20th June 17:52
The Role of the Immune Response to Microbial Pathogens (tuberculosis ankylosing spondylitis kidney cornea multiple sclerosis)
Arthritis and Rheumatism Volume 38
Number 4, April 1995, pp 458-476
1995, American College of Rheumatology
Mechanisms of Autoimmune Disease Induction
The Role of the Immune Response to Microbial Pathogens
Samuel Behar and Steven Porcelli
Autoimmune diseases are clinical SYNDROMES in which tissue damage appears
result from aberrant responses of the immune system to normal self antigens.
Many well-recognized conditions, including a majority of the systemic rheumatic
disorders, are currently grouped in this etiologic category. The central
mechanism of these diseases is thought ot be a defect in immunologic tolerance,
resulting in the activation and expansion of self antigen-specific T and B
lymphocyte clones and the production of circulating inflammatory mediators.
Although much information has ac***ulated concerning the detailed
immunopathology of autoimmune diseases, it is still not known what causes them.
Our failure to understand the events triggering these diseases a SERIOUS
obstacle to the development of more effective preventative or the****utic
The idea that microbial pathogens species, including bacteria, viruses, and
parasites, may represent the major enviornmental factors that initiate and
sustain anti-self immune responses continues to exert a powerful influence on
autoimmune disease research. This idea arises naturally from the obvious fact
that THE IMMUNE SYSTEM HAS EVOLVED MAINLY TO RECOGNIZE AND RESPOND TO MICROBIAL
PATHOGENS. Unlike the conceptually staightforward role of microbial organisms
in infectious diseases, the mechanisms by which these agents may cir***vent
immunologic tolerance to self antigens and trigger autoimmune disease remains
difficult to fathom. In this article we summarize some of the areas of current
research that may eventually clarify the mechanisms by which infectious agents
could act as the inciting agents of autoimmune diseases..................
Although conceptually staightforward, the importance of molecular mimicry
in the actual pathogenesis of autoimmune disease is still debated. This
hypothesis seems to provide a plausible explanation for inflammatory conditions
associated with autoimmune responses that occur in the setting or recent prior
infection by a distinct microrganism, such as the nonsuppurative sequelae of
group A streptococcal infections (i.e., rheumatic fever or glomerulonepheritis)
or epidemic Reiter's syndrome and reactive arthritis. Nevertheless, it must be
conceded that in spite of considerable research on a variety of diseases and
disease models, NO EXAMPLE OF AN INFECTIOUS PROCESS TRIGGERING AUTOIMMUNITY
THROUGH A MECHANISM BASED ON MOLECULAR MIMICRY HAS YET BEEN CONCLUSIVELY
DEMONSTRATED. FURTHERMORE, THE MODEL AS IT CURRENTLY STANDS LEAVES UNANSWERED A
NUMBER OF IMPORTANT QUESTIONS. Autoimmune disease models based on molecularly
mimicry PRESUPPOSE THAT AUTOREACTIVE T CELLS EXIST PRIOR TO AUTOIMMUNE DISEASE
induction but are maintained in a nonresponsive state of "anergy" or
"ignorance." Although this does appear to be the case.....it is necessary to
explain why these T cells escape the major mechanism of tolerance induction by
thymic deletion of autoreactive T cells, and also how they are normally
maintained in a silent state. Futhermore, models of autoimmune disease
initiated by infectious agents must explain how the autoimmune state is
sustained after the apparent disappearance of the inciting agent, leading to
the chronic or relapsing clinical course of many autoimmune syndromes.
Refining the molecular mimicry hypothesis: new insights from animal models
of autoimmunity. Many excellent animal models have been developed that support
the idea that under appropriate experimental conditions, immunization by
proteins with similarity to self antigens can stimulate an immune response that
ultimately leads to autoimmune disease. Most of these models, several of which
are summarized in Table 1, involve the hyperimmunization of genetically
susceptible animals with foreign
proteins that are homologous to tissue-specific self proteins. ALTHOUGH
STRICTLY SPEAKING THIS IS NOT MOLECULAR MIMICRY (which involves immunization
by nonhomologous microbial antigens that stucturally resemble unrelated
antigens of the host), the mechanism leading to autoimmune disease induction in
such models is generally believed to parallel that which comes into play during
molecular mimcry of a self antigen by an infecting microorganism. A NOTEWORTHY
FEATURE of most of these models is the REQUIREMENT FOR COADMINISTRATION OF
MICROBIAL PRODUCTS (usually Freund's complete adjuvant, an emulsion of heat
killed Mycobacterium tuberculosis suspended in an oil base) TO EFFICIENTLY
STIMULATE THE ANTI-SELF RESPONSE. The precise role these bacterial adjuvants in
such animal models and in immunologic research in general often receives
relatively little attention, promoting one noted expert to refer to this as
"THE IMMUNOLOGIST'S DIRTY LITTLE SECRET" 10.[Janeway CA, jr.: Approaching the
asymptote? Evolution and revolution in immunology . Cold Spring Harb Symp.
Quant Biol 54:1-13, 1989.] Although a few animal models in which autoimmunity
appears to follow a more natural form of immunization (e.g.; coxsackievirus
myocarditis in mice) also exist, the role of molecular mimicry in these models
is less well established.
An important concept that has recently emerged primarily from studies of
these animal models is that of the existence of an extensive repertoire of self
antigens that is normally not accessible to the immune system, but becomes so
upon induction of an inflammatory response directed against self antigens.
Earlier versions of this idea focused on "immunologically privileged" or
"sequestered" sites, i.e., anatomic locations that were not accessible to the
immune system because of avascularity (e.g., the cornea) or because of anatomic
barriers (e.g., Bowman's capsule in the kidney, and possibly some or all of the
central nervous system). More recently it has been recognized that ANTIGENS
EXIST IN ALL ANATOMIC SITES THAT ARE NORMALLY NOT RECOGNIZED BY THE IMMUNE
SYTEM because antigen-presenting cells do not normally process and present
them efficiently for recognition by T-cells. These self antigens that are not
normally perceived by the immune system are collectively referred to as
A variety of other mechanisms by which microbial infection could alter
antigen processing and presentation to promote cryptic self recognition have
been suggested, some of which are summarized in Table 2.........Experimental
evidence for most of these is only rudimentary at present, and it remains to be
determined which, if any, are actually relevant to the generation of
autoimmunity. IT IS NOTEWORTHY, HOWEVER, THAT SOME OF THE STUDIES SUGGEST THAT
SUBSTANCES DERIVED FROM PATHOGENIC BACTERIA OR EVEN NORMAL BODY FLORA MIGHT
AUGMENT THE PRESENTATION OF CRYPTIC SELF, LEADING TO THE ACTIVATION OF
PREVIOUSLY IGNORANT AUTOAGGRESSIVE T CELLS. An impressive example of this is
seen in a transgenic mouse
line that spontaneously develops experimental allergic incephalomyelitis (EAE),
an inflammatory demyelinating condition that has been widely studies as a model
for human multiple sclerosis (MS). Transgenic mice in which the vast majority
of T cells express an antigen receptor specific for the central nervous system
(CNS) self antigen myelin basic protein (MPB) were constructed. EAE was
observed to spontaneously develop in these mice if they were bred and housed in
nonsterile facility, but NOT if they were bred and maintained in a STERILE,
specific pathogen-free facility. THIS SUGGESTED THAT THE PRESENTATION OF MBP
LEADING TO ACTIVATION OF TRANSGENIC T CELLS WAS SOMEHOW AUGUMENTED BY
COLONIZATION OF THE ANIMALS WITH NORMAL MICROBIAL FLORA, OR PERHAPS BY CONTACT
WITH UBIQUITOUS PATHOGENS. In support of this idea, injection of these mice
with several different bacterial products, including pertussis toxin and
lipopolysaccharide, also led to an increased frequency of spontaneous
development of EAE.
The manner in which these and possibly other bacterial products lead to the
overt disruption of tolerance in these animals is not yet known, but might
involve an up-regulation of antigen presentation and the enhanced display of a
previously cryptic MBP epitope. Interestingly it has recently been reported
that among HLA-B27 transgenic rats that develop a spontaneous arthropathy with
other associated pathologic features similar to those of human Reiter's
syndrome and ankylosing spondylitis, clinical disease and pathologic changes
are greatly attenuated in animals bred and maintained in sterile, germfree
conditions. This suggests that AUTOIMMUNE DISEASE INDUCTION IN THESE ANIMALS
MAY ALSO BE TRIGGERED BY PRODUCTS OF UBIQUITOUS MICROBIAL FLORA......."
26th June 07:51
The Role of the Immune Response to Microbial Pathogens (panic autoimmune)
Good stuff! A couple of years ago, at a Cape Cod Conference on Chronic
Ilness, I ran into a woman who was a participant in the Klempner Tufts
study. The study had been stopped, and she and the others were told
"its all autoimmune". She was close to panic: really left dangling.
Has Rheumatolgy EVER identified a specifc molecule, or its mimic
antibody that attacks both. In anything, not just Lyme. It seems to me
that most of their bio-babble involves measures of inflamation or
tissue destruction that could equally well be explaned by infection.
But failing to find evidence of infection, they make the grand leap
to "its all autoimmune" without a shed of concrete evidence of any
specific self-attacking antibody. Its like its a ghost, but hey thats
I'll admit I'm no bio-person, so I could be way way off base. If so, I
I will be corrected.
28th June 19:39
The Role of the Immune Response to Microbial Pathogens
No one said that infection didn't precede autoimmunity. That is the
standard rheumatologist theory of autoimmunity.
Obviously you didn't read this article before commenting (not
surprising since you offer opinions without basing them on any facts
What these guys are saying is that instead of the molecular mimicry
theory that you are endorsing, there is persisting infection causing
Lisa you just agreed with Allen Steere and Len Sigal. But you're too
dense to realize it.
Next time try reading first and opining later. Instead of the shoot
first and shoot again later approach that you're so fond of.
28th June 19:40
The Role of the Immune Response to Microbial Pathogens (lupus)
You're out of your flaming skull.
Where does the "standard rheumatologist theory" say that lupus, MS etc are
caused by an infection?
Orthodox thinking says:
"We don't know why people's immune systems turn on their own tissue."
I am sure the offensive bioweapons merchant here and his crazy lawyer sidekick
("Anna") can help us with that puzzle.