Re: The HPA Axis and CFS

[Guest guest]

Doris,

It's great to hear that you have gotten relief from the fatigue by

taking T3. There definitely is a significant subset of PWCs who

have hypothyroid. It's not true of all, but it certainly is true of

some.

I suspect that the reason some PWCs develop hypothyroid is that the

depletion of glutathione in the thyroid leaves the cells there

defenseless against the hydrogen peroxide that they themselves

generate (on the outside of their cell membranes) in order to carry

out the reactions needed to make the thyroid hormones. These

reactions take place outside the cells, and glutathione is necessary

inside the cells to protect them from hydrogen peroxide that is able

to leak into the cells.

I agree that it's a good idea for PWCs to check for hypothyroid.

The fact that your TSH went high was a good tip-off. Some PWCs have

hypothyroid problems even with a TSH level in the normal range.

This may be due to a problem in converting T4 to T3, or it may be a

problem in how the T3 is able to influence the cells.

Rich

> To support your theory, I was sick for several years before I ever

had the classic " fatigue " . Prior to that I had flu symptoms,

tiredness, inability to stand up straight for very long, cognitive

problems. But never " fatigue " in the sense that doing physical

activity caused me to be sick the next day, or those days when I

could barely lift my arms. Those types of fatigue only came to me

the past year. And around that same time, my TSH went high.

>

> It took me over a year to get treatment for the thyroid, because

the first meds gave me a rash and I couldn't take them. So I went a

year with the constant fatigue, and finally understood that aspect

of CFS. Now I have been on T3 thyroid for over 2 months and I would

say it is close to a miracle. All those fatigue symtpoms

disappeared almost instantly. I still have recurrent infections and

the symptoms associated with those. But the " fatigue " is gone.

>

> I wonder how many people have tried treating their thyroid and

still have the fatigue. I understand it may be difficult to treat

because the adrenals go off at the same time in some people. But I

have to say to anyone who has strong " fatigue " symptoms, that you

should try thryoid meds and see if it helps.

>

> Doris

> ----- Original Message -----

> I was interested to see that he notes that

> recent prospective studies of people at high risk for developing

CFS

> do not show changes in the HPA axis in the early stages of the

> beginning of chronic fatiguing illnesses

>

>

[Guest guest]

Rich,

Since I have LD, my perspecitve is obviously bias regarding the

pathogenesis of CFS. I've posted my theory for a common

pathogenesis here before, and will post it again below.

Briefly, when we search for the origin of this disease, it's very

fruitful to investigate what is altering the immune system, causing

it to malfunction.

In regards to the HPA axis, I agree it's malfunction is secondary to

the origin of the disease.

Regarding CFS as a sequela of borreliosis, we know that the

hypothalamus, pituitary, and adrenals are susceptible to

inflammatory damage triggered by BLPs toxins. The thyroid itself is

susceptible to inflammation.

Neuroborreliosis causing encephalitis can do significant damage to

the hypothalamus and the pituitary. Infammation manifested as

vasculitis is the likely way it does this...this inflammation can

also lead to malfunction prior to actual damage.

That is, it's common for inflammation to cause dysfunction of an

organ or tissue. If the inflammation is chronic and progressive,

permanent damage and permanent malfunction may develop.

IMO, something that chronically triggers an inflammatory cascade is

likely the origin of CFS. I believe that chronic trigger is often

TLR stimulation as stated in my post below.

I also understand other factors can trigger chronic inflammatory

cascades...for example, insulin resistance and infammation is a

metabolic inflammatory cascade...so, diabetes for example leads to

chronic inflammatory cascades.

Thus, in these situations, a metabolic disorder is the origin.

Other origins are possible too, but IMO, less frequent than chronic

infections or metabolic dysfunctions.

Back to our point...it's critical that we understand the

pathogenesis of disease and not mistake sequelae as the origin.

Conventional medicine too frequently treat these chronic diseases

symptomatically.

What we really want is therapy designed to address the cause...and

that will be much more effective.

Pathogenesis of Borreliosis:

This disease is much easier to understand when we have a firm grasp

of its 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 through modification of 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, which 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 only the acquired immune

system that is 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 part that is responsible for

triggering the TLR2. There is a synthetic analog of this

lipopeptide, which 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.

Questions regarding the pathogenesis of borreliosis:

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.

The triggering of MMP may also lead to proteolysis of

immunoglobulins, which suppresses the effectiveness of a humoral

response and suppresses serological responses in diagnostic assays

such as ELISA, & western blot (WB).

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 of

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 collagenase, elastase, gelatinase…etc.

This protease activity is very damaging to tissues and itself can

stimulate even more inflammation and further cascade of the immune

system.

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.

The inflammatory cascade and MMPs can explain a lot of our

fibromyalgia symptoms.

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

pathogenesis, which is TLR triggering by of pathogenic microbes.

[Guest guest]

> To support your theory, I was sick for several years before I ever

had the classic " fatigue " . Prior to that I had flu symptoms,

tiredness, inability to stand up straight for very long, cognitive

problems. But never " fatigue " in the sense that doing physical

activity caused me to be sick the next day, or those days when I

could barely lift my arms. Those types of fatigue only came to me

the past year. And around that same time, my TSH went high.

>

>>

> Doris

Hi Doris

This was my experience too, I was unwell for 20 years but could

still carry on and be very busy but often sick. When I finally

crashed in 2000 I now realise that my thyroid and adrenals were way

off normal for probably about 8 years before the crash.

Because they were not treated until late 2002 I had developed

mercury poisoning and borrelia plus co-infections. I feel that had

my adrenals and thyroid been treated I would never have ended up

with CFS.

I am doing very well now and taking TOA free Samento plus Armour 1

grain and 2.5 Prednisone. However I still have to watch how much I

do but am about 80% better than I had been in 2000.

Best Wishes

Pam

www.bertiedog.com

[Guest guest]

Hi, .

Thanks for your comments. I certainly agree with you about the

importance of getting at the root causes rather than treating

symptoms. I've been " rooting " around, trying to find them for

several years. In my experience, this is often easier said than

done.

I appreciate your work on Borrelliosis. You have pulled together

some interesting information and ideas. I haven't looked into all

the details you discussed, so I can't vouch for all of them, but I

can at least say that the general argument you have put together

sounds plausible.

I do want to discuss the inflammation aspect a little, though, as it

applies to CFS. As I understand it, the symptoms of an acute, local

inflammation are swelling, redness, pain, and heat. Blood tests

during acute inflammation will show elevations in white blood cell

counts, elevated C-reactive protein, and/or elevated erythrocyte

sedimentation rate (sed rate).

In chronic inflammation, not all of these are present, but I would

expect that some would be, such as elevated C-reactive protein or

elevated sed rate.

My problem with this with regard to CFS is that I don't think these

things are observed in all PWCs. Some clearly do have signs of

inflammation (such as the local ones I mentioned in gums or sinuses,

but I would say from the cases I've studied that many do not.

Therefore, I don't think I can buy into an inflammatory process

being at the basis of all cases of CFS.

I have no doubt that Borrelliosis, being a bacterial infection,

produces inflammation. I also have no doubt that the symptoms of

long-term disseminated Lyme disease are essentially

undistinguishable from those of CFS.

As far as I can tell, people with healthy, normally operating immune

systems can develop Lyme disease from a tick bite. That is, I don't

think that prior immune system suppression is necessary to enable a

person to develop Lyme disease. I think this is different from the

situation in CFS, where the infections that are commonly detected

(such as EBV, CMV, HHV-6, mycoplasma, Chlamydia, coagulase-negative

staph) are caused by pathogens that are very commonly found in

healthy people, and are kept in control by their immune systems.

So I think there are some major differences between the pathogeneses

of CFS and Lyme disease, though the symptomatology has a great deal

of overlap. I wouldn't be surprised if some of the later parts of

the pathogeneses were the same, but I don't think that's the case

for the early parts.

I appreciate your efforts and your posts, and I hope you will

continue to work on these issues. It's really good to be able to

bat the issues around.

Rich

> Rich,

>

> Since I have LD, my perspecitve is obviously bias regarding the

> pathogenesis of CFS. I've posted my theory for a common

> pathogenesis here before, and will post it again below.

>

> Briefly, when we search for the origin of this disease, it's very

> fruitful to investigate what is altering the immune system,

causing

> it to malfunction.

>

> In regards to the HPA axis, I agree it's malfunction is secondary

to

> the origin of the disease.

>

> Regarding CFS as a sequela of borreliosis, we know that the

> hypothalamus, pituitary, and adrenals are susceptible to

> inflammatory damage triggered by BLPs toxins. The thyroid itself

is

> susceptible to inflammation.

>

> Neuroborreliosis causing encephalitis can do significant damage to

> the hypothalamus and the pituitary. Infammation manifested as

> vasculitis is the likely way it does this...this inflammation can

> also lead to malfunction prior to actual damage.

>

> That is, it's common for inflammation to cause dysfunction of an

> organ or tissue. If the inflammation is chronic and progressive,

> permanent damage and permanent malfunction may develop.

>

> IMO, something that chronically triggers an inflammatory cascade

is

> likely the origin of CFS. I believe that chronic trigger is often

> TLR stimulation as stated in my post below.

>

> I also understand other factors can trigger chronic inflammatory

> cascades...for example, insulin resistance and infammation is a

> metabolic inflammatory cascade...so, diabetes for example leads to

> chronic inflammatory cascades.

>

> Thus, in these situations, a metabolic disorder is the origin.

>

> Other origins are possible too, but IMO, less frequent than

chronic

> infections or metabolic dysfunctions.

>

> Back to our point...it's critical that we understand the

> pathogenesis of disease and not mistake sequelae as the origin.

>

> Conventional medicine too frequently treat these chronic diseases

> symptomatically.

>

> What we really want is therapy designed to address the cause...and

> that will be much more effective.

>

>

[Guest guest]

Rich,

Your observations are very well thought out and I appreciate the

opportunity to dialog with you regarding the pathogenesis of our

diseases.

Yes, getting to the root is vital for development of appropriate

therapy. I think we are closing in on it.

Regarding inflammation; first we need to understand that the

definition of inflammation used here is very broad. There's not a

very good terminology for what we are really suffering with. It's

not the same as acute inflammation as you mention ...it's a chronic

dysfunctional immune response caused by a imbalance or a cascade of

immune modulators...many factors are involved which makes this hard

to name or describe. Measuring this dysfunctional response isn't

easily done either...but we have some clues as to what's going on.

The clinical evidence is that we suffer with a chronic inflammatory

disease too. For example, we can look at the inside of our ankles

and usually see significant amount of vasculitis, which look like

spider veins...or we have congested conjunctivitis...many of us have

encephalitis, radiculitis, myositis, arthritis, tendonitis...a lot

of ...itis that indicate inflammatory involvement. We also

frequently have lyphadenitis...or swelling of lymph nodes which

strongly suggests an immune response is occurring.

Other clinical evidence suggests that symptomatic anti-inflammatory

therapy often helps reduce symptoms at least temporarily...this

suggests inflammation plays a role in the disease.

Medicines ability to measure chronic inflammation, isn't as good as

acute inflammation. This reminds me of a quote by Albert Einstein,

I'll have to paraphrase, " What's measured doesn't always count and

what counts can't always be measured. " I think that is frequently

the case with these chronic diseases...we still don't have the

ability to measure what really counts yet...hopefully we will soon.

It must be kept in mind that we didn't even know that the innate

immune system, called the toll family of receptors, existed until it

was discovered in the fruit fly back in 1996. This understanding is

still in it's infancy and the role it plays in chronic disease is

not well understood.

The process of inflammation can vary so that measurements may not be

meaningful. Depending on what branch of the immune response is

causing problems, determines what things are out of balance.

Something that triggers a cascade of cytokines which influence the

immune system to respond in such a way as to be detrimental to the

body is frequently called an inflammatory response... for lack of

better terminology. Inflammatory responses can look and be quite

differently...depending on what's causing or triggering them.

IMO, there's no doubt the immune system is closely involved with the

origin of these chronic diseases.

In CFS, where the infections that are commonly detected (such as

EBV, CMV, HHV-6, mycoplasma, Chlamydia, coagulase-negative staph)

which are pathogens that are very commonly found in healthy people,

and are kept in control by their immune systems. My interpretation

of this is that an immune dysfunction, maybe even caused by CFS, may

have allowed these opportunistic pathogens to establish

secondarily. If they are the primary pathogen, several other

factors can contributed to their ability to establish infections in

healthy individuals. These factors could be infectious, metabolic,

genetic, enviromental...etc.

For example, insulin resistance and the inflammatory syndrome

associated with it can lead to immune dysfunctions and immune

suppression...raising the risk of chronic infections with pathogens

which are relatively avirulent.

I disagree when you say, " So I think there are some major

differences between the pathogeneses of CFS and Lyme disease, though

the symptomatology has a great deal of overlap. I wouldn't be

surprised if some of the later parts of the pathogeneses were the

same, but I don't think that's the case for the early parts. "

IMO, the clinical & laboratory evidence suggests that the

pathogenesis are very similar and the root cause very close to each

other.

I too appreciate your efforts and your posts, and I hope to continue

this dialog regarding the pathogenesis. I believe it will help all

of us understand what we are battling.