Re: The common pathogenesis of CFIDS/FMS/LD/GWS...etc.

[Guest guest]

I see I can't save to the file so here's that info:

Pathogenesis of Borreliosis

This disease get's much easier to understand when we have a firm

grasp of it's pathogenesis.

As you know, knowledge of the pathogenesis helps us to understand

the development of symptoms...including psychological ones (remember

cause and effect here) and we recognize how it can cause strange

types of symptoms that seem unrelated.

It also helps us design appropriate therapies.

As you are aware, many bacteria cause disease via something they

produce such as endotoxins (lipopolysaccharides) ...etc.

These toxins usually cause disease by triggering an undesireable

response by the body...often the immune system.

An inflammatory response can cascade into numerous other problems.

An imbalance of inflammatory mediators are notorious for causing

disease and symptoms.

Thankfully, most of pathogenic bacteria can be controlled by the

immune system and with a little help from certain therapies, such as

short term antibiotics… the balance between disease and health can

be tilted in the favor of our health.

Regarding borreliosis, the culprit that appears to be at the center

of the pathogensis is the bacterial lipoproteins (BLPs) found within

the outer surface proteins of the cell membrane.

These BLPs have a key component, Pam3cys, that triggers an innate

immune response that cascades into the disease borreliosis.

These BLPs are fat-soluble toxins that are responsible for most if

not all of our symptoms.

So, it's the innate immune system, not the acquired immune system

that is strongly triggered by the presence of the borrelia BLPs.

This stimulation occurs through what is called Toll family

receptors, which the body uses to detect the prescence of bacterial

pathogens, not just borrelia.

BLPs are potent activators of Toll-like receptor-2 (TLR2). Thus,

through TLR2, BLPs induces the synthesis of the precursor of the pro-

inflammatory cytokine interleukin -1B (IL-1B).

BLPs also activates caspase 1 and potentiates apoptosis (programmed

cell death) via this route.

The lipid moiety of the BLPs contains a synthetic lipopeptide that

is responsible for triggering the TLR2, this lipopeptide is called:

tripalmitoyl-S-glyceryl-Cys-Ser-Lys4-OH (Pam3Cys).

Other important inflammatory mediators triggered by BLPs in immune

cells are tumor necrosis factor-alpha (TNF-á) and IL-6, IL-12, INF-ã.

Borrelia lack lipopolysaccharides (LPS) however, they have over 150

genes that encode for the BLPs that are the key to pathogenesis.

This is over 50 times greater than other pathogenic bacteria. That

is, other bacteria usually only have 3 genes for lipoproteins, while

borrelia have 150!

With this many BLPs triggering an imbalance of the immune system and

other innate responses in the body, it's not hard to see how a

cascade of problems can arise from this.

For example, when we look at psychological problems of

neuroborreliosis, it's clear that the cause of these symptoms arise

from BLPs triggering encephalitis and that this inflammation not

only causes imbalances in numerous neurotransmitters, it also causes

vasculitis which leads to hypoperfusion and hypoxia of the brain.

These toxins also cause a channelopathy, which lead to a dysfunction

of signals along neurons, muscles and cells making them easily

excitable, but not able to discharge correctly…since the electrical

potential across the cell membranes don't function normally.

This can attribute to numerous symptoms such as anxiety, parathesia,

hyperacusis, tremors and even susceptibility to static shock that

most of us have or have had.

Thus, the evidence is pretty clear that BLPs plays a large role in

the pathogenesis of borreliosis and is a key to understanding this

disease.

IMO, without BLPs, borrelia would not be virulent.

Q: What cells contain the TLR-2 receptors to which the BLP's attach?

A: Many cell types throughout the body carry the TLR receptors. It's

a basic innate immune response that even invertebrates have.

Q: I don't see anything so far that would describe why these

inflammatory mediators, which would be activating the T-cells, would

not be phagocytized by these and other macrophages.

A: Initially it does. The initial infection of borrelia can be acute

and flu-like or it may not even be noticable. Unfortunately, this

initial immune response doesn't completely rid the body of borrelia.

I don't think we have the complete answer to why this happens. But

there are probably several factors involved. Borrelia can adapt and

be very stealthy. Another reasonable theory is that apoptosis of

monocytes, macrophages, neutrophils and other immune cells triggered

by TLR-2 stimulation may account for immune dysfunction and

supression.

This makes a lot of sense to me since we see immune dysfunction &

suppression in chronic LD and in CFIDS, which I believe have a very

similar pathogenesis.

Q: Also, if it's somehow a more severe activation of these

mediators, especially if caspase and IL-12 are involved, why is

there not more obvious toxic shock-like symptoms apparent early on?

A: I wouldn't say that it's a more severe activation of these

mediators, but more of a long term chronic/relapsing imbalance them.

It may also have to do with borrelia's ability to grow slowly and

not trigger an acute toxic shock.

It also may have something to do with borrelia's ability to hold on

to it's BLPs and not release them into the surrounding tissue until

they are killed.

We know that when we kill borrelia (such as with abx tx) the BLPs

are released from them and we experience a herx reaction. In severe

cases this response can be quite acute.

There are probably several other factors such as lipid depot effect

and slow release.

The immune supressing effect of BLPs likely plays a role here too.

Q: It seems that many people are not even symptomatic until years

after the original tick exposure.

A: This is true with borreliosis...(this happened in my case). It's

also true with syphilis.

This may be due to borrelia's ability to code for so many different

BLPs. They have the genetic code for over 150 different BLPs.

Depending on which ones and how strong the expression of these BLPs

genes are may determine how virulent the borrelia is at different

times.

We know that borrelia change the expression of these genes when

exposed to different environmental factors such as temperature.

They express different BLPs in ticks since they are in ambient

temperature, but once inside a mammal, they begin to change the BLPs

that they express.

They also have an effective ability to accept plasmids and pick up

other pathogenic genes in this way.

Work has shown that removing certain BLPs from virulent strains

makes the borrelia avirulent.

The evidence is very suggestive that BLPs determines the

pathogenesis of borrelia.

This work has appeared very timely for this thread:

J Infect Dis. 2004 Jan 1; 189(1): 113-9. Epub 2003 Dec 22

Selective Induction of Matrix Metalloproteinases by Borrelia

burgdorferi via Toll-Like Receptor 2 in Monocytes.

Gebbia JA, JL, Benach JL.

Center for Infectious Diseases, Centers for Molecular Medicine, and

State of New York Department of Health, Stony Brook University,

Stony Brook, New York, USA.

Regulation of secretion of matrix metalloproteinase (MMP) underlies

the basis of numerous physiological and pathological processes in

multicellular organisms.

The Toll receptor family, which is conserved from Drosophila species

to humans, mediates pattern recognition of a diversity of ligands

involved in morphogenesis and innate immunity.

Here, we show that secretion of MMP-9 is selectively induced through

Toll-like receptor (TLR) 2 in human and murine monocytic cells

stimulated with Borrelia burgdorferi.

Secretion of MMP-1 was shown to be stimulated through a pathway

other than TLR2, under identical conditions. Analysis of nuclear

extracts indicated that activator protein (AP)-1 was reduced in TLR2-

neutralized monocytic cells, suggesting that AP-1 plays a role in

the transcriptional activation of MMP-9 through TLR2.

The specific induction of MMP-9 through TLR2 provides direct

evidence of a new role for this ancient receptor family in

regulating secretion of MMPs and demonstrates evolutionary

convergence between invertebrate morphogenesis and the vertebrate

innate immune system.

Gulf-War-Syndrome (GWS) has very similar symptoms to chronic

borreliosis.

Mycoplasma fermentans is being considered to be the likely

pathogen...whether it is or not, it's likely some BLP producing

microbe is.

Since the symptoms are similar, I'd expect the pathogenesis would be

similar.

Work such as this indicates that this may be the case:

Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with

membrane lipoproteins of Mycoplasma fermentans induces apoptotic

cell death after NF-kappaB activation.

Into T, Kiura K, Yasuda M, Kataoka H, Inoue N, Hasebe A, Takeda K,

Akira S, Shibata KI.

Departments of Oral Pathobiological Science and Oral Health Science,

Hokkaido University Graduate School of Dental Medicine, Nishi 7,

Kita 13, Kita-ku, Sapporo 060-8586, Japan. Department of Host

Defense, Research Institute for Microbial Diseases, Osaka

University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

Mycoplasmal membrane diacylated lipoproteins not only initiate

proinflammatory responses through Toll-like receptor (TLR) 2 and

TLR6 via the activation of the transcriptional factor NF-kappaB, but

also initiate apoptotic responses.

The aim of this study was to clarify the apoptotic machineries.

Mycoplasma fermentans lipoproteins and a synthetic lipopeptide, MALP-

2, showed cytocidal activity towards HEK293 cells transfected with a

TLR2-encoding plasmid.

The activity was synergically augmented by co-expression of TLR6,

but not by co-expression of other TLRs. Under the condition of co-

expression of TLR2 and TLR6, the lipoproteins could induce maximum

NF-kappaB activation and apoptotic cell death in the cells 6 h and

24 h after stimulation respectively.

Dominant-negative forms of MyD88 and FADD, but not IRAK-4, reduced

the cytocidal activity of the lipoproteins. In addition, both

dominant-negative forms also downregulated the activation of both NF-

kappaB and caspase-8 in the cells.

Additionally, the cytocidal activity was sufficiently attenuated by

a selective inhibitor of p38 MAPK.

These findings suggest that mycoplasmal lipoproteins can trigger

TLR2- and TLR6-mediated sequential bifurcate responses: NF-kappaB

activation as an early event, which is partially mediated by MyD88

and FADD; and apoptosis as a later event, which is regulated by p38

MAPK as well as by MyD88 and FADD.

Selective Induction of Matrix Metalloproteinases (MMP) by Borrelia

burgdorferi via Toll-Like Receptor 2 in Monocytes.

Gebbia JA, JL, Benach JL.>

In regards to this and other work showing that BLPs stimulates MMP-

9.

What this means is that the BLPs of borrelia have the ability to

turn our own immunes system against the extracellular proteins of

our body.

Extracellular proteins (ECP) make up the mortar between our cells,

it hold the cells together in tissues.

There are several proteins in ECP: collagen, elastin, gelatin, and

several others.

BLPs have the ability (thru TLR-2) to trigger our immune system to

produces protease enzymes that digest these important ECPs.

Proteases such as collegenase, and elastase.

This protease activity is very damaging to tissues and itself can

stimulate even more inflammation.

Borrelia takes advantage of these protease enzymes to penetrate

through the tissues of the body. As ECPs are digested in tissues it

is easier for borrelia to move through it.

This can explain a lot of our fibromyalgia symptoms.

IMO, FMS/CFIDS and borreliosis/Lyme disease have a similar

pathogenesis, which is TLR triggering by the BLPs or LPS of

pathogenic microbes.

[Guest guest]

Hi

I wondered if you are a member of the Eurolyme group??

Could this info be posted to the above board with your persmission?

TIA

e

-----------------------------------------

Email provided by http://www.ntlhome.com/

[Guest guest]

Neurology. 1999 Oct 12;53(6):1340-1.

Absence of Borrelia burgdorferi-specific immune complexes in chronic

fatigue syndrome.

Schutzer SE, Natelson BH.

Department of Medicine, University of Medicine and Dentistry, New

Jersey Medical School, Newark 07103, USA. schutzer@...

Chronic fatigue syndrome (CFS) and Lyme disease often share clinical

features,especially fatigue, contributing to concern that Borrelia

burgdorferi (Bb), the cause of Lyme disease, may underlie CFS

symptoms. We examined 39 CFS patients and 40 healthy controls with a

Bb immune complex test. Patients and controls were nonreactive.

Centers for Disease Control and Prevention-defined CFS patients

lacking antecedent signs of Lyme disease--erythema migrans, Bell's

palsy, or large joint arthritis--are not likely to have laboratory

evidence of Bb infection.

---------------------------------------------------------------

Clin Infect Dis. 1995 Feb;20(2):467-8.

Borrelia burgdorferi infection is rarely found in patients with

chronic fatigue syndrome.

Pollark RJ, Komaroff AL, Telford SR 3rd, Gleit, Fagioli L, Brunet LR,

Spielman A.

----------------------------------------------------------------

Just an FYI,

Beach

> I've been studying the pathogenesis of borreliosis and I'm posting

> some information I gathered from this work.

>

> It's becoming clear to me that we are experiencing a very similar

> pathogenesis that begins to explain why we seem to have so many

> similarities of symptoms and manifestations of disease.

>

> This is a MS word doc and it's about 6 pages long...so instead of

> posting it here I'll place it in the files.

>

> I hope you find it helpful

>

>

[Guest guest]

One, I made it clear in my discussion that I'm not saying all CFIDS

is Lyme disease or borreliosis. However, what I am saying is that

it is likely our disease has a similar pathogenesis and that it is

very likely caused by a microbial infection triggering our innate

immune system via toll-like receptors.

Two, since these chronic diseases cause immune dysfunction, immune

complexes cannot be relied upon as an indication of abscence or

presence of borreliosis or other infection either. The study you

refer to is a common problem that leads to frequent misdiagnosis of

chronic borreliosis.

Many of us with LD know that there is no definitive serological for

chronic borreliosis. As there is no serological test for CFIDS or

FMS...which is usually a clinical diagnosis of exclusion of other

diseases.

In summary, it's my opinon that we all have a similar pathogenesis

caused by a chronic microbial infection, which is likely not all

borreliosis. The common pathogenesis seems to center around the

triggering of these toll-like receptors by LPS or BLPs of pathogenic

bacteria. This common pathogenesis goes a long way in explaining

the very similar symptom and course of disease we all appear to be

dealing with.

> > I've been studying the pathogenesis of borreliosis and I'm

posting

> > some information I gathered from this work.

> >

> > It's becoming clear to me that we are experiencing a very

similar

> > pathogenesis that begins to explain why we seem to have so many

> > similarities of symptoms and manifestations of disease.

> >

> > This is a MS word doc and it's about 6 pages long...so instead

of

> > posting it here I'll place it in the files.

> >

> > I hope you find it helpful

> >

> >

[Guest guest]

I agree, . I also think that some people who feel their main

problem organism is lyme, may actually be dealing with other

organisms, like staph, which is equally hard to eradicate. If they

don't realize it, treating lyme alone, will never get them well.

If you really look at all of the effective treatments that seem to

help CFS/lyme in some significant way, most have antimicrobial

properties. It boggles my mind that modern medicine can't connect

the dots with this. It's the one common link, and doctors completely

overlook it, except for a few rare individuals. I have zero doubt

that our illness is a bacterial one. There are lots of conditions

that factor in and impact it, but the biggest culprit is a

microscopic bug.

penny

> > > I've been studying the pathogenesis of borreliosis and I'm

> posting

> > > some information I gathered from this work.

> > >

> > > It's becoming clear to me that we are experiencing a very

> similar

> > > pathogenesis that begins to explain why we seem to have so

many

> > > similarities of symptoms and manifestations of disease.

> > >

> > > This is a MS word doc and it's about 6 pages long...so instead

> of

> > > posting it here I'll place it in the files.

> > >

> > > I hope you find it helpful

> > >

> > >