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titers question..


ajcire
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Not sure if I am going to make sense or not but...

 

If titers take time to rise... does that mean that when you are first seeing what you think is a problem that there is likely a current infection.. or if you didn't have evidence of a current infection and were going to just check titers (aware that titers don't tell the whole story) would you want to wait a few weeks out from the start to see a rise or by time you are seeing symptoms if your kid is a titer rising kid in the past would you suspect it would already have risen..

 

I hope that came out as clear on here as it did in my head.

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With respect to your question...

If titers take time to rise... does that mean that when you are first seeing what you think is a problem that there is likely a current infection.

 

Not exactly. It is possible you are seeing a breach of BBB rather than an active infection. Just as a reminder, the antibodies thought to cause PANDAS are not the ASO or Anti-DNAseB, but rather a set of antineuronal antibodies to GABHS (e.g., see Kirvan2006 with antibody 24.3.1).

 

Current thought is that symptoms are due to the combination of three events

  • rise in anti-neuronal antibodies
  • anti-neuronal antibodies hang out in serum for ~3 months
  • breach of the blood brain barrier

 

The breach of the BBB just seems to take inflammation -- that can come from an infection or stress.

 

The rise in anti-neuronal antibodies seems to take about 1-2 weeks to occur -- however, the antibodies have a half-life of around 28 days. This means they hang around a while (i.e., the 3 months). So any disruption to the BBB could in theory cause symptom exacerbation.

 

if you didn't have evidence of a current infection and were going to just check titers (aware that titers don't tell the whole story) would you want to wait a few weeks out from the start to see a rise

 

Yes. However, timing is really tricky. I would strongly urge a throat culture within 3 days of symptom exacerbation. For 53% of people, ASO will rise 1-4 weeks after symptoms of strep throat.

 

or by time you are seeing symptoms if your kid is a titer rising kid in the past would you suspect it would already have risen.

 

No, in Swedo's studies (see http://www.ucdmc.ucdavis.edu/mindinstitute/events/toxicology_recorded_events.html ) for those kids who did have rising titers, their titers rose 1-2 weeks after symptom onset (i.e., correlated with a preceding strep infection).

 

I hope that came out as clear on here as it did in my head.

Hope my response is equally clear.

 

 

Now there are a few complexities here...

 

Nasal carriage might be enough to trigger a breach of the BBB. There are a couple of really nice papers on Th17, GABHS and breach of BBB. Probably the most impressive are Kerbir (2007) "Human Th17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation" http://www.nature.com/nm/journal/v13/n10/abs/nm1651.html. Here he showing that the BBB can be disrupted by Th17 cells in the blood.

 

Recently (2010), Wang and Cleary publish "Induction of TGF-β1 and TGF-β1-dependent predominant Th17 differentiation by group A streptococcal infection" (see http://www.pnas.org/content/107/13/5937.short). Where they show that Th17 autoimmune and highly inflammatory response can occur with only nasal colonization in mice.

 

Now Mice are not people, but this was a fascinating finding that might explain why colonization may be all that is necessary in PANDAS kids who already have the anti-neuronal antibodies in the serum.

 

What I'm trying to highlight is that ASO and Anti-DNAseB rises will just tell you if strep got into the blood. However you could have symptoms if the antibodies are still in the blood and the BBB is opened due to other causes (such as Th17).

 

I think this circulation of antibodies with breach is what makes this so darn hard to isolate -- two factors rather than just one.

 

Buster

Edited by Buster
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The antibodies thought to cause PANDAS are not the ASO or Anti-DNAseB, but rather a set of antineuronal antibodies to GABHS (e.g., see Kirvan2006 with antibody 24.3.1).

 

Sorry to veer a bit off topic here, but could you please explain exactly what antineuronal antibodies are, Buster? I know they're the bad antibodies that think they're attacking our strep when they're really just attacking out brain.. But that's about it. What makes them different? Why are they called "antineuronal"? & what sends them to the brain, of all places?

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Sure, I'll do my best....

 

The antibodies are just "normal" antibodies (meaning they have the typical Y shape pattern of antibodies) and are released by B cells into the blood stream. -- let me know if you'd like an explanation of B cells.

 

The antibodies are called "anti-neuronal" because the antibodies seem to interfere with signalling of neurons. I know they should have called this "neuron interfering antibodies" but for reasons lost to me they call them anti-neuronal. This interference is found through a technique called competitive ELISAs which means they add the antibodies and then add stuff that should bind with the neuronal cells. If the normal stuff doesn't bind like it should when the antibodies aren't there, they assume that the antibodies interfered with the binding.

 

Okay, so are anti-neuronal or neuronal interfering antibodies bad? -- well, actually, not really. There's this part of your brain called the Blood brain barrier. The whole purpose of the BBB is to keep proteins in your blood from interfering with stuff in the brain. Stuff does cross the BBB but it's a pretty good filter.

 

So now we call anti-neuronal antibodies "things that could interfere with neuronal signalling if they ever got across the BBB". A bit long...

 

If the antibodies don't reach the brain they don't do anything... they just hang out in the blood stream for about 2-3 months and then disappear as the blood is cleaned by the liver.

 

So are the antibodies damaging -- so far the evidence is no. They just sort of interfere, but don't cause permanent damage.

 

Do we really know it's these antibodies -- well, sort of. The antibodies (such as this funny one called 24.3.1 was found in Sydenham Chorea kids in the spinal fluid). Whether this antibody is actually causing the symptom or just a byproduct is really not known.

 

On your final question of what sends them to the brain -- that's really a great question. It's not that they go "to the brain" it's more that they are getting distributed throughout the body but have nothing to attach to. The pattern in the Y that makes up monoclonal antibodies has to find a very specific sequence. That sequence seems to be similar to lysogangliosides and similar to a portion of dopamine. Essentially, the antibodies are floating around going sort of everywhere but when they finally get across the BBB, they find some dopamine receptors in the basal ganglia and bind there.

 

Let me know if this was too much detail or not enough (i.e., please ask again).

 

Very best regards,

 

Buster

 

 

The antibodies thought to cause PANDAS are not the ASO or Anti-DNAseB, but rather a set of antineuronal antibodies to GABHS (e.g., see Kirvan2006 with antibody 24.3.1).

 

Sorry to veer a bit off topic here, but could you please explain exactly what antineuronal antibodies are, Buster? I know they're the bad antibodies that think they're attacking our strep when they're really just attacking out brain.. But that's about it. What makes them different? Why are they called "antineuronal"? & what sends them to the brain, of all places?

Edited by Buster
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Again Buster - since you do seem to have such a great handle on all the science behind this..........!!

 

If the antibodies go away after 3 months, why do so many kids seem to have exacerbations with any kind of immune system challenge?? Is it because as soon as the immune system starts to work, it brings out all of the antibodies in its memory (both good and bad) while it tries to figure out how to deal with this new assault - even if it is not strep (because our immune system keeps a memory of all of our antibodies right)?? And then if the BBB is open when our immune system "kicks in", these bad ant-neuronal antibodies (originally caused by untreated strep) find what they think they should attack (brain tissue) - and as a result more of these bad antibodies are made because they think they have found a job to do??

 

Sorry Buster - my mind isn't super scientific!! I hope you understand what I am trying to ask!

 

Thanks

PKM

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If the antibodies go away after 3 months, why do so many kids seem to have exacerbations with any kind of immune system challenge??

 

Frankly, I'm not sure. I've heard three good explanations that warrant further investigation:

  1. there is a targeted antigen that keeps the B-cells activated
  2. there is a superantigen that has incorrectly recruited the B-cell
  3. there is inflammation that causes the BBB to open

 

The first one is sort of saying that the T-cells/B-cells are finding a tiny bit of the real antigen (say GABHS) and generating a bunch of antibodies.

 

The second one is saying that GABHS (and other infections) can cause the release of antibodies even though the exact signature of the bacteria wasn't present -- there are a lot of reasons this happens in the immune system.

 

The third one is probably the most likely.

 

 

Is it because as soon as the immune system starts to work, it brings out all of the antibodies in its memory (both good and bad) while it tries to figure out how to deal with this new assault - even if it is not strep (because our immune system keeps a memory of all of our antibodies right)??

There are sort of two types of immune response. Normally, T-cells/Antigen Presenting Cells (APC) come along and find something not quite right and present fragments of that to B-cells. If the key fits, the B-cell "unlocks" and releases/creates a bunch of antibodies. A second type of immune response occurs when there is a super antigen. These can activate a lot of T-cells and a lot of B-cells directly (i.e., sort of exhausting a person's immune response). Lyme seems to work this way.

 

And then if the BBB is open when our immune system "kicks in", these bad ant-neuronal antibodies (originally caused by untreated strep) find what they think they should attack (brain tissue) - and as a result more of these bad antibodies are made because they think they have found a job to do??

 

That is actually a theory -- in the case of 24.3.1 it targets GlcNAC which is a pretty common carbohydrate and on the GABHS exterior wall.

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Thanks Buster........that was helpful. I don't know where this forum would be without you!

 

PKM

 

oops thought of one more question.

 

You said that #3 was probably the most likely - that there is inflammation (from whatever virus/infection) and that causes the BBB to open. I get that part but how do those bad anti-neuronal antibodies get triggered again to even cross the BBB if strep is not there to trigger them - just some other random immune system challenge. Is it because these anti-neuronal antibodies can now just be made again and again in the absence of strep because the immune system has a memory of them?? Like for as long as the BBB is open (or when it becomes open) they think they have a job to do (when they encounter the neuronal tissue they believe they should attack??)

 

Sorry to pick your brain so much - I'm just having a hard time understanding why the immune system seems to make those same anti-neuronal antibodies even in the absence of strep - if untreated strep is what originally caused the creation of those anti-neuronal antibodies in the first place. Anyhow - perhaps that is the million dollar question that no one really has the answer to yet!!!

 

Thanks again Buster.

 

PKM

Edited by PKM
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You said that #3 was probably the most likely - that there is inflammation (from whatever virus/infection) and that causes the BBB to open. I get that part but how do those bad anti-neuronal antibodies get triggered again to even cross the BBB if strep is not there to trigger them - just some other random immune system challenge. Is it because these anti-neuronal antibodies can now just be made again and again in the absence of strep because the immune system has a memory of them?? Like for as long as the BBB is open (or when it becomes open) they think they have a job to do (when they encounter the neuronal tissue they believe they should attack??)

 

That's my theory -- the antibodies think they are connecting with a true antigen when actually they're just finding host cells.

 

Essentially, I think the BBB is the real culprit here and the critical item is getting the BBB closed. After that you can address the antigens or the antibodies.

 

But that's just a theory -- rather than fact from some study.

 

Regards, Buster

Edited by Buster
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