The answer to the PANDAS mystery

[Dr_Rosario_Trifiletti]

This is a paper on Toll-Like Receptors, the overactivation of which, in my opinion, is the root cause of PANDAS

 

http://www.nature.com/msb/journal/v2/n1/pdf/msb4100057.pdf

 

The idea is this -

 

1. You have this basic system called TLR, a component of innate immunity - present and primed to go as part of your immune system even before encountering organisms

 

2. Different organisms use different TLR's (for example p41 flagellin signals through TLR5) but converge on the same, inflammatory like signaling pathway - this explains the phenomenon of co-infection. Let's say organism 1 signals through TLR1 and organism 2 through TLR2. Then getting them both together is particularly bad.

 

3. Organisms that tend to be persistent, i.e. develop carrier states like strep, mycoplasma and Lyme are particularly bad actors in this as they can chronically activate TLR's

 

4. Something about the TLR signaling pathway activation leads to a common neurochemical change resulting in tics, OCD or a rage-like syndrome. This will ultimately link to CaM-dependent signaling, i.e. CaMII kinase (see Fig.2) - so it all fits

 

This idea is testable as there are tests for TLR activation.

 

If I am right, the proper immunosuppressive treatment for PANDAS will be TLR-specific drugs (already in the drug company pipelines for other reasons).

 

 

P.S. I am a nerd and this is what I do in my spare time ...

 

 

Dr. T

[airial95]

There are many parents on these forums that appreciate your hard work and dedication - it makes you an angel - not a nerd!

 

Thank you!

[laura s]

So if your child tests positive for band 41 =IGG and IGM, plus they have the ocd, tics, meltdowns... sounds like my kid!

 

Which TLR test and which drug..... sign us up!!!!!!!!!!!!

 

Thank you for your constant research and updates.

 

Laura

[kcdc3]

So is this why some kids who don't have issues with strep, but have the Lyme or Mycoplasma or whatever else - is this why their CAM numbers are in the PANDAS range?

[jewels]

Thankyou Dr T.

 

Does this article link to my sons persistant nose infections, and his PANDAS sister!

 

 

Abstract:

 

Background:

 

The impact of Staphylococcus aureus on the development of chronic sinusitis with nasal polyps (nasal polyposis [NP]) is a controversial discussion because different S. aureus colonization rates have been reported. Aside from the presence of a microbial stimulus, elements of innate immunity such as Toll-like receptors (TLRs) and/or impaired TLR function could be relevant for the development of this disease. Because the 753Q TLR2 variant may predispose to staphylococcal infection, we simultaneously analyzed staphylococcal colonization and the R753Q TLR2 single nucleotide polymorphism (SNP) in NP.

 

Methods:

 

Sixty-eight patients with NP (47 men and 21 women; mean age [±SD], 51.8 years [16.3]) and 51 controls (32 men and 19 women; mean age [±SD], 36.3 years [12.2]) were included. Patient characteristics studied included status of allergy, asthma, aspirin intolerance, and endoscopic and CT polyp score. For detection of bacteria, standard procedures of bacteriology and 16S rRNA gene sequencing were used. The R753Q TLR2 polymorphism was studied by allelic discrimination assay.

 

Results:

 

Overall, 128 isolates were cultured from 68 NP specimens, with Staphylococcus epidermidis and S. aureus being the most frequent bacterial isolates. Other bacterial species were infrequently detected. Fifty-nine isolates were cultured from 51 controls. Similarly, S. epidermidis and S. aureus were the most frequent bacterial isolates. S. aureus colonization was significantly increased in NP (p < 0.05). However, SNP genotyping results showed no association of the 753Q TLR2 variant with NP.

 

Conclusion:

 

Although S. aureus detection was increased in NP, nasal polyp pathology is not related to the 753Q TLR2 variant.

 

Jules

[jewels]

I meant the "other bacterial species that were infrequently detected.

[Joan Pandas Mom]

I agree with Airial, that makes you an Angel and I am including brilliant, but not a nerd!

[momaine]

This is a paper on Toll-Like Receptors, the overactivation of which, in my opinion, is the root cause of PANDAS

 

http://www.nature.com/msb/journal/v2/n1/pdf/msb4100057.pdf

 

The idea is this -

 

1. You have this basic system called TLR, a component of innate immunity - present and primed to go as part of your immune system even before encountering organisms

 

2. Different organisms use different TLR's (for example p41 flagellin signals through TLR5) but converge on the same, inflammatory like signaling pathway - this explains the phenomenon of co-infection. Let's say organism 1 signals through TLR1 and organism 2 through TLR2. Then getting them both together is particularly bad.

 

3. Organisms that tend to be persistent, i.e. develop carrier states like strep, mycoplasma and Lyme are particularly bad actors in this as they can chronically activate TLR's

 

4. Something about the TLR signaling pathway activation leads to a common neurochemical change resulting in tics, OCD or a rage-like syndrome. This will ultimately link to CaM-dependent signaling, i.e. CaMII kinase (see Fig.2) - so it all fits

 

This idea is testable as there are tests for TLR activation.

 

If I am right, the proper immunosuppressive treatment for PANDAS will be TLR-specific drugs (already in the drug company pipelines for other reasons).

 

 

P.S. I am a nerd and this is what I do in my spare time ...

 

 

Dr. T

Though this is all over my head, I am ever thankful for your work in this field, for treating our children, and I hope that your findings will continue to bring our children relief from this dreadful disease and healing.

Angela

[ShannonOtown]

"If I am right, the proper immunosuppressive treatment for PANDAS will be TLR-specific drugs (already in the drug company pipelines for other reasons)."

 

Can you explain what the TLR drugs would do? Perhaps change or suppress the TLR signaling pathway activation?? Then IVIG treatment would not be needed?

 

What are they be developed for now?? What type of disorder are they focusing on?

[momto2pandas]

Hey, what's wrong with being a nerd?!?!

 

I'm telling you - inflammatory cytokines: TNF-alpha, IL-1.... coupled with self-directed antibodies coming from molecular mimicry. My hypothesis is that in PANDAS/PAND-type conditions, you have overreactivity of inflammatory cytokines in response to particular immune challenges (or maybe all immune challenges, in some cases.) Not baseline elevated levels of inflammatory cytokines, but "extra-elevated" levels in response to challenges. There is data demonstrating that this happens to quite a dramatic extent in some psych conditions (particularly in response to immunizations, but also in response to other challenges), there is data correlating these elevations and declines with psychiatric symptoms in both psychiatric and autoimmune diseases, and I believe that the "hyper-elevation" effect is associated with immunodeficiency states (at least I've seen papers about it for acquired immunodeficiencies). A lot more I could say on this - and it fits in with your idea of hypoimmune and hyperimmune subtypes of PANDAS -- but this is not the place.

 

Once you have any of the self-directed antigens in your system, elevated inflammatory cytokines will amplify them, in addition to increasing the permeability of the BBB and having their own effects on the HPA axis (and endocrine system) and nervous system. This is why I think that particularly when someone is still recovering from a PANDAS episode started by e.g. a Strep infection, or when someone has recently had the Prevnar/Pneumovax vaccine, even things like viruses or allergies/intolerances can set off a bad episode - it's all sort of a summation of autoantibodies and inflammatory cytokines from whatever sources. Even when molecular mimicry effects are low, the cytokines themselves can have effects. What we see in our family is that episodes surrounding actual bacterial infections and immunizations have more true OCD/tic/anorexia elements, whereas those set off by other things and distant from Strep infections are more affective. My guess is that this is because the molecular mimicry element is more at work in the former and the effects of the cytokines themselves are more center stage in the latter.

 

I really think that over-reactive TNF-alpha and IL-1 are significant links in this whole thing. It fits the data and the "findings" that we see informally. What's more, there are specific inhibitors of those already available on the market (the biologics). And many "less specific" inhibitors as well, including COX-2 inhibitors. What's more, the companies that work on these drugs are my past employers and current clients, and these drugs have been my own "babies" in development. I'd love to get some good scientific feedback on this idea for PANDAS (and make sure that I'm not seeing a nail because I developed the hammer!) and if it makes sense, I'd love to approach my clients to sponsor clinical trials (need to find willing investigators, patients, etc....). I'm pretty sure I could get it going.

 

I'll look at TLR-specific drugs too. Who is developing them? As you know, there is orphan drug money available for pharma companies to sponsor trials of these kinds of things on "rare" (ha ha) diseases, and significant incentives for them to do so.

 

I have been overwhelmed with work lately but still want to pursue the pharma company path at some point....

 

Dr. T - you know how to reach me if you'd like to discuss.

 

 

 

This is a paper on Toll-Like Receptors, the overactivation of which, in my opinion, is the root cause of PANDAS

 

http://www.nature.com/msb/journal/v2/n1/pdf/msb4100057.pdf

 

The idea is this -

 

1. You have this basic system called TLR, a component of innate immunity - present and primed to go as part of your immune system even before encountering organisms

 

2. Different organisms use different TLR's (for example p41 flagellin signals through TLR5) but converge on the same, inflammatory like signaling pathway - this explains the phenomenon of co-infection. Let's say organism 1 signals through TLR1 and organism 2 through TLR2. Then getting them both together is particularly bad.

 

3. Organisms that tend to be persistent, i.e. develop carrier states like strep, mycoplasma and Lyme are particularly bad actors in this as they can chronically activate TLR's

 

4. Something about the TLR signaling pathway activation leads to a common neurochemical change resulting in tics, OCD or a rage-like syndrome. This will ultimately link to CaM-dependent signaling, i.e. CaMII kinase (see Fig.2) - so it all fits

 

This idea is testable as there are tests for TLR activation.

 

If I am right, the proper immunosuppressive treatment for PANDAS will be TLR-specific drugs (already in the drug company pipelines for other reasons).

 

 

P.S. I am a nerd and this is what I do in my spare time ...

 

 

Dr. T

[kim]

So many interesting comments on this thread.

 

Wonder if there are any thoughts on LL37 and it's involvement with strep pyrogens? Could a similar mode of action be involved? Also, wondering if this gives insight into why biologicals might be more sucessful in some cases than others (TNFa not induced under certain circumstances...speaking of psoriasis here, but obviously looking at a possible PANDAS connection)? Hate to air ignorance publically, but can't resist missing the possible opportunity to have someone comment

 

http://www.ncbi.nlm.nih.gov/pubmed/1970398...ogdbfrom=pubmed

 

excerpt

 

Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA-LL37 complexes activate TLR7 and, like self-DNA-LL37 complexes, trigger the secretion of IFN-alpha without inducing maturation or the production of IL-6 and TNF-alpha. In contrast to self-DNA-LL37 complexes, self-RNA-LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-alpha and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA-LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.

 

 

 

Also, found the mention of MAP2K5 here, interesting. Had been looking at TNFa and it's involvement with NF-κB and MapK pathways.

http://www.mdvu.org/emove/article.asp?ID=1218

 

excerpt

 

To determine what role it may play in TS, the authors genotyped 322 unrelated patients with TS and 294 neurologically normal controls, for variants in BTB9 and two other genes identified in the RLS studies, MEIS9 and MAP2K5. Three single nucleotide polymorphisms in BTBD9, all within intron 7, were associated with TS. In each case, the allelic sequence difference that increased TS risk was the same as that which increased RLS risk.

[Buster]

I went down this path for quite some time and ended up wondering if the kids were actually MyD88 deficient. TLR2 and TLR4 both trigger MyD88 in response to bacteria. But clearance required MyD88 support. http://www.sciencemag.org/cgi/content/abstract/321/5889/691

 

Buster

 

 

 

This is a paper on Toll-Like Receptors, the overactivation of which, in my opinion, is the root cause of PANDAS

 

http://www.nature.com/msb/journal/v2/n1/pdf/msb4100057.pdf

[JAG10]

Those who attended the OCD conference mentioned talk shifting toward or back to casting a broader net of those infectious triggers that tend to linger. Was there any mention of this idea of toll-like receptors?

[saidie10]

What you say below is the only thing I really understand but thank you, thank you for all your hard work!!!

 

"4. Something about the TLR signaling pathway activation leads to a common neurochemical change resulting in tics, OCD or a rage-like syndrome. This will ultimately link to CaM-dependent signaling, i.e. CaMII kinase (see Fig.2) - so it all fits"

 

Thank you for sharing this...both my sons tested above 164 on the CAMK test. No one wants to do anything for my younger son though since he doesn't have an "immune deficiency" yet (although he is only 5 points away from being deficient) or elevated titers. He had tics, OCD and RAGE LIKE behavior during both previous strep infections. I am terrified for school to start as I know any given strep infection that follows is the one that could send him over the edge of reality! Our oldest son is scheduled for IVIG in a couple of weeks. It all fits together now with my youngest son. He also has elevated Quinolinic which could be due to inflammation because of recurrent infections. Something is happening in his brain and I want to stop it before it progresses any further!

 

How do I convince a doctor to put him on antibiotics or help him before we end up having to do an IVIG on him as well down the road!

[dut]

Hi - not sure who you have consulted with but we are working with our ped who is super knowledgable and also Dr T by phone. Our ped rxd abx and steroids for our 2 year old son (dd7 has a a more clear cut PANDAS dx) due to behavioural signs and an elevated CaMK and 1 elevated ANA but Dr T concurred and would have been willing to rx if we had needed him to. He has always been great at getting back to me quickly, although, some people seem to have an issue getting hold of him sometimes but that hasn't been our experiance.

 

I wonder if it may be worth talking to him.. just a thought.. good luck