The Complexities of Lyme disease

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The Complexities of Lyme Disease

A Microbiology Tutorial

by

M. Grier M.Sc.

Lyme Disease is a multi-system disease which can affect virtually

every tissue and every organ of the human body. It is a disease which

can be mild to some, and devastating to others. It can cripple and

disable, or fog your mind. It can affect men, woman, and children,

and even your family dog. (1-5,7-19) You may test negative for the

disease, and still have it, or test positive and be symptom free.

Some will get symptoms within days of a tick bite, while others may

have it for years before they are even diagnosed. Some Lyme patients

are told they have fibromyalgia, chronic fatigue syndrome, MS, or

some other disease of unknown origin. (See abstracts of the 1996

International Lyme Conference) There are some studies which strongly

support that the infection can be transmitted from mother to the

unborn fetus, and may even cause still birth and has been implicated

in some SIDs deaths. (Mac 20,45,52,53)

Why is Lyme disease such a mystery? Why does it mimic so many other

disease? Why is it so difficult to detect? The reasons come from the

microbiology of the bacteria that causes Lyme Disease.

Lyme disease is caused by a spiral shaped bacterium known as a

spirochete. Diseases that are caused by spirochetes are notorious for

being relapsing in nature, difficult to detect, and great imitators

of other diseases. Syphilis, Tick-Borne Relapsing Fever, and

Leptospirosis are other examples of spirochetal diseases. Lyme

disease is caused by a bacteria called Borrelia burgdorferi, named

after the man who isolated it from a Deer Tick in 1981, Dr. Willy

Burgdorfer. The following is a tutorial to help explain away the

mysteries of this bacteria, and why it causes so much controversy

between patients and the medical community. (1)

The Structure of the Lyme Bacteria

The structure of the Lyme spirochete is unlike any other bacteria

that has ever been studied before. It is one of the largest of the

spirochetes (0.25 microns x 50 microns) It is as long, as a fine

human hair is thick. Borrelia burgdorferi is a highly motile

bacteria, it can swim extremely efficiently through both blood and

tissue because of internal propulsion. It is propelled by an internal

arrangement of flagella, bundled together, that runs the length of

the bacteria from tip to tip. Like other Borrelia bacteria Borrelia

burgdorferi has a three layer cell wall which helps determine the

spiral shape of the bacteria. What makes this bacteria different from

other species, is that it also has a clear gel-like coat of glyco-

proteins which surround the bacteria. This extra layer is sometimes

called the Slime Layer or S-layer. (See diagram 1) (45,46,59)

This means: This extra layer of glyco-proteins may act like a

stealthy coat of armor that protects and hides the bacteria from the

immune system. The human immune system uses proteins that are on the

surface of the bacteria as markers, and sends attacking antibodies

and killer T-cells to those markers, called outer surface protein

antigens (OSP antigens). This nearly invisible layer is rarely seen

in washed cultures, but can be seen regularly in tissue biopsies.(46)

The Lyme bacteria is different from other bacteria in its arrangement

of DNA. Most bacteria have distinct chromosomes that are found

floating around inside the cytoplasm. When the bacteria starts to

divide and split in two, the chromosomes divide and the new copies of

the chromosomes enter the new cell. The arrangement of DNA within

Borrelia burgdorferi is radically different. It is arranged along the

inside of the inner membrane. It looks something like a net embedded

just underneath the skin of the bacteria. (46)

This means: We really don't understand the mechanisms of how Bb

regulates its genetic material during its division.

Another unique feature to Borrelia burgdorferi are Blebs. This

bacteria replicates specific genes, and inserts them into its own

cell wall, and then pinches off that part of its cell membrane, and

sends the bleb into the host. Why it does this we don't know. But we

do know that these blebs can irritate our immune system. Dr. Claude

Garon of Rocky Mountain Laboratories has shown that there is a

precise mechanism that regulates the ratio of the different types of

blebs that are shed. (46) In other bacteria the appearance of blebs

often means the bacteria can share genetic information between

themselves. We don't know if this is possible with Borrelia species.

There have been reports of a granular form of Borrelia, which can

grow to full size spirochetes, and reproduce. These granules are so

small that they can be filtered and separated from live adult

spirochetes by means of a micro-pore filter. (Stealth Pathogens Lida

Mattman Ph.D. 66)

The division time of Borrelia burgdorferi is very long. Most other

pathogens such as Streptococcus, or Staphylococcus, only take 20

minutes to double, the doubling time of Borrelia burgdorferi is

usually estimated to be 12-24 hours. Since most antibiotics are cell

wall agent inhibitors, they can only kill bacteria when the bacteria

begins to divide and form new cell wall.(35,59-62)

This means: Since most antibiotics can only kill bacteria when they

are dividing, a slow doubling time means less lethal exposure to

antibiotics. Most bacteria are killed in 10-14 days of antibiotic. To

get the same amount of lethal exposure during new cell wall formation

of a Lyme spirochete, the antibiotic would have to be present 24

hours a day for 1 year and six months! Note: Antibiotics kill

bacteria by binding to the bacteria's ribosomes, and interrupting the

formation of cell wall proteins.

Like other spirochetes, such as those that cause Syphilis, the Lyme

spirochete can remain in the human body for years in a non-metabolic

state. It is essentially in suspended animation, and since it does

not metabolize in this state, antibiotics are not absorbed or

effective. When the conditions are right, those bacteria that

survive, can seed back into the blood stream and initiate a relapse.

(59-62,70)

This means: Just because a person is symptom free for long lengths of

time doesn't mean they aren't infected. It may be a matter of time.

Whereas viral infections often impart a lifelong immunity, Lyme, like

other bacterial infections, does not retain active immunity for long

periods of time. People are often reinfected with Lyme. (96)

How does the Lyme bacteria travel from the bloodstream to other

tissues? While we have known for a long time that the Lyme spirochete

can show up in the brain, eyes, joints, skin, spleen, liver, GI

tract, bladder, and other organs, we didn't understand the mechanism

by which it could travel through capillaries and cell membranes.

(Abstract 644) Then Dr. Mark Klempner presented at the 1996 LDF

International Lyme Conference an interesting paper that gave us part

of the answer.

Many researchers have observed that the Lyme spirochete attaches to

the human cells' tip first. It then wiggles and squirms until it

enters the cell. What Dr. Klempner showed was that when the

spirochete attached to the human host cell, it caused that cell to

release digestive enzymes that would dissolve the cell, and allow the

spirochete to go wherever it pleases. This is very economical to the

bacteria to use our own cell's enzymes against us, because it does

not need to carry the genes and enzymes around when it travels. Dr.

Klempner also showed that the spirochete could enter cells such as

the human fibroblast cell (The skin cell that makes scar tissue.) and

hide. Here the pathogen was protected from the immune system, and

could thrive without assault. More importantly, when these Bb-

fibroblast cultures were incubated with 10 x the MIC for IV Rocephin,

two thirds of the cultures still yielded live spirochetes after two

weeks, and in later experiments for more than 30 days. If we can't

kill it in a test tube at these high concentrations in four weeks,

how can we hope to kill it in the human body? (22,48,79,80,)

This means: The infection can enter the tissue that is optimal for

its survival, and it may evade the immune system and antibiotics by

hiding inside certain types of cells.

Another interesting observation about this bacteria is how it

interacts with our body's immune system; Dr. Dorward of Rocky

Mountain Labs made a video tape of how Borrelia burgdorferi acts when

surrounded by B-cells. (The type of white blood cell that makes

antibody.) The spirochete attached tip first, entered the B

lymphocyte, multiplied and ruptured the cell. It repeated this

process for three days until the B-cells were able to come to an

equilibrium. A matter of concern was that some of the spirochetes

were able to strip away part of the B-cell's membrane, and wear it

like a cloak. (Dorward, Hulinska 1994 LDF Conference Vancouver BC)

This means: If this spirochete is evolved enough to attack our B-

lymphocytes, then it may also be evolved in other ways that we do not

yet understand. It is for certain that its ability to kill B-

lymphocytes evolved as part of a defense mechanism to evade its own

destruction. The observation that it can use the B-cell's own

membrane as camouflage indicates that it may be able to go undetected

by our immune system. The way our immune system is supposed to work

is that it recognizes foreign invaders as being different from self,

and attacks the infection.

Unfortunately, the immune system sometimes attacks our own cells.

This is called autoimmune disease. If a foreign invader has a

chemical structure similar to our own tissue antigens, our bodies

sometimes make antibodies against our own tissues. In people with

Lyme disease scientists have discovered auto-antibodies against our

own tissues including nerve cells (axons), cardiolipid, myelin (also

seen in MS), myelin basic protein (also seen in MS), and neurons

(brain cells) (23,28,38-40,43,45,56,57,60,88)

When the immune system finds a foreign invader, it tags that invader

in a number of ways. A cell called the macrophage can engulf the

bacteria, and then communicate to other immune cells the exact

description of the bacteria. Another cell might mark the cell with

antibody which attracts killer T-cells. Some types of T-cells

communicate to other cells what to attack, and regulate the immune

assault. But sometimes the body can produce a type of antibody that

doesn't attack or help. A blocking antibody will attach and coat the

intruder, but it won't fix compliment, and it shields the bacteria

from further immune recognition. In Lyme we have seen quantities of

IgG4 blocking antibody such as is seen in some parasitic infections.

(Tom Schwann RML 92 LDF Conference) *Note: Compliment is a term used

for a series of 18 + digestive proteins that are only activated by

signals from our immune system, such as compliment fixing antibodies.

In order for the immune system to make an attacking antibody, the

immune system must first find an antigen which it can attack.

Unfortunately, as seen by freeze fracture electron microscope,

photographs of the Lyme bacteria show that most of the antigens are

on the inside of the inner membrane, and not on the outside. (60)

This makes the bacteria less visible to the immune system and more

difficult to attack. The most intriguing fact about Borrelia

spirochetes is their well documented ability to change the shape of

their surface antigens when they are attacked by the human immune

system. When this occurs, it takes several weeks for the immune

system to produce new antibodies. During this time the infection

continues to divide and hide. (1,47,63,66)

It appears that Borrelia are able to change their surface antigens

many times, and can do it quickly. In one study by Dr. Pachner

MD, he infected mice with a single strain of Borrelia burgdorferi.

After several weeks, he was able to isolate two slightly different

forms of the bacteria. The bacteria from the bloodstream was attacked

and killed by the mouse's immune sera, but the bacteria isolated from

the mouse's brain was unaffected by the immune sera. The bacteria

isolated from the mouse's brain had a new set of surface antigens. It

appears that contact with the CNS caused the bacteria to change its

appearance. Since the brain is isolated from the immune system and is

an immune privileged site, the bacteria became its own separate

strain. (47,97)

This means: Infections of the bloodstream may be different from the

infections that are sequestered in the brain. While we continue to

have active immunity in the bloodstream, the brain has no immune

defenses except for circulating antibodies. So, if those circulating

antibodies are ineffective to attack the bacteria in the brain, then

the brain is left without any defenses, and the infection goes

unabated.

Over 100 references, abstracts and diagrams are inserted into the

text to support the statements in this chapter.

Another peculiar observation of these bacteria is seen inside the

bacteria. When the genetic control mechanisms of this bacteria are

inhibited with antibiotics known as DNA Gyrase Inhibitors

(ciprofloxin) the bacteria start to produce bacterio-phage. A phage

is a virus that specifically attacks bacteria. In this case there are

two distinct forms. This means the Lyme bacteria at one time were

attacked by viruses. It was able to suppress them, but the DNA to

make the phage is still incorporated within the DNA of the bacteria.

Perhaps activation of this phage could one day be beneficial to

treating chronic Lyme patients? (JTBD 94)

What happens when the infection gets to the brain? In the case of

Lyme disease, every animal model to date shows that the Lyme

spirochete can go from the site of the bite to the brain in just a

few days. (41,60, abstract 644) While we know these bacteria can

break down individual cell membranes and capillaries, its entrance

into the brain is too pronounced for such a localized effect. When

the Lyme bacteria enters the human body, we react by producing

several immune regulatory substances known as cytokines and

lymphokines. Several of these act in concert to break down the blood

brain barrier. (E.g. Il-6, Tumor Necrosis Factor-alpha, Il-1,

Transforming Growth Factor-beta etc.) In addition to affecting the

blood brain barrier, these cytokines can make us feel ill, and give

us fevers. (54,60,) (JID 1996:173, Jan)

Since the brain has no immune system, it prevents infection by

limiting what can enter the brain. The capillary bed that surrounds

the brain is so tight that not even white blood cells are allowed to

enter. Many drugs can't enter either, making treatment of the brain

especially hard. For the first ten days of a Lyme infection, the

blood brain barrier is virtually nonexistent. This not only allows

the Lyme bacteria to get in, but also immune cells that can cause

inflammation of the brain. (41) *Note: The breakdown of Bb was shown

to occur by tagging WBCs, albumin, and other substances known not to

cross the BBB with radioactive Iodine. The CSF was tested, and then

the animals were infected with Bb. Then the CSF was tested everyday

for several weeks. The result: No cross over of Iodine in the control

group, 100% crossover in the infected group for 10 days. The

infection had the same result as injecting the radioactive iodine

directly into the brain. (60)

When the human brain becomes inflamed, cells called macrophages

respond by releasing a neuro-toxin called quinolinic acid. This toxin

is also elevated in Parkinson's Disease, MS, ALS, and is responsible

for the dementia that occurs in AIDS patients. What quinolinic acid

does is stimulate neurons to repeatedly depolarize. This eventually

causes the neurons to demyelinate and die. People with elevated

quinolinic acid have short-term memory problems. (27,29-37,40-

42,74,75, 82-84,87-90)

This means: If we think of all of our brain cells like telephone

lines, we can visualize the problem. If all of the lines coming in

are busy, we can't learn anything. If all of the lines going out are

busy, we can't recall any memories. Our thinking process becomes

impaired.

A second impairment to clear thinking that Lymies experience is the

restriction of proper circulation within the blood vessels inside the

brain. Using an instrument called the Single Photon Emission Computer

Tomography scanner (SPECT scans), we are able to visualize the blood

flow throughout the human brain in 3-D detail. What was seen in the

brains of chronic neurological Lyme patients was an abnormal " swiss-

cheese " pattern of blood flow. The cortical, or thinking region of

the brain, was being deprived of good circulation; the occipital

(eyesight) regions had an increase flow. This could help explain why

most Lyme patients complain of poor concentration and overly

sensitive eyes. (91)

Lyme Tests

There's a Lyme test, so what's the problem? There are several Lyme

tests, but most of them are dependent on the body's ability to make

antibody against this bacteria. As we have seen, this may be a

problem. There is the S-layer protecting the bacteria; the surface

antigens are not readily exposed; there may be a blocking antibody;

the bacteria might be inside a human cell; the bacteria might be down

regulating the immune system through cytokines; the bacteria might

have altered its antigenic appearance to fool the immune system; the

bacteria might be cloaked in B-cell membrane; the bacteria might be

hiding in joints, tendons, white blood cells, skin cells or the

brain. Remember, if even just one spirochete survives, it could cause

a relapse. Then there is another problem - the tests that detect

antibody can only detect free uncomplexed antibody. (23,25,55,70)

When an antibody is formed, it is meant to latch on to something and

never let go until it is destroyed. Like a lock and key, antibodies

fit their associated antigens. Once the antibody attaches to the

antigen it is no longer is a detectable antibody, because it has now

become an antibody-antigen complex. This complex is not measurable

using today's commercially available tests. Also, as the amount of

antigen increases, the amount of antibody can decrease, because the

antigen will trap out the available antibody and sequester it. So, a

person who has a bad infection but is making a limited amount of

antibody can be overwhelmed by antigen, thus making antibody

detectable only if you can detect the complex.

This means: People who have the worst infections may have the lowest

antibody titers, and test negative. Note: It takes four weeks from

the tick bite to test positive.

There are two main categories of Lyme tests. The most common and

least specific is the Enzyme Linked Immune Sera Assay or ELISA, the

other is an Immuno Blot or Western Blot. The Western Blot essentially

makes a map of the different antibodies we make to the bacteria. The

map separates the antibodies by size and weight, and is reported in

units called kilo daltons or kDa. For example, a Western Blot may

report bands at 22, 25, 31, 34, 39, and 41 kDa. Each of these bands

represents an antibody response to a specific protein found on the

spirochete. The 41 band indicates an antibody to the flagella

protein, and is non-specific. The 31-kDa band represents the OSP-A

protein and is specific for Borrelia, as is the 34 band OSP-B and 25

kDa OSP-C.

In 1994, the NIH decided that there should be consistency between

labs reporting Lyme Disease Western Blots, and that a specific

reporting criteria should be established. This sounds good, but one

could argue they made a bad situation worse. The consensus committee

decided to set the standards for a positive test based on the number

of bands that appear. Whereas every lab prior to the hearing had

accepted bands 25, 31, and 34 as specific and significant, the NIH,

without any clear reasoning, disqualified those bands from being

reportable. The result was that what had been a fair good test had

now become poor or even useless. (90)

How badly did the NIH bootstrap this test? The following is an

analysis of the new guidelines presented as an abstract and lecture

at the 1995 Rheumatology Conference in Texas. (1995 Rheumatology

Symposia Abstract # 1254 Dr. Fawcett et al.)

This was a study designed to test the recently proposed changes to

Western Blot Interpretation. At the Second National Conference on

Serological Testing for Lyme Disease, sponsored by the NIH, the

committee proposed limiting the bands that could be reported in a

Western Blot for diagnosis of Lyme Disease. An IgG Western Blot must

have five or more of these bands: 18, 23,28, 30, 39, 41, 45, 58, 66,

and 93 kDa. An IgM Western Blot must have two or more bands of the

following three bands: 23, 39, 41. Conspicuously absent are the most

important bands, 22, 25, 31 and 34, which include OSP-A, OSP-B and

OSP-C antigens - the three most widely accepted and recognized

antigens. These antigens are so immuno-reactive that they were the

antigens chosen for human vaccine trials. Yet they are not considered

important enough to include in the diagnostic criteria. Why?

This abstract showed that, under the old criteria, all of 66

pediatric patients with a history of a tick bite and Bull's Eye rash

who were symptomatic were accepted as positive under the old Western

Blot interpretation. Under the newly proposed criteria, only 20 were

now considered positive. That means 46 children who were all

symptomatic would probably be denied treatment! That's a success rate

of only 31 %. The number of false positives under both criteria was

ZERO %. * Note: A misconception about Western Blots is that they have

as many false positives as false negatives. This is not true. False

positives are rare. The conclusion of the researchers was: " the

proposed Western Blot Reporting Criteria are grossly inadequate,

because it excluded 69% of the infected children. "

We are told by manufacturers, health departments, and clinics that

the Lyme ELISA tests are good and that they are useful, but in two

blinded studies that tested laboratories accuracy, they failed

miserably. In the latest study, 516 labs were tested. The overall

result: 55% inaccurate! You are actually better off to flip a coin!

(98, 99)

Repeatedly, there have been patients who are seronegative for

antibodies, yet culture positive. Despite this, our medical community

is dependent on these tests and relies upon them as though they were

100 % accurate. No matter how bad the tests are, as long as we have

them doctors will use them. This is why doctor Samual Donta, M.D.,

called for a complete ban of the Lyme ELISA test at the 1996 LDF Lyme

Conference. He found that, in some cases, Lyme ELISAs were more than

75 % inaccurate, yet it was relied upon as though it were the last

word - and all too often it is.

The worst problem for chronic Lyme patients is that, after they are

treated with antibiotics, they are told they are cured even if they

have a recurrence of symptoms. There is a persistent dogma in

medicine that 28 days of IV antibiotics cures all Lyme Disease. In

fact, the ongoing six-year-old Nantucket Island Lyme Treatment Study

showed IV antibiotics to have the highest relapse rate in late Lyme

disease! This was because doctors put too much faith in IV

antibiotics as being so powerful, that they did not follow up IV's

with oral antibiotics. The key to treating late Lyme appears to be

the length of antibiotic treatment, not the method. If IV's are

followed up by six months or more of oral antibiotics, the relapse

rate dropped to 13%. (Dr. Fein MD, MPH, Magnarelli MD, MPH 96

LDF Conference)

I have included in the references several published studies, case

histories and abstracts that deal with culture positive patients who

had been previously treated aggressively with antibiotics, often

including intravenous antibiotics. Most of these cases are patients

who are seronegative for any Lyme antibodies, yet are culture

positive. If we are repeatedly culturing this bacteria out of

patients who have been treated and who are negative by all other

tests, we need to rethink our understanding of this disease! We need

to treat symptoms, not tests; we need to recognize that, while Lyme

is a treatable disease, in some cases it appears to be incurable. I

would not like to be the doctor who under treats this disease, now

knowing that relapses are potentially more dangerous than treating

until the symptoms are gone. (4,6,42,49,67,68,70-96) (Lawrence C,

Lipton RB, Lowy FD, and Coyle PK. Seronegative Chronic Relapsing

Neuroborreliosis. European Neurology. 1995; 35(2): 113-117)