"Catching heart disease": Antigenic mimicry and bacterial
infections
Kurt Bachmaier, Jenny Le
& Josef M. Penninger
Amgen Institute, Ontario Cancer Institute Depts of
Medical Biophysics and Immunology University of Toronto, 620
University Avenue, Toronto, Ontario, Canada
M5G 2C1 kurtb@amgen.com
To the editor
Supporters of the "new germ theory" argue that common human
diseases are caused by infectious agents. Cardiovascular disease is predicted
to be the commonest cause of death worldwide by the year 2020. Half of heart
disease patients lack established risk factors, but epidemiological
evidence pointed to a linkage between infection with Chlamydia bacteria and
heart disease1. We have previously shown that Chlamydia-mediated
heart disease in mice can be induced by antigenic mimicry of a heart muscle-specific
protein, and thus provided a molecular link between Chlamydia infections and
heart disease2. However, studies designed to reveal a correlation
between future risk of heart disease and Chlamydia infection have been inconclusive3,
4. While these results mitigate against the "infection hypothesis",
they are not surprising if organisms other than Chlamydia also supply mimicking
epitopes.
We screened public databases for proteins sharing the pathogenic mouse
M7A peptide MA'ST motif (see Table 1).
This motif is found in proteins from a multitude of viruses, bacteria, fungi
and protozoa. We therefore limited our in vivo experiments to microorganisms
both possessing the motif and implicated in heart disease (see
Table 1): Borrelia burgdorferi, the spirochete causing Lyme
disease; Treponema pallidum, the causative agent of syphilis; Mycoplasma
pneumoniae, an etiologic agent of non-viral primary atypical pneumonia;
Mycoplasma genitalium, associated with urogenital infection; and Helicobacter
pylori, associated with duodenal and gastric ulcers; as well as the protozoon
Trypanosoma cruzi, the cause of Chagas disease. BALB/c mice were immunized
with the peptides listed in Table 1 as described2. Remarkably, 5 out of the 9 microbial peptides examined induced
inflammatory heart disease, albeit less severe than the endogenous heart-specific
pathogenic peptide M7A (Table 1). Peptides
derived from Borrelia burgdorferi (Fig. 1a),
Treponema pallidum (Fig. 1b), Mycoplasma
pneumoniae, and Mycoplasma genitalium induced inflammatory heart
disease whereas peptides from Helicobacter pylori, and Trypanosoma
cruzi, although it contained the MA'ST motif, failed to induce disease
(Table 1). The latter may be explained by the fact
that the T cell antigen receptor recognizes the tertiary structures of peptides
in the context of MHC molecules, and amino acids outside of the MA'ST
motif can change both antigen presentation and T cell activation. Inflammatory
heart disease is accompanied by T cell-dependent production of autoantibodies
to cardiac epitopes and immunization of mice with the endogenous M7A
peptide leads to the production of anti-M7A serum antibodies2.
Induction of inflammatory heart disease by the microbial peptides examined
in this study was also characterized by the production of serum autoantibodies
reactive to M7A (Table 1). It should be noted
that production of antibodies to endogenous heart muscle and mimicking bacterial
peptides strictly depends on antigen specific T cells. These T cell responses
need to be tested. Thus, immunization with peptides derived from diverse bacteria
leads to the breaking of immunotolerance towards a defined heart-specific
epitope, the activation of autoaggressive T and B lymphocytes, the production
of autoantibodies and histopathological changes within the heart muscle and
heart blood vessels.
Figure 1. Histopathology of inflammatory heart disease.
Infiltration of mainly mononuclear inflammatory cells and perivascular
fibrotic changes, in hearts from a mouse immunized with a Borrelia burgdorferi
(a) derived peptide or with a Treponema pallidum (
b) derived peptide. H.&E. staining. Magnifications 100
Table 1. Sequence alignment of microbial peptides with the pathogenic mouse
M7A and the non-pathogenic M7A peptides. Prevalence, severity
of inflammatory heart disease, and autoantibody titers in mice immunized with
indicated peptides.
Our results imply that pathogenic motifs mimicking heart epitopes are prevalent
in diverse bacteria. Interestingly, Borrelia burgdorferi, Treponema
pallidum and Chlamydia trachomatis, all of which can provide epitopes
mimicking heart-specific proteins, were discovered in specimen collected from
the subgingival flora of an apparently healthy 39-year old male5.
The immune system's response to a mimicking epitope depends on the genetic
background of the host explaining why not all of us develop cardiovascular
disease. Murine and human M7A epitopes are evolutionary conserved and
human MHC class II molecules and human heart muscle-specific autoantigens
such as M7A can cause inflammatory heart disease6. Our
finding of broad distribution of a pathogenic peptide motif may explain inconclusive
epidemiology and antibiotic treatment trials4. Antigenic mimicry
as a pathogenic mechanism supports the "infection hypothesis"
in the development of heart disease and has important implications on therapeutic
strategies and vaccine design for heart disease in the future.
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