A Cytokine Storm? Mr Spock

I have recently started learning the workings of the human immune system, while 12 year old Ted (“normal” except for a Star Wars obsession) has been discovering Star Trek.  Last weekend we went to the cinema with Adrian “Mole” to see the latest release.  Mr Spock made one interesting observation, regarding what can happen when the interests of the many outweigh the interests of the few; this will be the tittle of a forthcoming post about the fate of Dr Wakefield and his vaccine theory.

Cytokines

Cytokines really do exist, even though they sound like something from science fiction.  They are signalling molecules associated with inflammation.  Several inflammatory cytokines are induced by oxidative stress.  The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidant stress, makes them important in chronic inflammation.  In extreme cases, there is a downward spiral of inflammation making it worse and worse.  The Spanish Flue in 1918 and SARS in 2003 are given as examples of such deadly cytokine storms.

The Research

There is a vast amount of research about the role of cytokines in autism and some very good work has been done by Paul Ashwood.  Finally, I have found an Englishman, even though he has gone to live in California, publishing some really high quality and useful research.  It turns out he is a colleague of Dr Wakefield.  Much of Paul Ashwood’s research is not available for free.  This one is:-  The role of immune dysfunction in the pathophysiology of autism

This paper is very readable and shows how a dysfunction of the immune system is without doubt a major part of the autism story. In typical post-Wakefield fashion, nobody wants to stick their necks out and draw usable, if only hypothetical, conclusions; it is easier to just suggest further research.

All the research shows high levels of cytokines in autistic subjects in the brain, spinal fluid, blood and in the gut.  Recent research also shows high levels of cytokines in the siblings of autistic people:- Plasma cytokine profiling insibling pairs discordant for autism spectrum disorder

The researchers comment:-

Thus, the lack of significant differences between sibling pairs discordant for ASD found in our study is in line with the results of previous studies. It is possible that a common immunogenetic background shared by siblings might eventually lead to different clinical outcomes when an environmental stress (for example, prenatal exposure to environmental toxins, viral and bacterial infections, parental microchimerism, etc.) occurs during development.

This last finding was deftly understood by 12 year old Ted, who commented, “Well Dad, you nearly had two autistic children”

Well isn’t he a chip off the old block.

Peter Interpretation

So combining this knowledge with my other readings, drew me to the logical conclusion that the inherited immune dysfunction, combined with the oxidative shock, so well described by Chauhan et al,(in the 400 page book) most likely resulted in a cytokine storm that damaged the brain, and autism resulted.  Due to the feedback loop of the cytokines, the neuroinflammation continues for life.

This then led me to research cytokine storms, to see how the cycle could be stopped and some kind of homeostasis reinstated.  I did not expect to find an answer, but I did.   

First we have to introduce new terms, TNF and TNFR.

TumorNecrosis Factors (TNF)

Tumor necrosis factors (or the TNF family) refer to a group of cytokines whose family can cause cell death or apoptosis.  19 members of the TNF family have so far been identified; the one that caught my eye was OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production.

A tumor necrosis factor receptor (TNFR), or death receptor, is a cytokine receptor that binds TNFs.  The matching TNFR for the TNF OX40L is called OX40 (also known as CD134).

OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo. T helper cells (type 1 and 2) are white blood cells that play a major role in the immune system
OX40 has been implicated in cytokine storms.

Cause of the Cytokine Storm

When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.  Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs.

TNF inhibitors and Cytokine Storms

The cytokine storm is kept going by the TNF cytokines.  So if these cytokines could be inhibited the storm might abate. An existing medication developed for arthritis called a TNF-alpha blocker was proposed as a possible drug. Corticosteroids and NSAIDS (Non-steroidal anti-inflammatory drugs) have been found ineffective.

In 2003 researchers at Imperial College demonstrated the possibility of preventing a cytokine storm by inhibiting or disabling T-cell response. A few days after T cells are activated, they produce OX40, a "survival signal" that keeps activated T-cells working at the site of inflammation during infection with influenza or other pathogens. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40- immunoglobulin (OX40-Ig), a human-made fusion protein, prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with an immune overreaction while allowing the immune system to fight off the virus successfully. By blocking the OX40 receptor on T-cells, researchers were able to prevent the development of the most serious flu symptoms in these experimental mice.  Sadly, it appears this discovery has been abandoned by the small company that tried to develop it.

And now for the shock …

In 2009 researchers in China found that a statin induced down-regulation of OX40 and OX40L in a concentration-dependent manner.

Simvastatin reduces OX40 and OX40 ligand expression in human peripheral blood mononuclear cells and in patients with atherosclerotic cerebral infarction.

"These findings improve our understanding of the anti-inflammatory and immunomodulatory properties of simvastatin"

Antioxidants have been successfully trialled in cases of Acute Respiratory Distress Syndrome (ARDS), which is another example of cytokine storm.  Organ damage was reduced and there was an improved survival rate.

Conclusion

It would seem that the combination of antioxidant and statin is about as good a combination as is currently possible, to dampen down the remaining effects of a cytokine storm, which is the extreme case of neuroinflammation.

By skill, or luck, this combination is exactly what I am trialling with Monty.