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IgG and kids who are rarely sick


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What is the relationship btn IgG, IgA and immunity response?

 

If a PANDAS child appears to have hyperimmunity, high titers, asymptomatic of strep, rarely sick except occ. viruses/colds.... is it strange that their IgG and IgA would be on the low side? Not deficient low, but lowest end of the range. Why wouldn't it be high? Or do low IgG and IgA just signify dysfunction? Or is it low bcs the faucet never shuts off?? I'm sure my questions reveal my degree of ignorance ^_^

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Hi Jag10,

 

I think this question comes up a lot and I've been debating whether to add it to the FAQ. A number of kids (10% or so) with PANDAS symptoms do seem to have low IgG -- but this could be just a sampling issue - i.e., we're looking for stuff so we're just finding the normal distribution of PID and SID in kids. It's not at all clear whether there is anything causal here. Let me try to explain:

 

PANDAS appears to be the result of three things:

  1. a genetic predisposition to an unusual immune response
  2. an activation of T-cells that binds with a memory B-cell to create anti-neuronal antibodies
  3. a breach of the blood-brain barrier that allows the antibody to reach the basal ganglia

These three items are also seen in Sydenham Chorea. The genetic predisposition (1) is pretty clear. About 1% of children exposed to rheumatic strains of GABHS get Sydenham Chorea. This rate seems to be true regardless of ethnicity or geography -- i.e., it's a genetic trait.

 

Kirvan and Cunningham did a good job at isolating the antineuronal antibodies (2) and showing they are elevated in both SC and PANDAS kids.

 

The exotoxins of strep are pretty good at explaining the inflammation that might breach the BBB (3) -- however, there's not a great explanation for why SC happens 6 weeks after the clearance of the GABHS infection -- perhaps this is really the time it takes to create a memory B cell.

 

So what does all this have to do with IgG.... well, IgG levels are more measurement of current antibody levels and the anti-neuronal antibodies are just a drop in the bucket of all the antibodies in the IgG.

 

What seems significant about IgG is that people who have low IgG or low PREVNAR levels have a higher probability that the GABHS infection will last longer and that the GABHS exotoxins will activate the B-cells associated with SC, ARF or PANDAS. This is why doctors treat GABHS with antibiotics, to shorten the time the infection is in the body.

 

So you might be wondering why longer duration of GABHS increases risk of activation... well ...

 

GABHS has really powerful exotoxins that are known as super-antigens. A super-antigen can activate T-cells and B-cells that have nothing to do with the current infection. In particular the B-cells that produce the anti-neuronal antibodies could be activated by one of these super-antigens. There are about 25 of the super-antigens known so far.

 

If you have a predispoisition to creating anti-neuronal antibodies (1) and you have low IgG and aren't able to clear GABHS infection, then the GABHS exotoxins could be triggering the B-cell to create the anti-neuronal antibody (2), the inflammatory cytokines then open the BBB (3).

 

About here, someone is likely to be asking about non-GABHS infections (i.e., PITAND) -- well, yes indeed, another infection could have super-antigens (i.e., activate T-cells that have nothing to do with the infection) and could easily be causing enough inflammation to allow the existing antibodies to cross the BBB (3).

 

Now flipping the whole thing around --- For children who have normal IgG or even hyper-active IgG/IgE -- they seem to be mostly affected by the inflammation. I've been trying to find if anyone has been running cytokine panels and no luck yet. Seems peopel check SED rate, and C-reactive protein, but what we'd really like to know would be IL-1 Beta and other such immuno complexes. Anyway, the high dose IVIG being highly anti-inflammator could just be closing the BBB and thereby breaking the auto-immune cycle allowing the anti-neuronal antibodies in the blood to dissipate -- i.e., high-dose IVIG closes the BBB (#3) and breaks the cycle.

 

That's what I think is going on.

 

Let me know if I should try to write up more here.... I'm wasn't sure if you wanted to know more about asymptomatic strep or were really curious about IgG levels.

 

Buster

 

 

What is the relationship btn IgG, IgA and immunity response?

 

If a PANDAS child appears to have hyperimmunity, high titers, asymptomatic of strep, rarely sick except occ. viruses/colds.... is it strange that their IgG and IgA would be on the low side? Not deficient low, but lowest end of the range. Why wouldn't it be high? Or do low IgG and IgA just signify dysfunction? Or is it low bcs the faucet never shuts off?? I'm sure my questions reveal my degree of ignorance ^_^

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Thanks, Buster!

 

Tell me right track or wrong...

 

ASO and Anti-DNase B measure antibodies to strep and multiple measurements tell us whether the infection coming or going.

 

But it's (different) anti-neuronal antibodies that are sneaking through the BBB causing the chaos.

 

IgG is also an antibody measurement of a more generic sort, anti-neuronal just being one of many.

 

Here's where I'll try and get creative and mess the whole thing up.....

 

If a PANDAS child has low/lower IgG levels, does that mean that of the antibodies they are making, anti-neuronal antibodies are a higher concentration of them; like a cup in the bucket instead of just a drop???

 

What impact do you think PANDAS has on the child's IgG levels over time?

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Buster and JAG,

 

I just wanted to add some of my immune research I have done in regards to immune deficiency, ocd, tics and autoantibodies. I have consulted with 6 separate immunologists whom all agree that immune deficiencies and autoimmune disease are closely related. My dd has an immune def, not terribly low igg but low enough 480 level to justify treatment. She also has autoantibodies of dopamine one from cunningham. I had my dd submitted for a b cell study, where the study looks at the maturation process of b cells, starting at nymph b cells up to mature b cells. My dd's b cells came back in the mature stage as overactive signifying they are attacking her body. This b cell behavior is seen in other autoimmune disease. (This is seen in lupus and other au disease, but my dd only has pandas or SC) I think the issue here is that if you have a child with an immune deficiency (any, low igg, low iga, low igm, any low subclass, non existant pnuem titers) this predisposes them to have an autoimmune disorder. The theory is that the immune system cannot fight an infection and then overproduces antibodies to try to compensate for its immune deficiency. Anyway, many panda parents and families have a history of autoimmune disease. Can a one time infection trigger a hyper state and cause overproduction of antibodies? I doubt it, I believe these kids are predisposed genetically with either an immature immune system or deficient immune system. And once overstimulated (the moon and stars aligned ) they could start producing autoantibodies. With a broken immune system or one that is not mature enough yet, the signals could get crossed and over production of antibodies happens. We see it with all autoimmune diseases that flair with viruses. Once the autoimmune process is triggered its hard to calm it down.

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I'm just going to ask...what is meant by "hyperimmune"? Because it suggests to me that too many antibodies are being made...but that doesn't sound like what you guys are talking about. Can you be hyperimmune and immune deficient?

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This may end up being a really complex thread by the time we're done :)

 

ASO and Anti-DNase B measure antibodies to strep and multiple measurements tell us whether the infection coming or going.

Not quite -- being lawyer-ly specific, "ASO and Anti-DNAseB measure antibodies to two exotoxins of GABHS. Dual measurements taken 1-2 weeks apart by the same laboratory using the same technique will tell you if the antibodies are rising. Based on current science, only a rising titer is meaningful. The rate of fall or the meaning of a constant titer is not understood. Some individuals have chronically elevated titers with no other symptoms of GABHS. Some individuals have falling titers despite colonized GABHS. Thus a rising ASO and/or Anti-DNAseB can only confirm a prior strep infection and says nothing about whether there is a current infection.

 

But it's (different) anti-neuronal antibodies that are sneaking through the BBB causing the chaos.

Yes ASO and Anti-DNAse B are not anti-neuronal antibodies. Kirvan and Cunningham isolated 3 anti-neuronal antibodies and found one of the 24.3.1 to have significant binding potential with dopamine receptor 2.

 

IgG is also an antibody measurement of a more generic sort, anti-neuronal just being one of many.

Yes, but there's a danger in misreading this. IgG is a measurement of the amount of proteins associated with a class of antibodies (the most prevalent) and therefore is a rough estimate of the amount of active antibodies. It is not a measure of B-cells (plasma cells) or T-cells and does not measure the ability of the body to produce antibodies.

 

If a PANDAS child has low/lower IgG levels, does that mean that of the antibodies they are making, anti-neuronal antibodies are a higher concentration of them; like a cup in the bucket instead of just a drop???

Absolutely no way to tell without trying to test the concentration -- to an extent that is what Kirvan and Cunningham were doing by testing the concentration of antibodies that bind with certain receptors -- this is known as dilution. They are trying to measure the concentration of a particular type of antibody either in the CSF fluid or in the blood serum.

 

What impact do you think PANDAS has on the child's IgG levels over time?

No idea. My first reaction is nothing.

 

Buster

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I think it is referring to Trifilleti's types of pandas, one was hyperimmune, one was immune deficient. He was breaking down the different presentations of symptoms of pandas.

 

By the way peglem, I liked the article you posted on ivig in the previous topic.

 

 

I'm just going to ask...what is meant by "hyperimmune"? Because it suggests to me that too many antibodies are being made...but that doesn't sound like what you guys are talking about. Can you be hyperimmune and immune deficient?
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I'd imagine folks are using "hyperimmune" to be like allergies where some people have very intense antibodies/histamine/inflammatory cytokines response to an antigen -- i.e., react more to one type of antigen.

 

I'd imagine that IgG deficient would be that you don't react to some other types of antigen (such as PREVNAR). There's an expected baseline of background antibodies that most people have and those who don't have these antibodies have a hard time clearing infections.

 

Bottom line, yes, I think you can have an extreme reaction to one type of antigen and a low response to other types of antigens.

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I think that we can refer to what is published here:

http://www.stopcallingitautism.com/labsand...information.php

as you can see there is hyperactivation that is found in high levels of CD3, CD4 and especially CD19 (a marker of autoimmune disease) and also we have low IgG and IgA (second review published on this link, below)

 

immunodeficiency (low IgG and IgA) and autoimmunity induced by an immune system "hyper" coexist both togheter

 

we are going to redo the Immune Panel, which we had already made nine years ago at the same time - coinciding with the first episode of PANDAS ( undiagnosed). the results showed a situation similar to that posted in the link

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Buster,

 

I think I'm getting confused at an elementary level.

 

CamKinase II- is this a measurement of the anti-neuronal antibodies or the resulting activation w/BG tissue...or receptor? So, in PANDAS, is it that there is a higher amount generated by the B-cells or there aren't any more produced, but there is something wrong with the protein that causes a higher activation?

 

Let me try again...

 

Is the problem an activation issue bcs there are too many anti-neuronal antibodies being generated or the ones produced by those w/PANDAS aren't more numerous, there's just something wrong with their mediating protein that results in overactivation and swelling???

 

I think I'm having my own swelling...maybe I should give it up....

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CamKinase II- is this a measurement of the anti-neuronal antibodies or the resulting activation w/BG tissue...or receptor?

 

Simple question, I wish I had a simple answer:

 

Cunningham is measuring the ability of antibodies in serum (or CSF) to cause CaM Kinase II activation in neuroblastoma cells. It isn't the amount of CaM Kinase II (which is a protein), but rather the ability of the antibodies to cause state changes in CaM Kinase II that leads to state changes in neuroblastoma cells. The first measurement is about the state change in the CaM Kinase II protein.

 

CaM Kinase II activation affects the presynaptic transmitter release, phosphorylation of tryptophan hydroxylase (think catalyst of serotonin) and tyrosine hydroxylase (think catalyst for precursors of dopamine).

 

In addition, Cunningham was measuring whether antibodies inhibited binding of other chemicals to tubulin, dopamine receptors, or lysoganglioside receptors. This is known interference. It is an independent measurement from CaM Kinase II -- although there may be a correlation between the two. The measurement they are doing checks whether the antibodies bind to the receptors first inhibiting the binding of other chemicals (such as dopamine) to bind to the receptors.

 

http://books.google.com/books?id=az8uSDkB0...nin&f=false

 

So, in PANDAS, is it that there is a higher amount generated by the B-cells or there aren't any more produced, but there is something wrong with the protein that causes a higher activation?

Another hard question. What is thought to happen is that children with PANDAS (and SC) generate several unusual antibodies. Kirvan was able to isolate at least three of these antibodies in her studies. These antibodies do not seem to be present in non-PANDAS children -- but it is difficult to run experiments looking for just the single antibody -- so they looked for the effect of the antibody that could be measured. One effect effect they found was CaM Kinase II activation.

 

Only further experiments will demonstrate whether the increased CaM Kinase II activation is exclusively due to the antibodies, whether these antibodies are unique to the genetics of SC and PANDAS kids or whether they are byproducts of something else that is going on.

 

Is the problem an activation issue bcs there are too many anti-neuronal antibodies being generated or the ones produced by those w/PANDAS aren't more numerous, there's just something wrong with their mediating protein that results in overactivation and swelling???

There are some studies indicating localized swelling and this could come from macrophages or T-cells on the brain side of the BBB finding bound antibodies and releasing inflammatory cytokines. Some researchers think the basal ganglia is like a ball of rubberbands where the inflammation causes cross-talk as the rubber-bands slip and this is what's causing confusion and mis-signalling.

 

Cunningham's work is pursuing a slightly different perspective that perhaps it isn't swelling but rather the antibodies actually cause interference by binding to some of the dopamine receptors causing mis-signalling because the real signal can't get through.

 

Hope that helps... Only further research will tell who is right.

Edited by Buster
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CaM Kinase II activation affects the presynaptic transmitter release, phosphorylation of tryptophan hydroxylase (think precursor to dopamine) and the enzyme for serotonin synthesis.
Hey, hey now Mr. Buster :blink: , you made me go back and rethink tyrosine hydroxylase (i was looking at skin stuff and you pointed out the connection with CamK and dopamine) now your messing with me throwing tryptophan in here too. So it looks like CaM k activates tyrosine hydrox/ andtryptophan hydrox, correct?

 

Now this speaks of post synaptic density and the hippocampus/forebrain, but still :wacko:

 

http://www.bioreagents.com/products/produc...?catnbr=MA1-048

 

CaM kinase II, in a calcium and calmodulin dependent manner, phosphorylates many different brain substrates including synapsin I, tryptophan hydroxylase, tyrosine hydroxylase and nitric oxide synthase thereby performing regulatory functions associated with increases in intracellular free calcium. CaM kinase II is particularly abundant in the hippocampus and forebrain where it comprises ~1% of total protein. Within the neuron, CaM kinase II is a major component of the postsynaptic density fraction accounting for as much as 30% of total protein in the post synaptic density (PSD) region.
Edited by kim
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phosphorylation of tryptophan hydroxylase?

 

I understood the ball of rubberbands....

 

So is the PANDAS for Dummies version....researchers are leaning toward disordered production rather than hypo or hyper dysfunction or perhaps both with one leading to the other?

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Arggh, yes, I cut and paste and meant to write

 

tyrosine hydroxylase -- catalyst for epinephrine/dopamine

and tryptophan hydroxylase -- synthesis of serotonin

 

Sorry about that. I'll go back and edit my post

 

Buster

CaM Kinase II activation affects the presynaptic transmitter release, phosphorylation of tryptophan hydroxylase (think precursor to dopamine) and the enzyme for serotonin synthesis.
Hey, hey now Mr. Buster :P , you made me go back and rethink tyrosine hydroxylase (i was looking at skin stuff and you pointed out the connection with CamK and dopamine) now your messing with me throwing tryptophan in here too. So it looks like CaM k activates tyrosine hydrox/ andtryptophan hydrox, correct?

 

Now this speaks of post synaptic density and the hippocampus/forebrain, but still :)

 

http://www.bioreagents.com/products/produc...?catnbr=MA1-048

 

CaM kinase II, in a calcium and calmodulin dependent manner, phosphorylates many different brain substrates including synapsin I, tryptophan hydroxylase, tyrosine hydroxylase and nitric oxide synthase thereby performing regulatory functions associated with increases in intracellular free calcium. CaM kinase II is particularly abundant in the hippocampus and forebrain where it comprises ~1% of total protein. Within the neuron, CaM kinase II is a major component of the postsynaptic density fraction accounting for as much as 30% of total protein in the post synaptic density (PSD) region.
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phosphorylation of tryptophan hydroxylase?

 

I understood the ball of rubberbands....

 

So is the PANDAS for Dummies version....researchers are leaning toward disordered production rather than hypo or hyper dysfunction or perhaps both with one leading to the other?

 

It certainly is true that inflammation is a heck of a lot easier to understand than interference with feedback loops. To me, disregulation of dopamine and serotonin makes a lot of sense but only if I phrase it that way rather than talking about phosphorylation :-)

 

Buster

Edited by Buster
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