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Date: 06/23/04 

Date: 23 Jun 2004 00:51:01 GMT

Arthritis and Rheumatism Volume 38
Number 4, April 1995, pp 458-476
1995, American College of Rheumatology

Review

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
to
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 accumulated 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 therapeutic
measures.
    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 circumvent
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
"cryptic self"...................

     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......."
________________________________

J Clin Invest, April 2001, Volume 107, Number 8, 943-944
Copyright ©2001 by the American Society for Clinical Investigation

Commentary
Infection, mimics, and autoimmune disease
Noel R. Rose
Department of Pathology and The W. Harry Feinstone Department of Molecular
Microbiology and Immunology, The Johns Hopkins Medical Institutions, 720
Rutland
Avenue, Ross 659, Baltimore, Maryland 21205, USA.
Phone: (410) 955-0330; Fax: (410) 614-3548; E-mail: nrrose@jhsph.edu.
The observation that infection can precipitate an autoimmune disease dates
back more than a century. The first human autoimmune disease described,
paroxysmal cold hemoglobulinuria, was thought of as a late consequence of
syphilis,
and rheumatic fever is still associated with preceding streptococcal infection.

In modern times, these associations have been attributed to molecular mimicry.
In its simplest form, the concept of molecular mimicry states that antigenic
determinants of infectious microorganisms resemble structures in the tissues
of the host but differ enough to be recognized as foreign by the host’s
immune
system. It is now clear that mimicry on the molecular level is a common
phenomenon; that is, many sequential and structural determinants of infectious
agents simulate epitopes of host tissues (1). But, as Mackay and I remarked
recently, "There are, as yet, no firm instances of molecular mimicry by
microorganisms serving as initiating agents of human autoimmune disease..."
(2).
Molecular mimicry in Chagas’ disease
There is probably no better candidate for investigating mimicry than the
cardiomyopathy of chronic Chagas’ disease. It afflicts about 30% of the 20
million
individuals infected with the protozoan Trypanosoma cruzi in the Americas.
The presence of a cardiac inflammatory infiltrate in apparent absence of
parasites suggests that the trypanosome initiates an autoimmune response.
Indeed, a
number of cross-reactive human antigens have been implicated by their reaction
with sera of Chagas patients. They include, for example, a 23 kDa ribosomal
protein (3), a functional epitope on the ß1 adrenergic receptor (4), a 48 kDa
protein found in neuronal axons (5), and a heptapeptide of cardiac myosin heavy

chain (6). In this issue of the JCI, Gironès and colleagues have identified
another cross-reactive antigen (Cha), a novel peptide from human cells (7).
This
peptide, which reacts with the sera of patients with chronic Chagas’ disease
and of mice infected with T. cruzi, was found in abundance in human and mouse
hearts. Cross-reaction between the mammalian and trypanosomal peptides was
documented for both T and B cells. The finding that this peptide bears both B-
and T-cell epitopes makes it a leading candidate for the induction of the
cardiomegaly of Chagas’ disease through molecular mimicry, since it would
facilitate
T/B-cell cooperation (8).
This work leaves critical questions unanswered. Some patients with Chagas’
disease develop megacolon and megaesophagus due to destruction of
parasympathetic ganglia, but Cha is not found in nervous tissue. No functional
changes were
associated with Cha-specific antibodies. On the other hand, mice immunized
with a 13 amino acid ribosomal peptide of T. cruzi produced antibodies that
caused functional changes in the heart without evidence of mononuclear
infiltration
(9). Finally, living trypanosomes induce Chagas-like lesions in the hearts of
mice, but recombinant Cha does not. Thus, the question of whether molecular
mimicry using a single, defined antigen of the parasite in the absence of
infection actually mirrors clinical autoimmune disease remains unaddressed.
Molecular mimicry abounds
Recent insights into T-cell recognition have greatly broadened the original
concept of molecular mimicry. A number of studies have shown that there is a
fair measure of flexibility in the amino acid sequence acceptable for both MHC
class II binding and for recognition by the T-cell receptor (10, 11). Clearly,
microbial peptides with relatively limited sequence homology to myelin basic
protein (MBP) can activate autoreactive T cells. Using an extensive
combinatorial peptide library, Hemmer et al. (12) described differing
recognition
profiles of individual autoreactive T-cell clones from patients with multiple
sclerosis. Li et al. (13) showed that, because of topological differences in
their
peptide finding sites, different MHC class II molecules can create different
alignments of the same bound MBP peptide, thereby creating distinct T-cell
epitopes from the same peptide. Thus, T-cell recognition is even more
degenerate
than previously anticipated, and primary amino acid sequence similarities
provide
little clue to a molecular mimic.
Further expansion of the autoimmune response probably occurs due to epitope
spreading. Vanderlugt and colleagues (14) developed a murine model of relapsing

encephalomyelitis, using an immunodominant epitope of the myelin antigen,
proteolipid protein (PLP). In the course of the disease, T-cell clones
recognizing epitopes of MBP are detected that are not present on PLP,
suggesting that
the release of endogenous antigen during the initial response can stimulate
self-reactive T cells and play a critical role in disease progression. These
data
further suggest that an unrelated infection could mobilize a self-peptide and
potentiate but not initiate an attack of autoimmune disease in a subclinically
primed individual (15). All of these findings demonstrate why it may be
difficult to identify a single organism as the etiological agent of an
autoimmune
disease.
The adjuvant effect
The experiments described above remind us that the generation of an immune
response depends upon two types of signals: antigen-specific recognition
through
the T-cell and B-cell receptors and a number of non–antigen-specific,
nonclonal signals. An infectious agent may provide the specific signal by
molecular
mimicry or by release of endogenous antigen. The inflammatory process itself
enhances the nonclonal costimulatory signals necessary to mount an immune
response. Lack of appropriate costimulatory signals may account for the
difference
between a pathogenic and a nonpathogenic autoimmune response following
infection. Our own studies with Coxsackie B3–induced (CB3-induced)
myocarditis
exemplify such a situation. In genetically susceptible A/J mice, infection with
CB3
induces autoimmune myocarditis (16). Injection of killed virus does not,
suggesting that inflammation elicited by live virus provides costimulatory
signals
that influence subsequent immune responses. Evidence expanding this view came
from experiments using less susceptible B10.A mice. If cotreated with bacterial

LPS, as well as virus or cardiac myosin, the animals develop typical
myocarditis. LPS acts through toll-like receptor 4 (TLR-4) and potently
activates the
innate immune response; particularly, it upregulates production of
inflammatory cytokines such as IL-1 and TNF-. Administration of either of these
two
cytokines converts a less susceptible to a more susceptible mouse. Furthermore,
the
production of autoimmune myocarditis in the susceptible mouse strain could be
delayed or abrogated by administration of inhibitors of either of these two
cytokines.
These results point to the importance of the inflammatory response itself in
the generation of an autoimmune disease. They emphasize that an infectious
microorganism may play two roles in the induction of disease (Figure 1). The
first is to provide the requisite antigenic signal. This may come through
molecular mimicry or through the release of excessive amounts of self-antigen
from
tissue cells during the infectious process. The second role of the infectious
agent is to provide the adjuvant milieu in the form of upregulation of
costimulatory molecules and other products of inflammation. The activation of
antigen-presenting cells during microbial infection upregulates costimulatory
molecules
and secretion of inflammatory cytokines (17), thereby reducing the threshold
needed for activation of T cells by the antigenic signal. This effect, which
may promote protective immunity and thus benefit the host, may also prove be
detrimental when it increases susceptibility to damaging autoimmune responses.
 
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