A bit about the immune system

[Buster]

A brief summary of the immune system

 

Now that we're in a much better space with our dd, I thought I'd post a bit about what I learned regarding the immune system over the past year. Please help me make this accurate with your comments. If any of you know immunology grad students (or are one yourself) please send updates (either through post or IM).

 

Hope this helps...

 

A bit about GABHS

GABHS is a bacteria with two cell walls that is encapsulated in a capsule (hyaluronic acid). The capsule is sort of like a stealth enclosure that makes the bacteria difficult for the body to recognize. The bacteria produces a number of toxic substances such as streptolysins, NADase, Hyaluronidase, Streptokinases, Steptodornases, and Streptolysin Pyrogenic exotoxins. When doctors refer to Anti-DNAse B or Anti-Streptolycin, they are refering to antibodies that are created by the body in response to these toxins produced by GABHS. Technically the antibodies are to the toxins and not to the GABHS itself.

 

A bit about Macrophages

Macrophages are detectors in the blood stream that find bacteria. There are a series of "sensors" on the cell wall of the macrophage. Probably the most interesting are TLR2 and TLR4 (TLR stands for toll-like receptors). TLR2 and TLR4 "recognize" gram-negative bacteria. When these receptors fire, the Macrophage essentially engulfs the bacteria and then "digest" the bacteria figuring out what were the big features of the bacteria. The macrophages then publish the "big features" on the cell wall of the macrophages and discard the debris of the bacteria. This publishing of the big features is known as antigen presentation.

 

A bit about T-cells/T-helper cells

So the macrophage randomly wanders around and eventually bumps into either a T-cell (sometimes called Th0 cell) or a B-cell (known as the memory cells). The Th0 cells looks at the presenting "big feature" and based on a bunch of biasing factors creates either Th1 cells (which go after intracellular stuff) or some Th2 cells (which go after extracellular stuff). The Th1 cells typically turns into more macrophages to go ingest more of the bacteria but can also turn into Killer T cells (that kill off infected cells). There's some other things here, but that's sort of right. Some of the Th2 cells get converted into B-memory cells which produce monoclonal antibodies.

 

A bit about B-cells

The B-cells are part of the humoral immune system. If a macrophage runs into a B-cell, the B-cell is able to quickly produce a bunch of monoclonal antibodies that will bond with the antigen injested by the macrophage. These monoclonal antibodies act like "flags" that essentally make it easy for a Macrophage to know which cell to ingest. Essentially a monoclonal antibody bonded to a cell is like a red flag saying "ingest me." Monoclonal antibodies can bond to either the bacteria itself or to the exterior of cells infected by "invaders" indicating that either the bacteria or the surrounding cell should be killed.

 

A bit about T-regulatory cells

While the B-cells produce the monoclonal antibodies and the macrophages/dentritic cells find the bacteria and inject them, the T-cells control whether the feedback loop of activating more macrophages gets going. A certain number of T-cells are what is called T-regulatory cells and these cells watch for antigens and macrophages that present "big features" that are the same as a feature of the host. If the "big feature" is the same as the "host's feature" then the T-reg is supposed to suppress production of Th2 cells and slow/stop the feedback loop. It's sort of "yeah, you found one, but that's one of ours, ignore it and get back out there" type of thing.

 

So what does all this have to do with PANDAS

Well, in PANDAS it is thought that the antigen (bacteria) bumps into a MacroPhage and gets ingested and the GlcNAc carbohydrate is presented on the exterior of the Macrophage. The Macrophage then runs into a B-cell and the B-cell creates a bunch of anti-bodies for this GlcNAC which go around marking GABHS with the antibody. More Macrophages find these "marked" bacteria and put up a flag saying "there's more GlcNAc around" (this is the antigen presentation). The Macrophages run into a bunch of T-cells and they start creating more Macrophages (and more B-cells to make more antibodies) and the feedback system starts really getting going. The more GlcNAC found, the more the feedback system continues until eventually all the bacteria is ingested and the cycle slows down.

 

What does antibiotics have to do with this?

Well, remember that while the T-cells are replicating and the B-cells are producing antibodies, the bacteria itself is replicating. So it is sort of a race to who can replicate faster (the ingestors/killer cells or the bacteria). Antibiotics slow down the speed with which the bacteria can replicate. Macrolides (like azithromycin) prevent the production of an enzyme needed for replication. Penicillin derivatives weaken the cell wall of the bacteria causing many of the bacteria to self destruct. The effect, however, is basically the same, the antibiotics slow the replication of the bacteria so that the B-cells can produce enough antibodies and the T-cells can produce enough macrophages (and killer cells) to take out the marked bacteria.

 

What about intracellular strep?

Intracellular strep acts very similar to the ingestion by a Macrophage of a bacteria. Cells have a number of flags they can put on their exterior if they've been infected by a virus or a bacteria. Sometimes the Macrophage can find these cells, but often one has to wait until the cell bursts and then the macrophage has to catch the bacteria before it invades another cell.

 

One theory is that it is this intracellular strep with intermitent bursts that cause the antibodies to stay high because the antigen never truly disappears.

 

I hope the above is somewhat helpful as an explanation...

 

Regards,

 

Buster

[Alex]

Thanks Buster,

 

Interesting stuff, what I understood of it. In an autoimmune disease such as PANDAS, does the immune system response continue unabated even after the infecting bacteria is wiped out becasue the body's own cells are mistaken as the invader?

[KeithandElizabeth]

Yes, thank you Buster! I will need to read your post a few more times to process all of the information.

 

In response to your post as well as Alex's, I keep thinking about the kids who do so well on the 2000 mg. of Augmentin. Do they have a lingering, intracellular strep infection that has not been eradicated?

 

My other question is why do you feel that our particular children get PANDAS? I mean, do you think they have a weakened immune system? Of course that is what our immunologist says, but he is an immunologist! It is interesting that so many of these children have parents with immune issues. Even if you have a genetic tendency towards an illness/disease, wouldn't a strong immune system keep that tendency in check?

 

And then thinking of antibiotics, if we really strengthen our children's immune systems, do you think they will need antibiotics past the 1 year post IVIG mark?

 

Elizabeth

[Buster]

In an autoimmune disease such as PANDAS, does the immune system response continue unabated even after the infecting bacteria is wiped out becasue the body's own cells are mistaken as the invader?

 

The short answer is likely yes, but it's hard to tell. Part of it depends on what the monoclonal antibodies attach to. In acute rhuematic fever, the antibodies seem to bind to M3 and M18 serotypes of GABHS and the antigen presented is similar to heart muscle. Thus antibodies keep indicating an antigen when it is just normal cells around.

 

In Sydenham Chorea, Kirvan discovered that brain tubulin was a target for antibody 24.3.1. It appears this also applies to PANDAS (although I don't think they have published that yet). So, if the blood brain barrier opens and the blood can interact with tubulin, then I could imagine that the macrophages would report they found such cells and the feedback loop would continue even though no GABHS was found.

 

One inconsistency is that as far as they can find, there doesn't appear to be permanent damage from the bonding to tubulin. This would imply that either the macrophages are not ingesting the tubulin or that the ingestion of tubulin doesn't matter. I don't know enough here to even guess. It does seem, however, that as long as the BBB remains open, there's a strong likelihood of a feedback loop without requiring GABHS antigen.

 

Regards,

 

Buster

[Buster]

I keep thinking about the kids who do so well on the 2000 mg. of Augmentin. Do they have a lingering, intracellular strep infection that has not been eradicated?

 

I think this is a great theory and definitely worth pursuing. The high dose of Augmentin would dramatically reduce the ability of the strep that might burst from a cell to replicate and in addition the bacteriacidal nature of Augmentin could actually weaken and destroy those cells at that high concentration.

 

It seems perfectly reasonable to me that our kids already have weakened immune reactions to GABHS and as such don't mount the necessary response to destroy the strep -- either by producing the wrong antibodies or by not producing enough of the right ones. The recommended dosage is for "standard kids who have standard responses" and not for immune compromised kids.

 

So at the high dosage we're either holding the strep in check or actually killing it.

 

My other question is why do you feel that our particular children get PANDAS?

 

I think Swedo has it right that you have a genetic pre-disposition, then the right strain of strep, then the right circumstances that open the BBB. I'd love to know if there are kids with the high rates of the 24.3.1 antibody that don't exhibit symptoms. I keep thinking of the recent mouse model and wonder if the IgG was transferred into normal mice would the symptoms emerge or is it only when the IgG is transferred into similarly immuno-compromised mice.

 

If we really strengthen our children's immune systems, do you think they will need antibiotics past the 1 year post IVIG mark?

 

My belief is that we aren't really strengthening the immune system with anything we're doing so far (PEX, IVIG, ...). These are really temporary measures and unless they magically reset the T-regulatory cells we're in this for the long haul (just my opinion). This is why I think we'll have to stay on antibiotics for a long time until some other event resets the immune system (like puberty).

 

regards,

 

Buster

[peglem]

So, in light of this...how can a person be a strep carrier? If the strep is in the body and presenting antigens....why would there be no immune response? Could that be the T-regs giving an "ignore" order because the antigens resemble self. I'm probably showing how little I understand- thanks for your patience!

 

So, IgG is antibodies manufactured by B cells?

 

I hope you don't mind if I keep asking more questions as I think of them...part of how I process information.

[Buster]

So, in light of this...how can a person be a strep carrier? If the strep is in the body and presenting antigens....why would there be no immune response?

 

A carrier is thought to be one who has colonization but no invasion or infection. This means that the strep is on the surface of the mucosal lining or on the skin, but does not get into the blood stream. It isn't perfectly understood why in some folks the strep doesn't seem to get into the blood stream. Some theorize that there is some other bacteria interfering with the colonized GABHS that prevents it from continuing to spread, some believe that the strep doesn't break down the fibrin and hence can't invade without some breach (like a dental procedure). Bottom line, some folks seem to keep a long-standing colony of strep without having any significant invasion or immune response.

 

By the way, this is also why it's hard to clear a strep carrier -- there's essentially not enough blood flow for the antibiotic or immune system to get to the GABHS on the surface of the skin. The skin acts as a great barrier -- this is a good thing.

 

Could that be the T-regs giving an "ignore" order because the antigens resemble self.

 

Highly unlikely. It is more likely that the strep just can't penetrate the skin or mucosal lining without help.

 

So, IgG is antibodies manufactured by B cells?

Yes.

[kim]

TLR2 and TLR4 "recognize" gram-negative bacteria.

 

 

Just wanted to point out that TLR2 is involved in host response to gram positive bacteria too. Also, I thought that the antibodies that were created in the mouse model were transfered to normal mice when the abnormal response occured, thus ruling out a problem with host tissue. Did I get that wrong? I have the feeling, in our case, there is a slight problem with host glycan chains. I thought the mouse model kind of separated us from what might be happening in others case, because the antibody was problematic in normal mice (although maybe an abnormal host carbohydrate chain, could result in the abnormal antibodies in the first place?). I'm going to go back and see if I can come up with where I got that impression from.

 

 

Toll like 2 is a protein encoded by the TLR2 gene

 

http://www.ncbi.nlm.nih.gov/sites/entrez?D...rmToSearch=7097

 

TLR2 toll-like receptor 2

 

This gene is expressed most abundantly in peripheral blood leukocytes, and mediates host response to Gram-positive bacteria and yeast via stimulation of NF-kappaB

[peglem]

Are all the immunoglobulins made by B cells? - IgA, IgM, IgE?

 

What is the significance of the IgG subclasses? Does each have a different job? Do they work as a team, so that one player not doing its part lowers the efficiency of the whole team? Or is it a matter of each being made in response to different kinds of antigens? Is IgG subclass deficiency caused by the failure of production or just that the body is not fighting anything that presents with the antigens that would provoke that particular subclass?

[Buster]

Are all the immunoglobulins made by B cells? - IgA, IgM, IgE?

As far as I know yes.

• Immunoglobulin A (IgA) is found in mucous membranes, particularly those lining the respiratory passages and gastrointestinal tract, as well as in saliva and tears.
  
• Immunoglobulin G (IgG) is found in all body fluids and protects against bacterial and viral infections.
  
• Immunoglobulin M (IgM), which is found mainly in the blood and lymph fluid, is the first to be made by the body to fight a new infection.
  
• Immunoglobulin E (IgE), which is associated mainly with allergic reactions is found in the lungs, skin, and mucous membranes.
  
• Immunoglobulin D (IgD), which exists in minute amounts in the blood, is the least understood antibody.
  

What is the significance of the IgG subclasses? Does each have a different job? Do they work as a team, so that one player not doing its part lowers the efficiency of the whole team? Or is it a matter of each being made in response to different kinds of antigens? Is IgG subclass deficiency caused by the failure of production or just that the body is not fighting anything that presents with the antigens that would provoke that particular subclass?

Yikes, let me try a simple response and see if this helps:

Patients with IgG1 or IgG3 deficiencies are more likely to have chronic and recurrent infections of the lower airways. Patients with IgG2 or IgG4 deficiency are more likely to have sinusitis and otitis.

 

A good reference on this stuff is http://www.primaryimmune.org/publications/...s/book_pats.htm

[peglem]

So, if you had, say an IgA deficiency, could that contribute to a carrier state, since the mucosal attack would would be nearly absent?

 

Here's the thing- my daughter is IgA deficient (but not complete absence) and IgG4 deficient, but whenever I look up the significance...it seems like there isn't much known...IgA deficiency seems to be associated with autoimmune disorders....IgG4 is the most common deficiency. These are not low as "in lower range for normal- both are below normal range-

 

We will be seeing both a rheumatologist and an immunologist w/in the next couple of weeks, so I'd like to know what I'm (and they) are talking about. In the past, these specialists have declared my daughter a carrier and acted like I'm in denial about her autism. We have these immune system deficiencies, now + the Cunningham results, so more info for them to go on, and her PCP firmly believes she has PANDAS and now knows what it is. I just want to make sure she gets treatment.

[Buster]

So, if you had, say an IgA deficiency, could that contribute to a carrier state, since the mucosal attack would would be nearly absent?

 

That makes sense to me, but I don't think anyone knows. In the words of Ed Kaplan "despite over 4 decades of intense research, the carrier state remains an enigma." Something keeps the colony in check and seems to disable the M protein (i.e., a penetration factor). They do know that skin strep doesn't cause elevated ASO -- so something in the skin seems to neutralize streptolysin-O . So perhaps the carrier state is really the body has sufficient immune response to stop colony spread/replication, but not enough to clear. Seems like a great experiment to see if carriers have low IgA. I haven't seen any study on that -- but who knows what's out there.

 

Buster

[peglem]

Here's a study indicating that IgA deficiency in mice contibutes to a carrier state of streptococcus pneumonia.

http://www.jimmunol.org/cgi/reprint/173/7/4576

[Kayanne]

When I first read about IGA deficiencies, I had an AH HA moment (not that my AH HA moments have much significance because I have ZERO knowledge of biology/medicine)

 

If 20% of the population are walking around with an undiagnosed IGA deficiency, then could that account for the 10% of people who don't kick strep with a 10 day courses of antibiotics (as per a conversation with Diana)?

 

IGA is the antibody that is found primarily in the mucosal linings, right?

 

I brought this up to a rheumatologist, and he said no...IGA deficiencies in themselves tell us nothing because so many people are walking around with one, don't know it, and are perfectly healthy....apparently the dr who discovered IGA himself had a deficiency, was healthy, and thought that it was insignificant.

 

Am I crazy, or is this a really poor way to come to a conclusion? I don't know...IGA deficiency may have been thoroughly researched already, but I have a feeling the rhumy would have mentioned the research to us if it has....he had no problem trying to tell us about Singer and Kaplan's research.

 

And again I keep going back to drs unwillingness to be aggressive with antibiotics...if the general population was more routinely screened for immune deficiencies, then wouldn't it make sense that the drs would have a better understanding of who might need a longer course of antibiotics...thus decreasing the risk of bacteria resistance...if you fully wipe out the bacteria...it cannot evolve.

 

Maybe I am thinking too simplistically and missing a lot of details because I don't have any formal knowledge of biology, but the whole idea of over-prescribing antibiotics doesn't hold water with me anymore.

 

If a person only has a viral issue, and they are prescribed an antibiotic, how does that contribute to antibiotic resistance? There were no bacteria to mutate to begin with...right?

 

And who knows, maybe an unknown bacteria may work in harmony or become a host to a virus (pulling theories out of my #@@ now!) that is contributing to the rise in all kinds of issues...could a simple antibiotic taken with a common cold prevent them? Probably not...but my brain wandered down that path, and I had to get it out.

 

If a person does have a provable bacterial infection, is a doctor going to say, "No, I cannot prescribe you antibiotics because I think you will be non-compliant and not finish all of the medication." NO! He is going to prescribe the antibiotic...so non-compliance is always going to be a concern with antibiotics.

 

But if drs continue to ASSUME that everyone gets better after a 10 day course (some cases 5 days), then I do think we are setting ourselves up for more resistant strains of bacteria.---and sadly more cases of PANDAS, RF, and such....these are some of the the diseases that we KNOW are post-infectious and preventable...how many more are yet to be realized...

 

If we could just get PANDAS universally recoginized, I think it will open up the floodgates of research into all kinds of autoimmunity and mental heath issues.

[peglem]

Here's what I think pertaining to my daughter:

The IgA deficiency allows her mucousal passages to become colonized- w/o an immune response. According to doctors, this bacteria does not infect her, and its just harmless. That may be true, but biting your tongue, picking your nose, dental procedures...provide a way for this bacteria to get into the body at large. I think she is continually reinfecting herself.

What they do seem to know is that people w/IgA deficiency are at greater risk for autoimmune disorders.

She also has a IgG4 deficiency.