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Looking for something else I found this! It may be of great importance to

those who do not get relief from Antibiotics(notice the last few paragraphs)

Autoimmune Diseases: The Invasion by the Body

All autoimmune disease is a result of the body's immune system

" attacking " itself. For whatever reason, the body gets a signal to mount an

attack on " self " - basically on certain types of tissues or cell types in the

body. This is not a natural event, thank goodness; when the body attacks

itself, something quite bizarre has to be going on inside. The Big Question has

always been, " why? "

In rheumatoid arthritis, for example, the primary targets are the

joints. In scleroderma, the attack is mounted on skin and connective tissue.

Generally speaking, the primary pathology of autoimmune disease is inflammation,

as different cells and tissues are assaulted and become inflamed. In both of

the instances mentioned above there are many other far-reaching effects due to

inflammatory reactions elsewhere in the body. There is no mystery in the

primary issue here - inflammation - just a mystery as to how and why it happens.

Saying, " the immune system, " is really an attempt to simplify an

immensely complicated equation. The immune system has many ways to mount a

response. The three basic ways (there are others) are: 1) by producing

antibodies, 2) by using T-cells and 3) by way of literally scores (probably

thousands) of inflammatory " mediators " . Although all of these mechanisms are

involved in autoimmune disease to some extent, it is the T-cell response that

interests me. Since LDA immunotherapy is T-cell mediated (works by stimulating

certain T-cells), it is only logical that if you could tailor LDA to have a

beneficial effect on the T-cells involved in autoimmune inflammation - say in

rheumatoid arthritis - you'd really have something. Well, Dr. Len McEwen - the

discoverer and developer of EPD - found a way. It has to do with a principal

called molecular mimicry.

Molecular mimicry

Molecular mimicry is generally interpreted as the sharing of

molecular structures (or their protein products) by portions of dissimilar

genetic material (i.e. " resemblance " or cross-reactivity, most often between

different organisms). This produces an " error in identification " by the host.

The mimicking material is usually foreign ( " non-self " e.g. bacteria) but the

material contains components similar enough to certain host cells that the host

then mounts an attack on " self. " In other words, a bacteria can trick the body

into attacking normal cells that have a few characteristics of the bacteria.

When you think a great deal about this, the prospect is frightening.

Major histocompatibility (MHC) and the relationship to human leukocyte antigen

(HLA)

Discussion of molecular mimicry requires a short talk about HLA receptors, since

that's where mimicry takes place. So please bear with me. If you have

autoimmune disease, and you understand this, you will have an amazing revelation

as to why mimicry is so important to your illness.

Major histocompatibility (MHC) molecules (generally referred to as receptors)

are of two major types - Class I and Class II. A third type (Class III, not

discussed here) is a subset of serum proteins involved in the complement system.

Class I MHC receptors are found on the surfaces of all somatic (body) cells and

are unique to every individual. These molecules, or receptors, appear on the

cell membrane. No two individuals have exactly the same combinations of MHC

Class I receptors. It follows that these receptors govern " non-self "

recognition and are responsible for phenomena such as graft rejection.

Class II MHC receptors are found on the surfaces of macrophages and lymphocytes,

and are likewise expressed on their cell membranes. They provide the

self-recognition necessary to interact with one another and with other

immunocompetent cells. Many people have comparable Class II receptors.

Human leukocyte antigen (HLA) receptors are simply a type of MHC receptor

molecule. HLA receptors may be either Class I or Class II MHC receptors. Many

scores - if not hundreds - of HLA receptors have been identified, and there are

most likely very large numbers present on most all human cells.

HLA-B27, for example, is a class I MHC receptor found on most all cells in the

body (somatic cells). An individual must possess a specific genetic trait

(inherited on the sixth chromosome) in order to produce this type of receptor.

About 7% of the population in the USA is HLA-B27 positive, although certain

specific or isolated populations may average considerably higher.

One place where mimicry frequently occurs has been identified

specifically is this HLA-B27 receptor. When molecular mimicry occurs, the body

then targets cells elsewhere in the body (in tissues and organs) possessing

these same receptor sites. These cells may be those of synovial tissue, mucous

membranes, connective tissue, skin, the central nervous system or other body

cells, tissues and organs, and the immune response is generally adverse,

affecting that tissue or organ.

The HLA-B27 genotype has been the most studied HLA receptor site,

and is of particular importance to me and the concepts presented here. There is

now little question that it represents one of the " classical " and certainly the

most common site where molecular mimicry takes place. Importantly, HLA-B27 has

been associated with various spondyloarthropathies, and with a type of arthritis

called " reactive " arthritis (severe, usually fluctuating joint pain and

inflammation without antibodies for rheumatoid arthritis or autoimmune disease).

In short, the body mistakenly mounts an assault against " self "

because some incorrect information has been given, initially induced by an

outside " non-self " source. The effects and ramification of mimicry on human

tissue are critically important, and the proposed mechanism and the results of

this " sharing " which occurs with molecular mimicry will be discussed in the

material that follows.

The relationship of HLA to ankylosing spondylitis, rheumatoid arthritis and

other illnesses

Evidence of the first links of HLA receptors to ankylosing

spondylitis occurred in 1973, when it was found that there was a higher

occurrence of ankylosing spondylitis in patients with certain HLA subtypes.

However, Ebringer�s studies (see references at the end of this section) were

paramount in the identification of HLA-B27 and the concept of mimicry by

Klebsiella at that site. They were also crucial in the development of the

concept that the arthritis associated with ankylosing spondylitis was actually a

reactive arthritis secondary to mimicry. Ebringer also demonstrated that

HLA-B27 is expressed on the lymphocytes and synovial cells (cells in the joint

spaces) of virtually 100% of patients with ankylosing spondylitis, as compared

to 7% in most populations.

The presence of specific anti-Klebsiella antibodies in patients with ankylosing

spondylitis during the acute phase of the disease clearly indicates these

patients have been exposed to these specific bacteria. Ebringer proposed that

the subsequent immune response then causes a " reactive arthritis " , especially in

patients positive for HLA-B27. The concept of reactive arthritis is important.

Many other works have appeared which confirm the association of the

genetic HLA-B27 trait and the concept that Klebsiella functions via molecular

mimicry in the etiology of ankylosing spondylitis and other similar conditions.

The bottom line is that Klebsiella is an important cause of ankylosing

spondylitis.

Rheumatoid arthritis

Strasny made an association with the B-cell HLA receptor DRW4 and rheumatoid

arthritis as early as 1973. While Ebringer and others were investigating

ankylosing spondylitis and its association with Klebsiella, HLA-B27 and

molecular mimicry, these and other authors were studying the association of

rheumatoid arthritis, Proteus, HLA-DR4 (and HLA-DR1) and the identical principal

of molecular mimicry. The incidence of the genetic disposition for HLA-DR4 in

most of these studies of patients with rheumatoid arthritis has varied between

50-75%. Up to 93% of patients with rheumatoid arthritis are apt to carry both

HLA-DR1 and HLA-DR4.

Similarities between the work of Ebringer and others who associated

HLA-B27 and Klebsiella to that of many other authors who associated Proteus and

HLA-DR4 made the case of molecular mimicry in both diseases quite beyond

question.

Reactive arthritis and inflammation

Although the direct association of at these two organisms to ankylosing

spondylitis and rheumatoid arthritis via molecular mimicry was important, the

relationship of yet other organisms to yet other disorders has been taken this a

crucial step further. Indeed, much of the initial focus of the studies cited

above turned eventually to the " reactive " components of autoimmune and other

disorders as critically important doctrine.

The term " reactive arthritis " encompasses most all forms of arthritis where

blood tests are negative (including ankylosing spondylitis). Reactive arthritis

is an important concept to me, as the published literature has caused me and

others to feel that the majority of the different types of reactive disorders

may well be autoimmune events.

Since 60-80% of patients with reactive arthritis are positive for HLA-B27, one

would have to consider that these inflammatory disorders might also likely be

associated with molecular mimicry. Many authors have since drawn this

conclusion. Much has appeared in the literature demonstrating that reactive

arthritis (and other disorders, some discussed below) may be induced by a

variety of organisms, and is by no means confined to Klebsiella and Proteus

organisms.

Various types and species of intestinal organisms have now been clearly shown to

cause rheumatoid or non-rheumatoid (reactive) arthritis in patients, in addition

to Klebsiella and Proteus. This list includes, but is certainly not limited to:

Strongyloides stercoralis, Taenia saginata, Endolimax nana, Dracunculus

medinensis, Giardia lamblia, Yersinia enterocolitica, Shigella, Salmonella,

Campylobacter, Clamydia, Hemophilus influenza, E. coli, Bacteroides and

numerous others.

Gastrointestinal disorders can themselves be due to bacteria via mimicry, even

though the intestine may be the natural habitat of the bacteria involved. This

includes gastritis, irritable bowel syndrome, ulcerative colitis and others.

Foods may also cause intestinal disorders by way of mimicry. Other inflammatory

disorders, many of them autoimmune, have been studied in relation to molecular

mimicry caused by various organisms.

Other examples of illnesses that have been attributed to molecular mimicry and

organisms are primary biliary cirrhosis by urinary tract bacteria, hepatic

stenosis or inflammation by Bacteroides, experimental colitis by anaerobic

bacteria, juvenile dermatomyositis and necrotizing arteritis by streptococcus,

and arthritis by H. influenza meningitis. This is only a small sampling of the

growing link between bacteria, inflammation, autoimmune disease and molecular

mimicry.

The anaerobe, Bacteroides has been of particular interest to me and others.

Predominantly anaerobic bacteria proliferate in blind loop animal (and human)

models, and the resultant vitamin B-12 deficiency, iron loss and protein-losing

enteropathy has been reversed by metronidazole and tetracycline, both of which

inhibit Bacteroides spp.

Bacteroides has been shown to be a major cause of reactive arthritis, liver

disease and dermatitis, and it has also been demonstrated that patients with

these complications resulting from jejuno-ileal bypass for obesity responded to

metronidazole, a drug rather specific for Bacteroides.

One would postulate that if bacteria associated with molecular mimicry could

cause disease, the use of other appropriate antibiotics might provide temporary

(or even long-term) relief for patients suffering with a disease caused by

mimicry. This has been demonstrated by several authors, and is probably the

reason Dr Brown's low-dose tetracycline protocol works for many patients

with rheumatoid arthritis.

Molecular mimicry: the mechanism and its ramifications

Perhaps the most complete and comprehensive scenario to help one to

understand the concepts of molecular mimicry was developed by Oldstone,

Schwimmbeck, Yu and colleagues, spanning a series of 14 published papers,

beginning in 1972 and culminating in 1989. These authors have provided a likely

model for the primary mechanism for molecular mimicry.

Srinivasappa and colleagues tested over 600 of these monoclonal antibodies, all

directed against specific viral polypeptides. They then charted the

cross-reactivity of these same monoclonal antibodies with host proteins

expressed by a large variety of normal tissues. Through their testing,

corroborated by Oldstone, the monoclonal antibodies selected reacted with 14

different viruses. These included both common RNA and DNA viruses, such as

herpes, human retroviruses, vaccinia and others. Most importantly, over 4% of

the monoclonals reacting with the viruses cross-reacted with host cell protein

expressed on uninfected tissues, and some with more than one host organ.

This observation showed that molecular mimicry (cross-reactivity) is

indeed common and not necessarily restricted to any particular class, virus or

group. It demonstrated that many viruses share specific antigenic groups with

normal host cells, tissue and organ proteins.

Oldstone then proved experimentally that molecular mimicry could cause

autoimmune disease, as had been advocated and proven by Ebringer and others,

primarily via mimicry at HLA-B27. To do this, Oldstone's group chose myelin

basic protein or MBP for study, a major component of nerve sheath, because its

entire amino acid sequence is known. Also critical, the encephalitogenic site

where myelin basic protein is attacked to produce encephalitis is a recognized

sequence of 8-10 amino acids, and it has been mapped on several animal species.

Using computer-assisted analysis, they found that several viral proteins showed

similar amino acid sequences closely matching just the encephalitogenic site of

MBP in the rabbit. The closest was hepatitis B virus polymerase (or HBVP). Of

the 8-10 amino acid sequence at the encephalitogenic site of MBP, six sequential

amino acids in HBVP matched.

When rabbits were inoculated with either the 8 or the 10 amino acid

peptide fractions, both the humoral and the cellular products produced in the

rabbits' tissues and serum reacted against whole myelin basic protein. The

peptide also caused perivascular infiltrates localized to the rabbits' CNS,

similar to that produced by inoculation of whole MBP or just the MBP fragment

containing only the encephalitogenic site. The matching site was the six amino

acid sequence Tyrosine-Glycine-Serine-Leucine-Proline-Glycine. The rabbits did

not contract hepatitis, but contracted encephalitis due to mimicry.

This conclusively showed that molecular mimicry, caused by injection

of a non-homologous (not from the same species) amino acid peptide containing a

known sequence of only six amino acids matching a site on host protein could

cause both autoimmune humoral (antibody) and cellular responses, and cause

autoimmune disease itself.

Perhaps the most convincing paper to describe the mechanism of a " mimic "

involved with molecular mimicry was published by Husby, Tsuchiya, Schwimmbeck

and colleagues, (Oldstone included) in 1987. This time they found a sequence of

six amino acids, QTDRED, in Klebsiella pneumoniae nitrogenase that exactly

matched that of the HLA-B27 antigenic epitope (the actual HLA-B27 receptor

protein).

When Husby and associates used rat antiserum reactive to HLA-B27 and antiserum

to Klebsiella pneumoniae nitrogenase to stain the synovial tissue of patients

with ankylosing spondylitis or reactive arthritis, they repeatedly demonstrated

cross-reactivity: both stained the synovial tissue. The part of the HLA-B27

antigen encompassing the QTDRED sequence was strongly expressed on the synovial

joint lining cells of 11 out of 12 patients with ankylosing spondylitis, which

confirmed the impression that direct molecular mimicry was taking place at the

actual tissue level. The possibility of a six amino acid sequence being the

same in two dissimilar protein species is 1 in 620, so there is little doubt as

to the validity of this observation.

Several other investigators have demonstrated amino acid homology between

organisms and host tissue (Table 6). There is still debate as to the precise

mechanism of mimicry, such as whether a " superantigen " is involved at HLA-B27

and elsewhere, or whether mimicry is a reaction to an antibody. However, the

concept as a whole remains concrete.

A rapidly growing number of autoimmune diseases are associated with

HLA-phenotypes. Certainly HLA-B27 has been associated with ankylosing

spondylitis, reactive arthritis, autoimmune thyroiditis, " reactive " hepatitis,

inflammatory diabetes and Reiter's syndrome. HLA-DR4 has been associated with

rheumatoid arthritis. We now know that Sjogren's syndrome occurs more commonly

in patients who are HLA-B8, HLA-DR3 or HLA-DRW-52 positive; scleroderma occurs

more commonly in those who are HLA-DQ+ positive. Behcet's disease has shown to

be associated with HLA-B51.

The primary purpose of the preceding discussion is to demonstrate that there

exists a phenomenon allowing host tissue to inappropriately misidentify foreign

protein in some fashion and, as a result, mount an attack upon itself.

The T-cell, mimicry and autoimmunity

In 1993, Hermann and Yu tested CD8 T-lymphocyte clones derived from the synovial

fluid of 4 patients with reactive arthritis and 2 with ankylosing spondylitis.

CD8 cells were indeed found which killed Yersinia-infected HLA-B27 target cells

in a patient with yersinia-induced reactive arthritis. Similarly,

salmonella-induced and yersinia-induced CD8 cells from one patient with

salmonella-induced arthritis reacted with infected target cells. In 5 of the 6

patients autoreactive CD8's were found, some of which demonstrated

HLA-B27-restricted killing of uninfected cell lines.

In killing uninfected target cells - true autoimmunity - the CD8 cells may have

recognized a cross-reacting autologous peptide, created in some fashion by the

presence of infected HLA-B27 cells. By 1994, only a few of these peptides had

been identified. Since that time more possibilities have surfaced, and the more

recent concept of " frameshifting " of peptides in the MHC groove expands the

possibility of T-cell confusion by an unknown, perhaps enormous factor.

Probst and colleagues found that a urease β-subunit of Yersinia enterocolitica

produced CD8 T-lymphocyte stimulation, which added another possible peptide for

HLA-B27 mimicry. Patients with Guillian-Barre syndrome have demonstrated they

have the polypeptide (ganglioside) GQ1b, which recognizes similar epitopes on

specific Campylobacter jejuni strains of bacteria, which presents another

peptide possibility [105].

If a peptide bound by HLA-B27 were the result of molecular mimicry between host

and organism, the receptor site would be considered by the host to be " foreign " .

This could easily explain autoimmunity, or the breaking of self-tolerance, since

autoreactive cytotoxic CD8 cells could then continue to attack the HLA-peptide

reaction site and persist, despite the absence of any initial triggering agent,

such as bacteria, virus, etc.

More recent research has been conducted which has shown the

phenomenon of Th1-Th2 switching [42,76]. This is the ability, with antigenic

stimulation, of a certain type of helper T-cell (Th1) to " switch " to another

type of helper T-cell (Th2) that produces a different group of interleukins.

This may be the actual mechanism of production of the so-called T-suppressor

cell.

Even if CD8 T-cells are not fundamental to HLA-related mimicry, many

other possibilities exist. If indeed CD4 T-cells do proliferate in greater

amounts than do CD8 T-cells, it is possible that the CD4 cell is produced as

part of a defense mechanism to abrogate the effects of bacterial invasion,

rather than being directly associated with mimicry at HLA-B27, HLA-DR4 or

elsewhere.

Mimicry, the T-cell and EPD immunotherapy

In 1966, Dr. Leonard M. McEwen, an immunologist in London, England,

began development of a type of immunotherapy called Enzyme Potentiated

Desensitization (EPD). This immunotherapy has the ability to effectively

desensitize patients to a wide variety of allergens and other agents to which a

patient has somehow become allergic or " sensitized. " EPD employs several

combinations (mixtures) of various antigens which may include pollens, molds,

danders, foods, bacteria, chemicals and other antigens. The principal

differences between EPD and conventional immunotherapy is that the enzyme,

β-glucuronidase, is added to the EPD mixture immediately before the injection

is given, and the dosages used for EPD are very small.

β-glucuronidase appears to act as a lymphokine, which carries a " signal " via

dendritic cells, to regional and systemic lymph nodes. These lymph nodes are

then induced to produce T-suppressor cells, generally over a period of about

36-48 hours, which have been specifically activated by the particular allergens

administered with the β-glucuronidase.

The role the CD8 " suppressor " cells selectively enhanced by EPD are

postulated to play is to " suppress " CD4 T-cells which are " mis-calibrated " , as

these particular CD4 cells generally result in the production of allergy or

intolerance in patients.

EPD antigen mixtures are extremely dilute (approximately 10-14 to

10-6). Treatment is generally given by intradermal injection into the skin of

the forearm, and is administered every two months at first, decreasing in

frequency as time goes on. Since T-cells have a relatively long half-life, many

may survive in the circulation for several years. The accumulated total number

of " activated " or " immunized " T-cells produced by EPD treatment over time

increases with each additional injection, and the immunotherapy may often be

discontinued or decreased to very long intervals between injections (1 to 5

years or more).

EPD immunotherapy has been employed by a significant number of

physicians in the USA, Europe and a number of other countries. Several studies

have been conducted which have investigated the efficacy of EPD for various

conditions.

This author was the principal Investigator for a multi-center study

of EPD immunotherapy. Over a period of 10 years, the study group collected data

for over 10,500 patients with highly variable disorders who have received EPD.

Additional material will be published from this outcome study.

Given the knowledge that Proteus sp. and Klebsiella sp. play a major

role in the etiology of rheumatoid arthritis and ankylosing spondylitis, McEwen

developed a specific EPD bacterial antigen component, containing both Proteus

and Klebsiella, called (P/K). At my request, McEwen also has produced a

Bacteroides bacterial antigen, which I and several investigators employed in

this study.

It is rather clear that EPD works by activating a type of CD8 T-cell. Whether

this type of T-cell is the direct cellular agent that mitigates arthritis (MHC

class II), or whether it plays a role simply by suppressing activated CD4 cells

(MHC class I) makes little difference in clinical outcome.

In the EPD study it was found that when patients who had illnesses historically

associated with mimicry secondary to certain bacteria were treated with EPD (a

T-cell-based immunotherapy), most improved considerably. To me, this is in

indication that the mimicry concept is valid, and that treatment with a specific

vaccine is desirable.

When EPD became unavailable in 2002, LDA was developed for use in this country.

FDA-approved bacterial antigens are few and far between in this country, and

since LDA was now compounded, and compounding pharmacies must purchase the

material they use from FDA-approved suppliers, the bacterial antigens became

unavailable. I still compound these and treat with these antigens in my office,

for my own patients, but it is not possible to send substances like this to

other physicians. Hence I still treat rheumatoid arthritis and ankylosing

spondylitis in Santa Fe as I did with EPD. I am able to tell other physicians

how to compound these allergens for LDA themselves, if they are interested and

they are able to obtain the bacterial antigens themselves.

Conclusions

It requires little stretch of the imagination to consider that perhaps most or

all autoimmune disorders might be associated with interaction of organisms or

even other substances with the body's MHC HLA-receptors. It is possible that

any or all of these interactions could easily involve molecular mimicry.

Although of limited availability due to the relatively small numbers of

physicians who use them, LDA and EPD immunotherapy both employ the principals of

bacterial molecular mimicry to directly target T-cells and mitigate the adverse

physical effects of rheumatoid arthritis, ankylosing spondylitis and certain

types of reactive arthritis.

References: