Moysés Sadigursky
Faculdade de Medicina, Universidade Federal da Bahia, Av. Reitor
Miguel Calmon s/no, 40140-001 Salvador, BA,
Brasil
Fax: +55-71-245.8562.
Received 9 June 1999
Accepted 9 August 1999
Code Number:OC99178
Key words: Chagas disease - autoimmunity in Chagas disease
The pathogenesis of Chagas disease is still controversial. The
lesions that occur in the acute phase of infection are initially
due to rupture of the heart fibers by the Trypanosoma cruzi.
When the parasite antigens sensitize the immune system, the
inflammatory process is due to a sum of the traumatic mechanism and
the immune reaction against the parasite.
After the acute phase and the development of the specific immune
response occur an equilibrium between the host and the parasite
which can last for all the life of the host. The T. cruzi as
a true parasite do not kills the host and the immune system of the
host do not kills all the parasites. Despite it can be detected
specific humoral and cellular immune response against the T.
cruzi, this parasite evades the immune response mainly
penetrating and proliferating in host cells. The equilibrium phase
is called indeterminate phase when occur a clearance of parasites
from bloodstream and tissues. Patients present positive serology to
T. cruzi antigens but do not present signs and symptoms of
disease.
At about 10 to 15% of infected individuals develop a chronic
heart disease characterized by chronic diffuse and fibrosing
myocarditis with absence or very few parasites. Different
mechanisms have been proposed to explain that aggressive
myocarditis similar to a rejection of an allogeneic heart
transplant. It has been suggested that the lesions result from
gradual destruction of the heart fibers by parasites or by a
mechanism of cellular hypersensitivity directed to parasite
antigens which affect also the heart tissue. Another mechanism
proposed is the autoimmune mechanism.
Soares and Ribeiro dos Santos presented results of several
experiments about immunopathology of cardiomyopathy in experimental
Chagas disease that indicate autoimmune mechanism as an strong
candidate to explain the pathogenesis of chagasic myocardiopathy.
They show an elegant experiment where mice chronically infected
with T. cruzi reject syngeneic heart grafts. Hearts grafted
into normal or T. cruzi immunized syngeneic recipients are
not rejected. The study shows that only CD4 and not CD8 T cells
from chronically infected mice were able to promote rejection. Mice
chronically infected with T. cruzi were treated with
anti-CD4 and anti-CD8 monoclonal antibodies before transplantation.
The in vivo depletion of CD4 cells, but not CD8 cells
abrogates rejection.
In another experiment it was shown that chronically infected
mice treated with anti-CD4 monoclonal antibodies presented
tolerance with abolishment of the chronic carditis. The opposite
occurred when animals were treated with anti-CD8 or anti-Thy1.
Tolerant animals presented low mortality and negative parasitemia.
I can not understand why animals that had T-CD4 cells destroyed had
a negative parasitemia. The expectance was to have immunodeficience
similar to Aids with a high parasitemia. The phenotype of cells
present in chagasic myocarditis has been controversial as in mice
as in humans. Some authors refer predominance of CD4 cells and
others predominance of CD8 cells. In our experience with material
of necropsy of humans who died with Chagas disease (Castro-Silva
& Sadigursky) we had in 80% of patients predominance of CD4
cells, 10% with predominance of CD8 cells and 10% with predominance
of macrophages. Macrophages were seen in variable number in all the
cases.
Other experiments with lines of autoreactive CD4 cells from mice
chronically infected with T. cruzi reinforce the hypothesis
of autoimmunity in chronic Chagas disease.
Correa-Oliveira et al. presented "The role of the immune
response on the development of human severe clinical forms of
Chagas disease". The secretion of IFN g
can be correlated with the severe cardiac form of Chagas disease.
The opposite was observed for in vitro secretion of IL10.
The studies indicated that as the cardiac function worsens, IFN
g
secretion by PBMC increases with a parallel decrease on secretion
of IL10. They conclude that IFN g
secretion can be correlated with the development of severe cardiac
form of the disease. I believe that the high level of IFN g
secretion indicates that an intense process of stimulation of
cellular immunity is occurring. The high level dosage of IFN g
can be useful for the diagnostic of severe cases of chronic
myocarditis. Is not the high level of IFN g
the cause of severe myocarditis but a consequence. I agree that
IFN g
is involved in the augmentation of the cytolitic potential of
lymphocytes in the cardiac inflammatory process.
Patients with megaesophagus and megacolon present different kind
of infections and subnutrition. The characterization of cells of
the inflammatory process in those cases to correlate to
pathogenicity is very difficult.
Simões-Barbosa et al. presented a very interesting
experiment. They show that sequence of minicircle of kDNA of T.
cruzi can integrate into the host genome. They show that a
lineage of murine macrophage infected with T. cruzi
incorporates genetic material of the parasite kinetoplast.
Subclonal lines of transfected macrophage continue synthesizing
proteins proper of the parasite. This phenomenon demonstrated in
vitro, I believed, has not importance in vivo since it
will appear to immune system as a foreign cell and destroyed. The
antibodies in the chagasic sera recognized the T. cruzi
antigens produced by transfected macrophage and they do not consist
in autoreactive antibodies to proteins proper of the host cell.
If this mechanism really occur in vivo it can explain why
animals treated with specific chemotherapy continue presenting
positive serology. On the other hand it is possible that some
macrophages are transfected with cross-reactive antigens and so are
not rejected while persist the autotolerance.
The trigger mechanisms of autoimmunity are policlonal
activation, anti idiotipic reaction and cross-reaction antigens
present in the T. cruzi. We have demonstrated that T.
cruzi have cross reacting antigens which induces antibody that
reacts against antigens present in the cardiac muscle. One purified
antigen is an ATPase Ca++ and Mg++ dependent. Sera of chronic
chagasic patients have high titer of antibodies and also reactive
cells against this antigen (Sadigursky & Santos-Buch). We also
demonstrated that heart muscle cells have receptors to T.
cruzi that facilitate the parasite get into the cell. The
immune response directed to the protein of the parasite can induces
an anti idiotipic reaction that damage the heart.
Another point necessary to be stressed is that to induces an
autoimmune disease is necessary the presence continuous of the
antigen. The demonstration of T. cruzi or T.
cruzi antigens in the host is a necessary condition to the
development of auto-immune reaction. Barbosa Jr. and Andrade,
demonstrated that in Chagas disease the parasites can be found in
many different organs and tissues but only in the heart occur a
chronic diffuse inflammatory infiltrate. This findings corroborate
to the hypothesis of autoimmunity in Chagas disease. Andrade et al.
also showed those dogs in indeterminate phase of Chagas disease
when treated with low doses of cyclophosphamide which destroy cells
suppressor function, evolved to a chronic diffuse myocarditis,
indicating also an autoimmune mechanism.
Copyright 1999 Fundacao Oswaldo Cruz - Fiocruz