Animal Models of Rheumatic Fever
Although investigators over the past sixty to seventy years have tried to understand the pathogenetic mechanisms involved in the initiation and progression of ARF, to date we still do not have a clear picture of the factors involved in the microbe-host relationship.
The most significant drawback to our understanding is that the relation-ship of the group A streptococcus to this disease is primarily human, and animal models have not been helpful to date. These have involved (1) whether persistent and sub-clinical infection by the organism was a factor, (2) whether direct injury to the myo-cardium or valves by streptococcal toxins was involved, or (3) whether streptococcal antibodies cross-reactive with human tis-sues can initiate immune-mediated injury. Unfortunately, none of these approaches have yielded any unequivocal evidence of the classic lesions of ARF. Further-more, none have clearly demonstrated the known clinical features of the human dis-ease such as a prior streptococcal pharyn-gitis followed by a latent period followed by clinical and pathological signs of an ARF episode.
However, since the 1970s, observation in ARF patients both in circulatory blood samples and serum as well as studies in tis-sues removed from ARF and RHD patients have strengthened the concept that an abnormal response to streptococcal anti-gens at a cellular and humoral level in the genetically susceptible host results in the clinical and laboratory signs of ARF. Fur-ther studies have revealed the following:
(1) heart-reactive antibodies cross-reactive with streptococcal antigens are present in the sera of these patients; (2) the number of CD4+ cells are increased both in the plasma and tissues of ARF patients compared with CD8; (3) the total number of B cells is increased compared with age-matched controls; (4) the inflammatory cytokines such as TNF-α, IL-2, and IL-1 are elevated in the acute phase and return to normal levels after the episode; and (5) group A streptococci secrete several exotoxins called SPEA, SPEB, and SPEC, which are called superantigens because they bind to the lateral side of TCR and the MHC stimulating a large release of cytokines that could initiate the ARF process. Furthermore they are even capable of deleting certain TCR alleles, possibly inducing loss of self-tol-erance and the induction of self-reactive autoantibodies.
All of these observations coupled with the unique association of group A streptococcal infections in humans ver-sus animals suggest that introduction of human genes in mice or rats to create transgenic animals may be more helpful in understanding the human rheumatic fever process. These animals are now available for study mainly based on the long-term commitment to transgenic mice by Dr. Chella David. These mice contain the gene for human CD4+ cells and genes for several different MHC molecules. These mice are more susceptible to the lethal efforts of the superantigen toxins (similar to humans) when compared with nontransgenic littermates, but to date, no studies have been carried out to determine how these mice might react to oral infection with several different group A streptococcal M types, particularly with respect to myo-cardial and valvular damage. The gene for human B-cell production may also be needed to complete the pathological find-ings seen in human disease.
Whether these human gene introduc-tions are sufficient to mimic the human disease is not known. But the creation of these and other transgenic models may well be more fruitful since all natural mod-els tested so far have had little success.