Jump to content
ACN Latitudes Forums

AutoAntibody-mediated neuronal cell signalling


Recommended Posts

Reading through a bunch of recent papers I now understand Dr. Swedo's comment at a recent Autism Conference that based on recent research "the controversy around PANDAS should be over."

 

Over the past several months I've spent a good amount of time reviewing papers on molecular mimicry and the auto-immune aspects of PANDAS. I thought I'd post what I learned and also request comments from others who've been tracking this.

 

I started this with the post "PANDAS research for your doubting doctor" http://www.latitudes.org/forums/index.php?showtopic=3911 because I found that a lot of the doctors were really ill informed about the research on PANDAS.

 

One of the most significant papers is by Kirvan and Cunningham in the July 2003 issue of Nature Medicine (a very prestigous journal) about "Mimicry and auto-antibody mediated neuronal signalling" http://www.nature.com/nm/journal/v9/n7/pdf/nm892.pdf . They also published a 2006 paper in the Journal of Neuroimmunology http://www.pandasnetwork.org/CunninghamJNICaMKinase.pdf on "Antibody-mediated neuronal cell signaling in behavior and movement disorders". Finally Kirvan in 2007 published a paper on "Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea."

 

 

What they found was the following:

 

They were able to isolate three auto-antibodies that were created in response to Group A B-Hemolytic Streptococcal infections in patients with Sydeham Chorea and PANDAS. Now these auto-antibodies have nothing to do with ASO or Anti-DNAse B or those tests. I really want to underscore this because so much attention is often paid to ASO and Anti-DNAse B, but it appears neither of those antibodies have anything to do with PANDAS (except confirm whether you once had a strep infection -- and even then with a 33% false negative rate -- see A little bit about ASO titers and More about ASO ).

 

These newly discovered antibodies (which go by the names 24.3.1, 31.1.1, and 37.2.1) cross-react with a lysoganglioside in the brain. By cross-react, what they mean is that if those antibodies are present, they bind with neural tissue in a similar manner to one of the brain's own chemicals.

 

In addition, they discovered that if the antibody exists in enough concentration, it can signal neuronal activity (i.e., make a muscle move or stimulate a thought/action). This is a really significant finding and could explain a lot of the tics and behavioral abnormalities.

 

The only party I have found who tried to replicate Kirvan's experiment was Kurlan and Singer in their June 2008 Pediatrics report. However, Kurlan and Singer ran their experiments on Tourettes kids with waxing and waning tics and not PANDAS kids with episodic OCD symptoms (see Problems with Kurlan Paper). It looks like Cunningham and Kirvan's results apply only to PANDAS OCD and not to Tourettes or non-PANDAS OCD.

 

In reading through reviews of the Kirvan paper, it appears the biggest complaint is that Kirvan and Cunningham have not described how the antibody in blood serum crosses the blood brain barrier and gets into central spinal fluid (CSF). For this to occur, there has to be some breakdown of the blood-brain barrier.

 

Tracking this down, there are a number of interesting reports where streptococcal infections themselves can interfere with the blood brain barrier -- http://www.neurology.org/cgi/content/abstract/54/7/1433 . In addition, there are papers that epinephrine (from fear or stress) causes a breakdown of the barrier. In addition, inflammation (such as that produced during an immune response to an infection) can cause a breakdown in the barrier.

 

What's interesting about this item around inflammation is that prednisone and IVIG are both big anti-inflammatories and immunosuppressors. So they could be closing the blood brain barrier and reducing the replication of the pro-inflammatory cytokines and auto-antibodies.

 

So folks, have you run across papers that show PANDAS OCD kids have an open blood brain barrier (other than the observation that something is getting to the brain :lol: ?)

 

What is interesting to me about Kirvan and Cunningham's papers is that it provided significant supporting evidence of Swedo's original 1994 theory and explained why Plasmapherisis would work (removes the auto-antibody), why Prednisone would work (suppresses the auto-antibody and reduces inflammation of blood brain barrier), why IVIG would work (high anti-inflammatory impact and IgG has been found to have B and T cell suppressors that would supress certain auto-antibodies).

 

Comments? Other papers?

 

Regards,

 

Buster

Link to comment
Share on other sites

OMG, Buster this is amazing...this (your work!) will help so many kiddos out there (here!). This must have taken so much time and I am so grateful to you for doing it!!! Outstanding. These docs just do not have time to keep researching this stuff in the detail that you did. The docs are generally scheduled so back-to-back with appointments and then their extra time is ridden with patients in crisis (ours ARE!!!) but ---easier fixes than this...

if there is not really easily acsessible evidence on how to treat...they just defer to a higher level...and then it continues...(but they have to do this!)

 

Kudos to you Buster for this work....From me....for my family's sake...thank you for this hard work and for sharing! My advice to new comers to pandas .... start printing out any evidenced based- peer reviewed literature ...even if you don't understand it (NOT FORUM CHAT---docs will discount that in a heartbeat) and try to understand this stuff as much as you can to help direct your pediatrician in the right direction so you can obtain referrals and treatment as necessary. I've been a nurse for 18 years now and I still don't understand it all. It takes more than hands on care...heavy analysis is involved.

 

You and EAMom (and other mainstays) are doing so much to help support this forum... It is much appreciated. I wish I could contribute more than I do. But I honestly believe I am suffering from PTSD after the stuff we've been through in the past almost 2 years and I'm still trying to recover. I'm sure that others have had similiar feelings...

I think about you all.

 

 

Best regards,

amy s

Link to comment
Share on other sites

Very impressive. This is exactly what Dr. Leckman at Yale just told me. This is wonderful stuff and really gets to the heart of the matter. This is a diseade that needs to be treated like an autoimmune disease. Antibiotics can help but do not solve the issues in most severe cases.

Once, again...great work!

Mommd

Reading through a bunch of recent papers I now understand Dr. Swedo's comment at a recent Autism Conference that based on recent research "the controversy around PANDAS should be over."

 

Over the past several months I've spent a good amount of time reviewing papers on molecular mimicry and the auto-immune aspects of PANDAS. I thought I'd post what I learned and also request comments from others who've been tracking this.

 

I started this with the post "PANDAS research for your doubting doctor" http://www.latitudes.org/forums/index.php?showtopic=3911 because I found that a lot of the doctors were really ill informed about the research on PANDAS.

 

One of the most significant papers is by Kirvan and Cunningham in the July 2003 issue of Nature Medicine (a very prestigous journal) about "Mimicry and auto-antibody mediated neuronal signalling" http://www.nature.com/nm/journal/v9/n7/pdf/nm892.pdf . They also published a 2006 paper in the Journal of Neuroimmunology http://www.csus.edu/bios/faculty/Kirvan/Ki...JNI_article.pdf on "Antibody-mediated neuronal cell signaling in behavior and movement disorders". Finally Kirvan in 2007 published a paper on "Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea."

 

 

What they found was the following:

 

They were able to isolate three auto-antibodies that were created in response to Group A B-Hemolytic Streptococcal infections in patients with Sydeham Chorea and PANDAS. Now these auto-antibodies have nothing to do with ASO or Anti-DNAse B or those tests. I really want to underscore this because so much attention is often paid to ASO and Anti-DNAse B, but it appears neither of those antibodies have anything to do with PANDAS (except confirm whether you once had a strep infection -- and even then with a 33% false negative rate -- see A little bit about ASO titers and More about ASO ).

 

These newly discovered antibodies (which go by the names 24.3.1, 31.1.1, and 37.2.1) cross-react with a lysoganglioside in the brain. By cross-react, what they mean is that if those antibodies are present, they bind with neural tissue in a similar manner to one of the brain's own chemicals.

 

In addition, they discovered that if the antibody exists in enough concentration, it can signal neuronal activity (i.e., make a muscle move or stimulate a thought/action). This is a really significant finding and could explain a lot of the tics and behavioral abnormalities.

 

The only party I have found who tried to replicate Kirvan's experiment was Kurlan and Singer in their June 2008 Pediatrics report. However, Kurlan and Singer ran their experiments on Tourettes kids with waxing and waning tics and not PANDAS kids with episodic OCD symptoms (see Problems with Kurlan Paper). It looks like Cunningham and Kirvan's results apply only to PANDAS OCD and not to Tourettes or non-PANDAS OCD.

 

In reading through reviews of the Kirvan paper, it appears the biggest complaint is that Kirvan and Cunningham have not described how the antibody in blood serum crosses the blood brain barrier and gets into central spinal fluid (CSF). For this to occur, there has to be some breakdown of the blood-brain barrier.

 

Tracking this down, there are a number of interesting reports where streptococcal infections themselves can interfere with the blood brain barrier -- http://www.neurology.org/cgi/content/abstract/54/7/1433 . In addition, there are papers that epinephrine (from fear or stress) causes a breakdown of the barrier. In addition, inflammation (such as that produced during an immune response to an infection) can cause a breakdown in the barrier.

 

What's interesting about this item around inflammation is that prednisone and IVIG are both big anti-inflammatories and immunosuppressors. So they could be closing the blood brain barrier and reducing the replication of the pro-inflammatory cytokines and auto-antibodies.

 

So folks, have you run across papers that show PANDAS OCD kids have an open blood brain barrier (other than the observation that something is getting to the brain :blink: ?)

 

What is interesting to me about Kirvan and Cunningham's papers is that it provided significant supporting evidence of Swedo's original 1994 theory and explained why Plasmapherisis would work (removes the auto-antibody), why Prednisone would work (suppresses the auto-antibody and reduces inflammation of blood brain barrier), why IVIG would work (high anti-inflammatory impact and IgG has been found to have B and T cell suppressors that would supress certain auto-antibodies).

 

Comments? Other papers?

 

Regards,

 

Buster

Link to comment
Share on other sites

Printed off all of the research to keep in my file. Thank you!!

 

I know I ask this question repeatedly (I have a hard time living w/o answers...)

 

Does your research, and does Dr. Leckman think, IVIG is a cure, or a treatment. I am new to all of the science, so am trying to wrap my head around this info. If a child's episodes can be resolved with antibiotics, would IVIG still (theoretically) work to get rid of the pandas autoimmune issues overall- or will it only help that episode?

 

Any thoughts would be appreciated...

 

Thank you, as always, to everyone for their kindness and insight...

Link to comment
Share on other sites

Hi DcMom,

 

In terms of the research, I wasn't quoting any of Leckman's work. Leckman seems to be working on the theory that T-cell regulation is messed up and so the anti-host antibody isn't properly supressed. Other auto-immune diseases treated with IVIG tend to be multi-dosing. What I mean is that for some diseases IVIG adds in suppression of host-attacking antibodies... however, over time, this suppression antibody gets all used up and you need more of them.

 

In PANDAS, Dr. K and Dr. Leckman seem to think that there is a disfunction of the T-regulators and that IVIG does a reset on the immune system and helps the body relearn how to separate host attacking from foreign body attacking. If this "lesson" is learned then a single IVIG may suffice.

 

As far as I know, no one has studied the long term effects of IVIG and whether it is a cure of the disease or just a cure of the symptom. There's good anecdotal evidence from Swedo's studies that the single dosage was sufficient, but I couldn't find second experiments that supported that theory. Dr. K probably has the best anecdotal evidence -- even if not blinded. At this point there just doesn't seem to be enough data to say one way or the other...

 

Buster

Link to comment
Share on other sites

These newly discovered antibodies (which go by the names 24.3.1, 31.1.1, and 37.2.1) cross-react with a lysoganglioside in the brain. By cross-react, what they mean is that if those antibodies are present, they bind with neural tissue in a similar manner to one of the brain's own chemicals.

 

I got a number of questions regarding my comment above so let me try to explain what is thought to be going on.

 

The streptococcal infection is thought to be a seminal event or initial trigger that produces the anti-neural antibodies. These anti-neural antibodies are then circulating in blood serum at some concentration. If the strep is destroyed (antibiotics or otherwise), then most of the antibodies disappear because the triggering antigen is gone. It is likely, however, that the antibody is remembered by the B-cells for future use.

 

Now a subsequent strep exposure occurs. The B-cell "remembers" the antibody and produces it to attack the strep. It replicates and rebuilds a concentration of antibodies in the serum.

 

On the presumption that these anti-neural antibodies can't touch anything but neural tissue, all is fine as long as the blood brain barrier is closed (i.e., the anti-neural antibody can't get to the brain tissue).

 

Suppose now the blood brain barrier opens (due to illness, trama, infection, disease, genetic predisposition, ....). Now the circulating antibodies can interact with neural tissue and signal it found what it was looking for. This signal generally causes inflammation and more antibodies to be produced. Hence the auto-immune problem.

 

So there are really two ways that the antibody concentration grow:


  1. * Another strep infection or exposure occurs and so the B-memory cell triggers up more antibodies
    * the antibodies in the serum find what they are looking for and announce the need to replicate more antibodies

The key is clearly the blood brain barrier. As long as the antibodies are stuck in serum, nothing happens (provided they only cross-react with neural tissue). If the blood brain barrier opens, then inflammation, replication and odd signalling can occur.

 

So, while Strep is likely the seminal event, other infections can open the Blood Brain Barrier and an exacerbation can occur.

 

Note, the above is a theory and not yet proven. Kirvan and Cunningham have isolated the antibody, but not explained the crossing. Leckman has demonstrated some interesting findings on T-cell regulation but not shown that deficiency in PANDAS.

 

 

Regards,

 

Buster

Link to comment
Share on other sites

It seems many researchers are also pointing to a failure of the blood brain barrier in MS as the main cause. There also seems to be evidence linking food allergy/hypersensitivity to causing/aggravating this weakness. Many on this forum seem to be heading in that direction as well. I am going to start a thread to take a survey of those who have tested for allergies...

 

There is some evidence that Bilberry extract helps to strenghten the blood brain barrier. Has anyone used this? Also suggested is an increase in blueberries, red grapes, and cherries.

 

Buster? Anyone? Thoughts?

Link to comment
Share on other sites

There is some evidence that Bilberry extract helps to strenghten the blood brain barrier. Has anyone used this? Also suggested is an increase in blueberries, red grapes, and cherries.

 

Buster? Anyone? Thoughts?

 

I've been reading about this product as well to reduce brain inflamation... wondering if anyone has any experience or thoughts.....

 

http://www.lutimax.com/

http://www.luteolin.com/health_benefits.html

Link to comment
Share on other sites

Cunningham's work really drives home the point that PANDAS should not be simply viewed as a form of tourettes/tics, but rather a close cousin to SC. Hopefully her tests will soon be available as a tool to help diagnose PANDAS (and very important!!) distinguish PANDAS from tourettes/non-PANDAS tics.

 

In SC, group A streptococcal infections induce cross-reactive antibodies that deposit in the basal ganglia and lead to CaM kinase II activation in neuronal cells (Kirvan et al., 2003). PANDAS sera were found to induce significantly higher levels of CaM kinase II activation than sera from non-PANDAS OCD, tic, and ADHD groups not associated with streptococcal infection. In fact, PANDAS patients diagnosed with isolated tics produced the highest level of CaM kinase II activity similar to chorea.

 

It is interesting that tic (non-PANDAS) serum tended to have even lower rates of CaM kinase II activation than even Normal Human Serum (NHS). (see figure 3b from http://www.csus.edu/bios/faculty/Kirvan/Ki...JNI_article.pdf ) And that PANDAS with tics serum tended to have higher (approaching SC) levels of CaM kinase II vs. PANDAS w/out tics.

 

In other words, it seems that when PANDAS tics show up, the CaM kinase II is at a pretty high level, whereas with PANDAS ocd (without tics) CaM kinase II tends to be lower (and could be in the range of NHS). This might be an explanation of why (in Swedo's 1999 IVIG/pex study) it appeared that tics were more resistant to IVIG/pex treatment vs. PANDAS OCD...was it because there was simply more CaM kinase II (and perhaps more anti-neural antibiodies in type and overall number) thus making these tic-ky PANDAS kids more resisistant to treatment. ???? Just a theory...

Link to comment
Share on other sites

Hi DCMom,

my theory, it that IVIG could be a cure but it would be important to prevent a new strep infection (post IVIG) to prevent another "sentinal episode" and re-creation of PANDAS. And, if you can keep these kids from getting another sentinal strep infection until well after puberty they are "cured"??? On the theory that the immune system changes at/after puberty (which is why kids don't tend to get a first PANDAS epidose after puberty) making the child resistant to getting PANDAS (although if they already have it, that's a different story).

 

however, very tic-ky PANDAS kids seem to have a more severe form of the dz (at least higher CaM kinase II levels) thus making harder to treat. (Do these kids need more than 1 IVIG? ) So, that is a question...the differences between (including anti-neural antibody levels, CaM kinase II, response to IVIG) between OCDish pandas kids and tic-ky PANDAS kids. I think that difference is quantitative (CaM kinase II levels etc), not qualitative.

 

It will be certainly be fascinating to find out what happens to these kids' CaM kinase II levels (and anti-neural anti-body levels) post IVIG...and if this correlates with improvement of symptoms.

Link to comment
Share on other sites

In other words, it seems that when PANDAS tics show up, the CaM kinase II is at a pretty high level, whereas with PANDAS ocd (without tics) CaM kinase II tends to be lower (and could be in the range of NHS). This might be an explanation of why (in Swedo's 1999 IVIG/pex study) it appeared that tics were more resistant to IVIG/pex treatment vs. PANDAS OCD...was it because there was simply more CaM kinase II (and perhaps more anti-neural antibiodies in type and overall number) thus making these tic-ky PANDAS kids more resisistant to treatment. ???? Just a theory...

 

Hi EAMom,

 

Your point above is excellent and I too have been fascinated by Kirvan's 3b figure. I sure wish someone else had replicated this study.

 

A slight difficulty in the 3b figure is that Kirvan was taking kids with acute PANDAS (i.e., in exacerbation) and comparing them with non-PANDAS OCD, Tics and ADHD kids. If I replot the convalescent kids (taking data from figure 2a and plotting it in figure 3a), it shows that the PANDAS kids in convalescence look a lot like Non-PANDAS kids. Out of the 16 kids, only 4 kids maintained high CaM Kinase II activation in the convalescent state . What's interesting about this is that for 75% of the kids, the antibodies reduced with symptom decline. For 25%, the antibodies remained at same or elevated levels.

 

This makes me think that there are two things going on:

  • for some, the convalescent state comes from a reduction of the auto-antibodies
  • for others, perhaps the blood brain barrier has closed preventing the auto-antibodies from crossing into CSF

As far as I could tell, Kiran didn't have CSF matches to Serum in this 2006 study. This means we can't look at the question of whether the decline in symptoms is tied to a decline in CSF auto-antibodies independently of the amount of auto-antibodies in serum. I went back to her 2003 Nature article and while the data sets are undoubtedly disjoint (i.e., can't link the results), the Nature article (figure 4 d) seems to support the hypothesis that it is the amount of auto-antibodies in the CSF and not the Serum auto-antibodies.

 

This even more supports the notion that there are two independent triggering events:

  • in one, the auto-antibodies are removed and another sentinel event is required to raise the auto-antibodies
  • in the second, the auto-antibodies are in the serum, but can't get to the CSF

So for some people, they need both the strep infection and a break down of blood brain barrier due to infection, stress, .... In others they need only the break down of the blood brain barrier because the B-cells are already stuck maintaining a high set of auto-antibodies.

 

I'll keep digging and see if I can get anything from Husby's paper on this. He did work on this topic back in 1976.

 

Regards,

 

Buster

Link to comment
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now
 Share

×
×
  • Create New...