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.
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