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The Complexities of Lyme Disease
A Microbiology Tutorial
by Thomas M. Grier MS

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 ther disease of unknown origin. (See abstracts of the 1996I nternational 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. (MacDonald 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. Borreli 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. David 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 (braincells)    (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. Andrew 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.

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 BBB 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 thecomplex.  

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. Paul 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 20were 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. Leslie 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 re-think 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 undertreats 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)

Too often, I have seen the word cured used in Lyme Disease Studies, only to find that the researchers have redefined the word cure to mean seronegative. Seronegativity is not synonymous with cure. The numerous culture positive cases in  recent years should have negated that kind of logic years ago, and yet, in 1997,  researchers are still publishing studies that use antibodies and PCR as the end point for cure. It's time to ask the patients one simple question: How are you feeling?      So, let's say hypothetically you are bitten by an infected tick, you get a rash, you get  sick, and you have a positive test. So you get
2-4 weeks of antibiotics and you get  better, but then you get sick again. No problem! You go back to your doctor, and he says, "Well, we'd better give you another Lyme test" - and its negative. Why? Even though you have an active infection, the antibiotics cleared that infection from your  blood stream. That is where your immune system is. The rest of the pathogens are hiding from the immune system inside your joints, your tendons, and your brain. Only  now you don't have antibiotics to fight the infection, or any antibodies!

In a study by Dr. Musher, M.D., he looked at incompletely treated Tertiary Syphilis patients, and compared them to those Tertiary Syphilis patients who never got antibiotics. He found that the incompletely treated group went into dementia faster.  Why? Because they had no natural immunity left. Their ability to make sufficient  antibody was diminished, because the antibiotics eliminated the stimulus from the blood stream, but the infection was still hidden in the brain! (35,61,62,65,74,83)

Conclusion: Lyme is an extremely complex disease that can cause long term chronic     infections. Patients can be seronegative, yet culture positive (even after aggressive  antibiotic therapy). The infection enters the brain early in the infection (within days).  The sequestered bacteria within the CNS can be so different from the initial infection  that serum antibodies are ineffective. Incomplete antibiotic treatment of Lyme Encephalitis can harm the patient.

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