The Role of Periodontal Disease and Other Infections in the Pathogenesis of Atherosclerosis and Systemic Diseases



Cardiovascular disease is predicted to be the most common cause of death worldwide by the year 2020. Half of heart disease patients lack established risk factors such as elevated lipids, hypertension, tobacco abuse, and positive family history. Additionally, these risk factors are generally associated with the disease, and the exact mechanism by which they may contribute to the development of atherosclerosis is not clear.[ 1-3] However, previous and recent studies point to a linkage between infection with different bacteria and heart disease in the other 50% of observed incidences. Moreover, pathogenesis of the disease induced by infectious agents is described by three different mechanisms of action: induction of inflammation, release of toxins or superantigens, and molecular mimicry or cross-reactivity. This may result in plaque formation or antimyosin cellular and humoral immunity and subsequently, to myocarditis or other autoimmune diseases.[ 4-5]

Infectious Agents

Through the years many reports have incriminated various infectious agents in the pathogenesis of autoimmune disease. Beta-hemolytic streptococcus has been implicated in rheumatic fever, Epstein-Barr virus in rheumatoid arthritis, Coxsackie virus B4 in diabetes, Herpes type-6 and measles virus in multiple sclerosis, cytomegalovirus, chlamydia pneumoniae and many other infectious agents in coronary artery disease.[ 6-19]

In addition, evidence has accumulated to suggest that chronic dental infection may be another factor for the development of atherosclerotic heart disease. Patients with poor dentition, especially those with periodontal disease are noted to have frequent recurrent episodes of bacteremia.[ 20] The infectious agents involved are usually anaerobic proteolytic bacteria. These studies indicate that the most common strain of bacteria in dental plaque may cause blood clots. When blood clots escape into the bloodstream, they may increase the risk of heart attack and other heart illnesses. The plausible cause was further strengthened by the study of Dr. Beck and his associates published in The Journal of Periodontology, October 1996.[ 21]

In this study, the severity of periodontal disease during a three-year period in the 1970's was determined in 1147 men who were followed for 20 years. For those men with significant periodontal disease, the odds ratios for fatal coronary disease or stroke were 1.9 and 2.8, respectively.

An association between periodontal disease and atherosclerotic or thrombotic events could arise from underlying inflammatory response or prothrombotic traits that place some people at high risk for both periodontal disease and atherosclerosis or thrombosis. It may also be that the chronic inflammation induced by the periodontal disease contributes to the pathogenesis of atherosclerosis.[ 3, 21, 22]

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Mechanisms by Which Infectious Agents Induce Atherosclerosis and Other Diseases

Traditionally, it is assumed that infectious agents induce disease by direct tissue damage via secretion of toxins or different antigens, particularly myosin. These toxins directly or indirectly (via cytokines) may induce tissue damage and cause release of tissue antigens.[ 3-5] The presentation of self-tissue antigens (myosin) to T-Helper cells may result in T-Helper 1 response (cell mediated immunity) or in T-Helper 2 response (humoral immunity) against myosin in the form of IgG and IgM antibodies. This cellular and humoral immune attack to the self tissue (myosin) may result in autoimmune condition, such as myocarditis. (Figure 1)

How Bacteria or Virus Could Set the Stage for Myocarditis or Heart Attack

Additional studies have approached the pathogenesis of vascular disease from the inflammatory component caused by infectious agents. This is based on the fact that patients with acute myocardial infarction have long been recognized to have a high plasma concentration or count of markers of inflammation, such as an erythrocyte sedimentation rate, C-reactive protein, fibrinogen or white blood cell count.[ 3]

This mechanism of action, illustrating how bacteria or virus could set the stage for heart attack, is shown in Figure 1, as well. This figure shows how an infectious agent from diseased gums or the lungs can be taken up by macrophages and transferred to the bloodstream and arteries. When a macrophage burrows into the wall of a blood vessel to gobble up irritants such as LDL and oxidized LDL, it transfers the infectious agent(s) into the neighboring arterial cells. Infected arterial cells then attract more macrophages and other inflammatory responses, such as platelets, and then die. As a result, anti-platelet and endothelial cell antibodies are produced. If this vicious cycle of inflammation continues, it can result in fibrous lesions or plaque formation. When pieces of the plaque break loose, they can start blood clots and cause heart attack.[ 1-5]

These findings have direct relevance to the diagnosis and treatment of the many human diseases in which a microbial infection is linked. In fact, very recently, the American College of Cardiology issued a list of harmful pathogens as possible bacterial links in the disease process for heart and vascular failure. These pathogens may induce their pathologic responses through one of the above-mentioned mechanisms of action or by sharing mimicking epitope with pathogenic peptides. (Figure 2)

Possible Mechanisms of Triggering Autoimmune Response by Environmental Agents

Molecular mimicry is defined as structural similarity between antigens coded by different genes. Molecular mimicry has long been implicated as a mechanism by which microbes can induce autoimmunity. The best-known example of molecular mimicry and autoimmunity is rheumatic fever, in which antigenic cross-reactivity between cardiac tissue and streptococcal polysaccharides is believed to induce an autoimmune reaction targeted at the heart valves.[ 6] Antigenic similarity between infectious agents and host cell proteins is common, and in one analysis of 600 monoclonal antibodies raised against a large variety of viruses, it is found that 4% of the monoclonal antibodies cross-reacted with host determinants expressed in uninfected tissues. The clinical importance of molecular mimicry between mycobacteria and self-antigen was highlighted by the observation that patients treated with Bacillus Calmette Guerin immunotherapy developed arthritis. Furthermore, anti-DNA antibodies were shown to have amino acid sequence homology with anti-Klebsiella pneumonia antibody. Anti-DNA idiotype has also been found in the serum of patients with the parasitic infections filariasis and schistomsomiasis.[ 23-32]

Mice infected with reovirus type 1 developed an autoimmune polyendocrinopathy and generated a panel of autoantibodies directed against normal pancreas, pituitary, and gastric mucosa, suggesting an antigenic similarity between a reoviral antigen and an endocrine tissue antigen. Also molecular mimicry has been reported between Yersinia enterocolitica and thyroid stimulating hormone receptor, based on the observed cross-reaction between sera from Yersinia and Grave's patients.

Another finding suggesting a possible role for molecular mimicry in Autoimmune Thyroid Disease was that 42% of sera from lepromatous leprosy patients contained anti-thyroglobulin anti-bodies compared to 3% in the controls.[ 33]

Recently, molecular mimicry or immunological cross-reaction between Candida albicans and human tissue was demonstrated in our laboratory. The cross-reaction between C. albicans and mammalian tissues was shown by electrophoresis immunodiffusion, Western blot and immunoabsorption assays. The results of immunodiffusion showed a clear precipitation line against tissue antigens when rabbit anti-Candida or human positive anti Candida serum was used. Similarly, Western blot assays with rabbit or human anti Candida sera showed several positive bands with Candida and one or two positive bands with different tissues. The common antigens were located in the regions of 72 and 36 KD. The 72 KD was detected in capsule antigens, placenta, ovary, adrenal, thymus, liver, pancreas, spleen, brain and kidney, but not in sperm or epithelial cell antigens. The 36 KD antigen was positive in placenta, spleen adrenal, pancreas and capsule tissues. Moreover, the rabbit anti Candida reacted with several food antigens including wheat, soy and walnut, indicating clear cross reactivity between Candida and food antigens.[ 33, 35]

These findings resulted in the United States Patent Number 5,707,816, which was awarded to Dr. Aristo Vojdani and Immunosciences Lab, in January 1998. This action or fingerprint of human tissue antigen(s) is found in proteins from a multitude of viruses, bacteria, fungi and protozoa including those shown in Table 1.

Bacteria or Protozoa, which share similar antigens with human tissue and may induce cardiovascular disease

Due to these immunological reactions, both in animal models as well as in human blood, high levels of IgG antibodies against bacterial antigens and pathogenic peptides, for example myosin, are detected. In a recent study reported at The American College of Cardiology, in 890 blood samples, levels of IgG antibodies against some of these bacteria or viruses were significantly higher in 167 patients who later suffered a heart attack or cardiovascular death. We confirmed these findings by examining 500 blood specimens from patients with cardiovascular disease and compared them to 500 blood samples of healthy controls. We subsequently found that 33% and 22% of patients versus 9% and 3% of control subjects, respectively, had significant elevations in IgG and 3 antibodies against cardiac myosin and pathogens involved in periodontal and/or cardiovascular disease.


In inflammatory heart disease of patients without established risk factors, infectious agents play a crucial role.

Inflammatory heart disease is developed by three different mechanisms, including the T-cell dependent production of autoantibodies against cardiac epitope (i.e., myosin) found in many infectious agents.

Early detection of these antibodies against cardiac and pathogenic epitopes is the best indicator of the involvement of infectious agents and inflammation in the subpopulation of patients with cardiovascular disease.

Detection of IgG or IgM antibodies against antigens of infectious agents should be used for the determination of the presence of potentially pathogenic organisms.

Early intervention and eradication of these microorganisms from the oral cavity, lungs and blood with antibiotic use may improve clinical conditions and quality of life for patients with cardiovascular disease.


Aristo Vojdani, PhD, MT Immunosciences Lab, Inc. 8730 Wilshire Bird, Suite 305 Beverly Hills, California 90211 USA 310-657-1077 / 800-950-4686 Fax 310-657-1053 Email: Website:

1. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attack? Annals of Internal Medicine 130:933-937, 1999.

2. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. The New England Journal of Medicine 342:836-843, 2000.

3. Muhlestein JB. Chronic infection and coronary artery disease. Science & Medicine, Nov/Dec 16-25, 1998.

4. Horwitz MS, La Cave A, Fine C, Rodriguez E, IIic A, Sarvetnick N. Pancreatic expression of interferon-y protects mice from lethal coxsackie virus B3 infection and subsequent myocarditis. Nature Medicine 6:693-697, 2000.

5. Bachmaier K, Le J, Penninger JM. Catching heart disease: Antigenic mimicry and bacterial infections. Nature Medicine 6:841-842, 2000.

6. Williams RC. Molecular mimicry and rheumatic fever Clin Rheum Dis 11:573-590, 1985.

7. Fujinami RS, Oldstone MBA, Wroblewska Z, Frankel ME, Koprowski H. Molecular mimicry in virus infection: Cross-reaction of measles virus phosphoprotein or of herpes simplex virus protein with human intermediate filaments. Proc Main Acad Sci USA 80:2346-2350, 1983.

8. Fujinami RS, Oldstone MBA. Amino acid homology and immune responses between the encephalitogenic site of myelin basic protein and virus: a mechanism for autoimmunity. Science 230:1043-1045, 1983.

9. Haspel MV, Onodera T, Prabhakar BS, Horita M, Suzuki H, Notkins AL. Virus-induced autoimmunity: monoclonal antibodies that react with endocrine tissues, Science 220:304-306, 1983.

10. Benedict, EP, Barrett T, and McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci USA 80:6386-6389, 1983,

11. Melnick JL, Petrie BL, Dreesman GR, Burek JM, McCollum CH, De Bakey ME. Cytomegalovirus antigen within human arterial smooth muscle cells, Lancet 2:644-7, 1983.

12. Nikoskelainen y, Kalliomaki YL, Lapinleimu K, Stenvik M, Halonen PE. Coxsackie B virus antibodies in myocardial infraction. Acta Med Scand 214 :29-32, 1983.

13. Adam E, Melnick JL, Probtsfield JL, Petric BL, Burek J, Bailey KB, MCollum CH, and De Bakey ME. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet ii:291-293, 1987.

14. Speir E, Modali R, Huang E, Leon MB, Shawl F, Finckel T, Epstein SE, Potential role of human cytomegalovirus and P53 interaction in coronary restenosis. Science 265:391-394, 1994.

15. Visser MR and Vercellotti CM. Herpes simplex virus and atherosclerosis. Eur Heart J 14(Suppl. K):39-42, 1993.

16. Linnanmaki E, Leinonen M, Mattila K, Valtonen V, Saikku P. Chlamydia pneumoniae-specific circulating immune complexes in patients with chronic coronary heart disease. Circulation 87:1130-1134, 1993.

17. Saikku P, Leinonen M, Mattila K, Ekman MR, Neiminen MS, Makela PH, Hutunen JK, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with coronary heart disease and acute myocardial infraction. Lancet ii:983-986, 1988.

18. Saikku P, Leinonen M, Tenkanen L, Ekman Linnanmarki E, Manninen V, Manttari M, Frick MM, and Huttunen JK. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Am Intern Med 116;273-278, 1992.

19. Vojdani A, Magaziner A, Rogers JT Detection o Chlamydia pneumoniae infection in patients with atherosclerosis by PCR and enzyme immunoassay, presented at Microbial Linked Diseases: Shifting the Pathogenic Paradigm June 1998, San Diego California.

20. Olsvik B, Olsen J, Tenover FC. Detection of tet(M) and tet(O) using the polymerase chain reaction in bacteria isolated from patients with periodontal disease. Oral Microbiology and Immunology 10:87-92, 1995

21. James Beck et al., Journal of Periodontology 67:1123-1137, October 1996 [Periodontal disease.]

22. Kroes I, Lepp PW, and Relman DA. Bacterial diversity within the human subgingival crevice. Proc Natl Acad Sci USA 96:14547-14552, 1999

23. Elias D, Markovits D, Reshet T, Van der Cohen IR. Induction and therapy of autoimmune diabetes in the non-obese diabetic , mouse by a 65-kDa heat shock protein, Proc Natl Acad Sci USA 87:1576-1580, 1990.

24. El-Roeiy A, Gross WL, Ludermann J, Isenberg DA, Shoenfeld Y. Preferential secretion of a common anti-DNA idiotype (16/6 Id) and anti-polynucleotide antibodies by normal mononuclear cells following stimulation with Klebsiella pneumoniae. Immune Left 121:313-319, 1986.

25. Abu-Shakra M, Shoenfeld Y. Parasitic infection and autoimmunity. Autoimmunity 9:337-344 1991.

26. Rose NR, and Mackay IR. Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci 57:542-551, 2000.

27. Albert LJ, and Inman RD. Molecular mimicry and autoimmunity. N. Engl. J. Med. 341:2068-2074, 1999.

28. Backmaier K et al. Chlamydia infections and head disease linked through antigenic mimicry. Science 283:1335-1339, 1999.

29. Hughes RA, Allard SA, Maini RN, Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder. Ann Rheum Dis 43:432-434, 1989.

30. Laitinen O, Leirisaio M, Skylv G. Relation between HLA-B27 and clinical features in patients with Yersinia arthritis. Arthritis Rheum 20:1121-1124, 1997.

31. Thomas M, Grampton G, Isenberg D, Shoenfeld Y, Akissola A, Ramzy M, Lillywhite J, Williams DA. A common anti-DNA antibody idiotype and anti-phospholipid antibodies in sere from patients with schistosomiasis and filariasis with and without nephritis. J Autoimmunity 2:803-811, 1989.

32. Tolvanen A, Granfors K, Lathesmaa-Rantala R, Leino R, Stahlberg T, Vuento B, Pathogenesis of Yersinia-triggered reactive arthritis: immunological, micro-biological and clinical aspects. Immunol Rev 86:47-70, 1985.

33. Cox SP, Phillips DIW, Osmond C. Does infection initiate Graves' disease? A population based 10-year study. Autoimmunity 4:43-49, 1989.

34. Vojdani A, Rahimian P. Immunological cross-reactivity between Candida albicans and human tissue J Clin Lab Immunology. 48:1-15, 1996.

35. Vojdani A. Immunological cross-reactivity between Candida albicans and human tissue or food antigens United States Patent #5,707,816. Awarded January 13, 1998.


By Aristo Vojdani

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