Wednesday, December 17, 2008

Proposed mechanism of Lyme IgM response

The initial immune response to pathogens occurs through innate responses. Macrophages express pattern recognition receptors which distinguish pathogens from host tissue. They recognize microbial components called pathogen-associated molecular patterns. The innate immune system is more specific than previously thought. It shares certain features with the acquired immune response. These include: cytokines, chemokines, complement activation, phagocytic cells- macrophages and neutrophils, natural killer T cells and natural autoantibodies.

Ordinarily the initial innate response transitions into the acquired immune response which involves captured antigen presentation to lymphocytes leading to antibody production. The initial response releases IgM antibodies. A molecular switching causes the production of blocking IgG antibodies. For this process to occur continued immune stimulation via continued antigen presentation is required.

The Lyme bacteria are quickly put on notice shortly after infection due to the vigorous innate immune response. They quickly gear up to avoid immune destruction. Once they become intracellular or cystic, available antigens for presentation to lymphocytes become increasingly scarce. One can imagine that antibody producing antigens are present only long enough for the acquired immune response to initiate IgM production. At the time that IgG switching should occur, antigen loads may be so low that follow through IgG switching does not occur, or occurs very poorly.

If the germs lacked the ability to morph into antigenically invisible forms, as is the case with extracellular germs, then the full complement of IgG antibodies would be produced.

From time to time the spriochetes reappear from the hidden niches. The same process is repeated. There is an IgM response. The spirochetes in this adverse environment go back into hiding and the antibody producing machinery is shut down once again.

Hence, Lyme always looks like a "new infection" because of these atypical IgM only responses. These ideas may be useful as novel strategies for vaccine development are considered.

14 comments:

bumblebee said...

Would this explain why in a person that has had lyme for a number of years,(most likely 12, diagnosed 2 years ago) has only one marker on their Western Blot for IGG, but has four markers on their IGM? Also, patient has very low immunoglobulin G, plus on weekly labs lymphocytes are always high, neutrophils low and monocytes bounce around from 0 to 10.

gale said...

I know it does not belong here.
Info on Lymenet seems to indicate that "mystery bug" has been named.(FRY??)
Rumors? The poster also mentions Telithromycine.
Hate that kind of info.

jenbooks13 said...

Don't forget the vls cassette mechanism. It presents a new antigenic surface whenever it wants.

More cases, please! Me no like Lyme for Dummies ;).

bugged said...

But this is not always the case is it? Do you think that anyone who has had Lyme disease will always carry IgM antibodies? I have cycled through IgG antibodies a few times but alway carry the IgM. Why is that?

Seibertneurolyme said...

LymeMD,

I am having a real hard time understanding hubby's immune sytem responses to these pathogens.

As I mentioned before he is basically sero-negative. Been tested to the moon and back for other illnesses. Normal IgG subclasses. Also normal CRP, sed rate and ANA. C4a extremely elevated. C57 low.

But this is the real kicker. Clongen has found the "mystery bug" in his bloodstream. Symptoms are primarily neurological (Parkinsons like presentation) and gastrointestinal.

The other piece that doesn't fit is he has herx type reactions (increased tremors, myoclonus, seizure-like episodes and nausea or vomiting) to almost every single dose of every antibiotic he has tried. With the exception of Levaquin and Clindamycin which just seemed to make him feel better.

I always assumed these were cytokine type responses but am wondering if it could actually be a response to endotoxins from the die-off of this as yet unidentified gram-negative pathogen? Any comments?

Lyme report: Montgomery County, MD said...

We can pose theories. The bottom line is clinical response. If Cleocin and Levaquin work stick with them. The other bacteria is not dying. It is resistant to almost everything. He may have a lot of inflammation in his central nervous system. High C4a levels indicate activation of the complement cascade. This is a major effector mechanism of both the innate and acquired immune systems. Antibiotics are probably causing autoimmune responses due to excessive immune stimulation. The low CD57 count might correlate with innate immune responses which activate NKT cells which are being consumed. This is just a guess.The germ load may need to be gradually lowered. At some future point he may be able to tolerate more active anti-microbial therapy.

Seibertneurolyme said...

Thankis for the comments.

Actually hubby has been ill for 7 1/2 years and in treatment for 5 years. Has toughed out many meds -- has been on a total of 25 different antibiotics and antiparasitics during the course of treatment.

Not currently on either Levaquin or clindamycin and was never on those 2 together. But those are the 2 he had the best clinical response to.

SPECT scan from June 2007 showed typical hypoperfusion of entire brain. Currently on hydrocortisone and Benicar to control brain swelling so, yes there is lots of CNS inflammation.

lymie said...

It is my understanding that there are more latent pathogens in a human than frank disease. And that latent germs may or may not ever become fulminant. So are we looking at tolerance? A lot of people without symptoms are apparently testing positive for lyme disease.

Maybe these mystery critters that are being found in the blood are tolerated, but can at some time cause symptoms. Just trying to figure out why all of these things are being found. Of course, we don't know what would be found in people who are well, no one is looking. And those with the mystery critters ARE sick. So we can't say they are not pathogenic.

Switching subjects, how about patients who have never had a positive IgM response, and varying IgG responses....fewer bands as time goes by. Does this represent failing immune system, giving up on trying to respond to ever changing genetics of borrelia?

How would antibiotics cause excessive immune stimulation? Thru killing of borrelia?

Lyme report: Montgomery County, MD said...

Benicar for brain swelling???

SPECT scans show decreased glucose utilization in areas of the brain. This does not mean there is hypoperfusion. These areas of the brain are not metabolically active. These areas of the brain can improve over time.

Use what works best.

Lyme report: Montgomery County, MD said...

Lyme infection creates a huge cytokine response, proteins with names like interleukin one and others. This causes the inflammatory response which can be damaging. If the germs in a relatively quiescent phase cytokine stimulation is minimal. When the bacteria are killed the released antigenic proteins cause this reaction to occur. This suggests that concomitant immune
modulators may be used with antibiotics in sensitive cases
where Herx reactions do more harm than good.

Antibody responses are variable and are of no help in treatment or predicting the course of the illness.

Seibertneurolyme said...

Benicar is a strong vasodilator so in theory should improve blood flow to the brain if brain swelling/inflammation is constricting blood vessels.

5 mg 3 times daily stopped headaches and myoclonus and dystonia but now hubby has side effects such as dizziness from low blood pressure.

I could be wrong, but I felt like maybe the Levaquin and Clindamycin were maybe bacteriostatic and not bacteriocidal for the "mystery bug". Both meds lost effectiveness over time as if something was developing drug resistance. At least it appeared that way to us.

Anthony Murawski said...

I believe epitope switching is an additional explanation. for the continuing IgM response. See, e.g.,
Liang, F. et al., "An Immune Evasion Mechanism for Spirochetal Persistence
in Lyme Borreliosis." J. Exp. Med. Volume 195, Number 4, February 18, 2002 415–422
http://www.jem.org/cgi/content/full/195/4/415

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