The over-activated immune system, Kv1.3, ASD-IE, Acacetin and sloppy science

One of the people I have met during my investigation into autism, recently pointed out to me that much scientific research cannot be trusted.  He forwarded a study to me showing just how many researchers admit is omitting data that did not suit what they were trying to prove.  I replied that I made a point of checking the credentials of the lead author.  He then replied that it is not the lead researcher who collects the data, he has a little army of PhD students doing this and nobody is checking them.

The study showed it was the younger researchers, eager to prove themselves that were the most likely to “fiddle” the results.  The problem is that by the time you become an “older researcher” you are not the one collecting the data.

Doubts about Sprouts 

One of the people who I keep forgetting to add to my Dean’s list is John Gargus; he is a professor at University of California at Irvine and Director of the Center for Autism Research and Treatment at UCI.  He is also a specialist in the complex field of ion channels and channelopathies.

He was asked to comment about the Johns Hopkins broccoli/Sulforaphane autism trial.

Trial sprouts doubts about broccoli extract for autism

Cruciferous caution: 

Some independent researchers have similar reservations, noting that the control group showed an unusually small placebo response.“You always see a 20 to 25 percent improvement in placebo,” says John Jay Gargus, director of the Center for Autism Research and Translation at the University of California, Irvine. For example, the placebo effect plagued trials of the gut hormone secretin and antidepressants for autism.
“It’s stunning that they’ve managed to have found a placebo that doesn’t give the placebo effect that we see in every other neuropsychiatric drug trial,” Gargus says.

Now as regular readers will know, at least in Monty, aged 11 with ASD, broccoli sprout powder and we assume the Sulforaphane produced by it, does have a near immediate effect.

But as Gargus says, you will always have some people with the placebo appearing to improve.  In an old post I looked at the placebo effect in autism.  It seems that the more involved the trial and hence the more 1:1 attention the child gets, the more the placebo appears to make things better.  In fact it was not the placebo, it was the 1:1 attention that improved the autism.

So, just as we have to be cautious of the placebo effect, we have to be cautious of sloppy science/scientists.  When financial interests are involved you need to be even more cautious.

The other thing I have learnt to be cautious of, is scientists who have spent many years in one very narrow field, often trying to prove their initial hypothesis to be correct.  Their eyes are then closed to everything else.

Autism Flare-ups, Summertime raging and GI issues

We have investigated in depth the fact that in some people with autism their immune system appears to be over-activated, as the result of an allergic response.  What then happens is that their autism “flares-up” and therapies that previously worked, seem to stop doing so.

The conclusion was that the allergy had caused mast cell activation and this triggered the release of pro-inflammatory chemicals (IL-6, histamine etc).  The solution was:-

·        Avoid the allergen (a type of food, or even airborne pollen)
·        Use mast cell stabilizers to minimize degranulation; even common H1 anti-histamines are partially effective
·        Inhibit the potassium ion channel Kv1.3, which seems to mediate the resulting “over-activation” of the immune response.

The good news is that it really does work and not just in Monty.  The bad news is that the optimal therapy uses a prescription drug (Verapamil).

While trawling through the research on novel anti-oxidants, I stumbled upon something that may help those people who cannot access Verapamil.

There is a flavonoid called Acacetin, which is found in asplenioid ferns.  This flavonoid has long been has used for its anti-inflammatory and immunomodulatory effects.  Now it has been shown to block Kv1.3 channels and inhibits human T cell activation.  This is one of the effects of Verapamil (there are others).  Acacetin has also been shown to have anti-cancer properties in prostate cancer cells.

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin (5,7-dihydroxy-4'-methoxyflavone)exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signaling in prostate cancer cells

Remember the odd therapy used to block Kv1.3, those TSO parasites, I mentioned in previous posts.  My favorite is this one:-

Immunomodulatory Therapy in Autism - Potassium ChannelKv1.3, Parasitic Worms, and their ShK–related peptides

Acacetin is available as a supplement.  So if you think blocking Kv1.3 might help and cannot access Verapamil or TSO, there are other options.

Indeed, for completeness, there at least two other Kv1.3 blockers that are available.  One is progesterone, the hormone and the other is Curcumin.

  

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes.  Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activities.

  

You may recall that Progesterone was found to be highly neuro-protective and for this reason was trialed for use in the ER, immediately after a traumatic brain injury.  It was shown to save lives.  In autism, we previously found that some people, at the high functioning end, find they feel better when they apply progesterone cream, i.e. transdermal route.

Curcumin has been used for centuries as a drug.

I have not tried them, but I will continue to use Verapamil.  Acacetin, Progesterone and Curcumin share some, but not all of each other’s effects.

Progesterone, in common with Verapamil, affects both potassium and calcium channels.

There are many different potassium and calcium channels and you would hope to find a selective channel blocker and hence affect only the ones you need to.

ASD-IS  (Inflammatory Subtype)

I came across a promising study on Paul Whiteley’s blog.  It is a study of a sub-type of autism characterized by fluctuating behavioral symptoms following immune insults.  In the trial group the children all had GI problems, some had enterocolitis or esophagitis.  The entire group had been noticed by teachers/therapists to lose cognitive skills following immune insults.

Cytokine profilesby peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

Regular readers of this blog will see lots of familiar points.  This appears to be exactly the same thing as my “over-activated immune response”.

Now this study comprised children who had Non-IgE mediated allergies.  This does matter because classic allergies are called IgE-mediated and they result in little cells called mast cells getting activated and then releasing IL-6 and histamine in the blood supply.

From Wikipedia we have a summary:-

Conditions caused by food allergies are classified into 3 groups according to the mechanism of the allergic response:

1.     IgE-mediated (classic) – the most common type, occurs shortly after eating and may involve anaphalaxis.

2.     Non-IgE mediated – characterized by an immune response not involving immunoglobulin E; may occur some hours after eating, complicating diagnosis.

3.     IgE and/or non-IgE-mediated – a hybrid of the above two types.

Treating allergy is a “fuzzy” area and, depending on which country you live in, some aspects are seen as science and others pseudo-science. 

Perhaps we should see it as an important, but emerging field of science.

I am not an allergist/immunologist, so I have to look things up.

Since in the trial the children had Non-IgE mediated allergies, we can then look to see whether mast cell activation is relevant.

NON-IgE MEDIATED FOOD ALLERGY 

Mast cell and eosinophil activation is an important component of the non-IgE-mediated response

The authors of the autism study believe that the research subjects with allergy did not have mast cell activation, because they had NON-IgE mediated allergies.

Since I am not an allergist, all I can say is the author of the above paper from the Royal Free & University College School of Medicine in London thinks that mast cell activation is an important component of the non-IgE-mediated response.

Anyway, make your own mind up and continue to see what the study found.

The study looked at children with autism and allergy, whose autism flares up and affects (impairs) their cognitive function.  This group is ASD-IS (Inflammatory Subtype)

ASD-IS children: ASD-IS children are defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection). Symptoms must have been documented by individuals other than parents, such as teachers/therapists, a minimum of three times. In addition, a history of persistent GI symptoms, often diagnosed as non-IgE mediated food allergy (NFA - see next section for diagnostic criteria), is required. Among the ASD-IS subjects, 14/24 subjects were diagnosed with food protein induced enterocolitis syndrome (FPIES), a severe form of NFA, prior to enrollment in this study, and two ASD-IS subjects were diagnosed with eosinophilic esophagitis (EoE) on the basis of biopsy results. These ASD-IS subjects reported to have had loss of once-acquired cognitive skills based on the reports of teachers, therapists and/or previous records of developmental assessment.

We defined ‘flares’ as worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults). Most of the immune insults in this study were clinically judged to be microbial infection (mainly viral syndrome). In ASD-IS children, we obtained samples at least once in the ‘flare’ and ‘non-flare’ states. Changes in behavioral symptoms by parental reports were confirmed by reports from

teachers and other caregivers.

The authors have an entirely different hypothesis to mine.

But I find their data remarkably similar to what I see being caused by a pollen allergy in my son - summertime autism flare-up and regression.  This is why there were so many posts about the inflammatory cytokine IL-6 and how to minimize it.

Have the authors stumbled upon exactly the same phenomenon as I did?  I very much think so.

I have shared my therapy with the authors, but they think that Non-IgE mediated allergies have nothing to do with mast cell activation.   That sounds odd to me.