Significance

It is now clear that many microbes share antigenic determinants not only with other microbes but also with a variety of human tissues. Cross-reactions between streptococci and heart tissue, E. coli antigens and colonic antigens, HLA-B27 and shigella antigens, gram-negative bacteria and blood groups are but a few examples of these cross-reactions seen in nature. The majority of these cross-reactions are generally harmless and may serve the purpose of protecting humans against a wide variety of microbes which might be pathogenic. However the combination of the right microbe infecting the genetically susceptible host may result in serious autoimmune consequences.

As indicated above, perhaps the two best examples of microbially induced autoimmune cardiomyopathies are RF and Chagas disease. Here the cross-reactions between host and relevant target organs have been well defined; there is an abnormal host cellular and humoral response to tissue and microbial antigens. Further, in RF, there appears to be a genetic predisposition to the disease. Whether this genetic predisposition allows for breakage of tolerance on the part of the host, an abnormal response to the specific cross-reactive determinant or production of anti-idiotypic antibodies bearing the cross-reactive epitopes is unknown and will require further investigation.

In terms of the immune response of the host, it is becoming increasingly apparent that the cellular response to cross-reactive antigens may play a more significant role in the observed pathological damage then previously thought. In both rheumatic fever and Chagas disease, T cells are specifically cytotoxic for the target organ and the addition of antibody does not enhance the cytotoxicity, suggesting a more crucial role for cellular immunity in the disease process. Similar studies of experimental models of autoimmune heart disease point to the same conclusion. To date, these studies have not been done in either the PPS syndrome of the idiopathic cardiomyopathies.

In more general terms, what is the significance of heart-reactive antibodies in these disease states? It is well-known that organ-specific antibodies increase with age; appear in a variety of other disease states (e.g. systemic lupus erythematosus, RA) and in many instances do not appear to cause damage. Even for rheumatic fever and Chagas disease, is it a question of the 'chicken or the egg'?

In other words, are these cross-reactive antibodies directly involved in the disease process or are they merely a reflection of prior heart damage and a fortuitous cross-reaction with a given microbe? The evidence in rheumatic fever suggests the latter concept is not true since these heart-reactive antibodies are absorbed by both streptococcal and cardiac antigens while heart-reactive antibodies in PPS are absorbed only by cardiac tissue. Thus in RF the heart-specific antibody appears to relate to the infection whereas in PPS the antibody appears to relate to tissue damage.

Whether or not these heart-reactive antibodies (from whatever origin) play a direct role in the disease process is difficult to ascertain with certainty. They do correlate with the disease state and disappear during convalescence; they are seen in the pathological tissue specimens but they do not apparently kill target organ cells or enhance specific cellular cytotoxicity in vitro. Perhaps complement activation and/or other factors are needed in situ to produce the observed immunoglobulin staining seen in the lesions of several cardiomyopathies. To our knowledge, these experiments have not been attempted in vitro.

What is becoming increasingly clear, not only in cardiac autoimmunity but also in other autoimmune diseases such as rheumatic arthritis, is that cellular activation specific for a given target tissue appears to be important in the pathogenesis of disease. Cytotoxic T cells specific for cardiac myofibers are seen in both rheumatic fever and Chagas' disease, and it is our impression they may be important in the pathogenesis of other cardiomyopathies as well. Obviously, it will be important to define the exact nature of the cross-reactive epitopes recognized by these active cells and their role in causing cytotoxicity to human tissue.

Finally, the specific mechanisms operating in the interaction between host genetic factors and environment resulting in the induction of autoimmune disease of the heart is still not clear. In rheumatic fever there appears to be a marker called D8/17 which is inherited in an autosomal fashion and is preferentially increased in the B cells of rheumatic fever patients. However it is well-known that not all strains of group A streptococci cause rheumatic fever, even in the genetically susceptible individual. The most plausible explanation for this discrepancy is that only certain strains exhibit the epitopes that activate the immune system to produce tissue cross-reactive antibodies and activated T cells. Then, only in the context of the immune response (a heightened response, break in tolerance, etc.) will the disease occur. A similar mechanism can be postulated for the other cardiomyopathies, as it appears that only select individuals will develop progressive autoimmune disease following active infection. Future studies of each of the cardiopathies mentioned above should concentrate not only on the immune response of the host to a given cross-reactive antigen (either in the microbe or host) but should examine more carefully whether or not a particular microbe exhibits a specific epitope.

Obviously the field is ripe for applying the modern tools of molecular biology to the study of these intriguing host-microbial relationships in cardiac disease.

See also: Autoimmune diseases; Autoimmunity; Chagas' disease; Circulatory system infections; Molecular mimicry; Streptococcus, infection and immunity; Trypanosomiasis, African.

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