and ROS, respectively). Bi-directional exchanges between microglia and astroglia amplify inflammatory signals within the central nervous system (CNS). Cytokines including interleukin (IL)-1, IL-6, tumor necrosis (TNF)-alpha and interferon (IFN)-gamma induce indoleamine 2,3 dioxygenase (IDO), the enzyme responsible for degrading tryptophan, the primary precursor of serotonin (5-HT), into kynurenine, which is eventually metabolized into quinolinic acid (QUIN), a potent NMDA agonist and stimulator of glutamate (Glu) release. Multiple astrocytic functions are compromised due to the excessive exposure to cytokines, prostaglandins, QUIN and RNS/ROS, ultimately leading to downregulation of glutamate transporters, impaired glutamate reuptake, excessive glutamate release and compromised synthesis and release of neurotrophic factors. Oligodendroglia suffer damage due to toxic overexposure to cytokines such as TNF-alpha, and diminished neurotrophic support, both of which promote apoptosis and demyelination. Copious amounts of glutamate are released from astrocytes in the vicinity of extrasynaptic NMDA receptors, whose activation leads to inhibition of BDNF synthesis. Excessive NMDA activation, caused by QUIN and D-serine, is compounded by diminished glutamate reuptake by astrocytes and oligodendroglia. NMDA-mediated excitotoxicity, combined with a consequent decline in neurotrophic support, and an increase in oxidative stress, synergistically disrupts neural plasticity and induces apoptosis (cell death).

So it doesn’t matter if we are talking about autism, post-stroke inflammation, Alzheimer’s, HIV dementia; the central mechanism is largely the same.

Now this is important to understand: if we have persistent inflammation in the brain, what is driving that signal? The immune system has lots of regulatory steps designed to keep it in balance, but despite all the intrinsic safeguards in the system – it has lost control. Why?

Some perspective: About 5 years ago I was sitting on a bus with Professor Thayne Sweeten. We were on our way to dinner to relax after a full day of brainstorming as a group of researchers interested in autism. Thayne is a bright guy. His PhD dissertation was Immune Activation and Autoimmunity in Autism. He explained from everything he had seen regarding the immune system of autism; the CSF observations, the increase in neopterin, etc,, that at least a significant subgroup of children had the immunological footprint of a persistent viral pathogen.

I agreed – and I still do agree – especially after 5 years of discoveries. And it doesn’t have to be a virus: many other pathogenic bacteria and fungi could cause the same response. But for simplicity let’s just say virus.

We don’t have to agree about which virus is persistent in autism, it actually doesn’t matter that much. I am surprised to hear myself say that, but after what I have learned in the last few months, I don’t think the actual virus is that important.  That is because most do not have a specific anti-viral drug (apart from HIV and some Herpes viruses).  Even in those cases the drugs are inadequate and something else is needed.



The picture depicts the blind miraculously being given sight. I would love to see a miracle of immune unblinding in autism, or any of these other disorders.  Absent that we need to give it sight medically.

If you read my blog about this last night I spoke about the problem.  We have a raging immune response just like we would expect with a viral infection, except it doesn’t go away. Why?  The immune cells (particularly macrophages) seem to be blind and cannot find the enemy they are looking for.  So while they stumble around, unable to find the viral enemies, the entire system stays turned on.  And it will stay turned on until either stem cells say enoughits time to heal, or until the virus is eliminated.

The evidence is we don’t generate enough stem cell response to regulate this type of immune response – presumably because the viruses are still present.  Therefore, extra stem cells may help cool the immune fires. BUT, and it is an important but, do we want to down-regulate the immune system if a virus is still present? My belief is – no.

What we want is to make the virus go away and with that have the immune response naturally calm down.

To do that we have to give sight to the blind and help the macrophages find their targets.

To do this we are working with some of the finest biotech labs in Europe and we believe we have the solution.  More on that to come.

A brief but helpful discussion about TNF alpha is on wikipedia.