"Catching heart disease": Antigenic mimicry and bacterial infections

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 Full Figure and legend (111K)

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. Full Table

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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1. Saikku, P. et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2, 983–986 (1988). | Article | PubMed  | ISI | ChemPort |
2. Bachmaier, K. et al. Chlamydia infections and heart disease linked through antigenic mimicry. Science. 283, 1335–1339 (1999). | Article | PubMed  | ISI | ChemPort |
3. Ridker, P.M., Kundsin, R.B., Stampfer, M.J., Poulin, S. & Hennekens, C.H. Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 99, 1161–1164 (1999). | PubMed  | ISI | ChemPort |
4. Anderson, J.L. et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study [see comments]. Circulation 99, 1540–1547 (1999). | ChemPort |
5. Kroes, I., Lepp, P.W. & Relman, D.A. Bacterial diversity within the human subgingival crevice. Proc Natl Acad Sci U.S.A. 96, 14547–14552 (1999). | Article | PubMed  | ChemPort |
6. Bachmaier, K. et al. Generation of humanized mice susceptible to peptide-induced inflammatory heart disease. Circulation. 99, 1885–1891 (1999). | PubMed  | ISI | ChemPort |

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