Immunological Challenges to the Development of Chagasic Mega Syndromes-Juniper Publishers
Juniper Publishers- Journal of cell science
Abstract
Chagas´ disease is one of the most serious parasitic
diseases in Latin America, with a social and economic impact that far
outweighs the combined effects of other parasitic diseases such as
malaria, leishmaniasis and schistosomiasis. Chagas’ disease presents two
well-defined phases, the acute phase and the chronic phase. The acute
phase lasts for approximately two or three months. After this phase, the
patient enters an asymptomatic state, which characterizes the beginning
of the chronic phase. In the chronic phase of the disease, the
destruction of components of the enteric nervous system leads to the
development of megaesophagus and megacolon. Mega syndromes are
characterized as dilatation of the organ associated with an inflammatory
infiltrate that is the main responsible for the destruction of the
enteric neurons. This review aims at organizing the data previously
known about the challenges faced by the immune system in the presence of
Chagas disease and the establishment of the chagasic megaesophagus and
megacolon in an attempt to discover which is the key mechanism that
defines the installation and the protection against the digestive form
of this pathology.
Keywords: Chagas’ disease; Chagasic megacólon; Immune system
Introduction
The first suspicion of the existence of the digestive
form of Chagas disease came in 1916, when Carlos Chagas himself
observed that during the acute infection, some adults exhibited a marked
dysphagia for foods whose ingestion needed to be accompanied by water.
Patients reported that food transit was interrupted in the esophagus,
causing immense pain. Even the ingestion of fluids could be difficult,
being sometimes impossible, and in this way, the need for it to be
administered in small doses. This phenomenon, without pathogenic
explanation, was then termed “Mal do engasgo” [1]. The digestive forms
of Chagas’ disease are present prominently in the regions below the
equatorial line, with esophagopathy occurring in approximately 7 to 10%
of cases and colopathy in 3 to 7%. The chagasic megacolon affects, above
all, the sigmoid and the rectum. It may manifest as an isolated
disease, but is often found associated with megaesophagus or Chagas’
heart disease. It is more common to adult (30 to 60 years) and more
incident in the male sex. As the first symptom of mega colon is
constipation, both the clinical and
the anatomical diagnosis are usually late, after the establishment
of the dilatation [2]. Optical light microscopy shows chronic, focal and
diffuse inflammatory infiltrates in the muscularis of the mucosa, in
the sub mucosa and in the muscular layers, lesions of the enteric
nervous system, especially of the my enteric plexus, periganglionite and
focal or diffuse gang lionitis with intense regressive phenomena of the
neurons arriving at the complete destruction of the nervous ganglia of
the my enteric plexus, with consecutive fibrosis, ulcerations and
chronic inflammation of the mucosa, focal or diffuse in more advanced
cases, reaching the sub mucosa, inter muscular interstitial fibrosis,
focal or diffuse, due to myositis, periganglionitis and ganglionitis
[3]. Ultra structural changes of my enteric plexus consist of lesions,
usually focal, of all components of the ganglia: neurons, Schwann cells
and nerve fibers. Therefore, it is common, in the same ganglion, the
existence of neurons, sometimes deeply damaged alongside others
morphologically intact. In severe cases, the lesion may be diffuse and
the ganglion ends up being replaced by dense fibrous connective tissue
[4]. It is permissible to admit a progression of the lesions of the
plexus, which worsen proportionally to the duration and degree of the
mega. The accumulation of feces in the colon causes light dilation and
compression of the mucosa.
Compression, in turn, leads to ischemia, and secondarily to
degeneration, necrosis and ulceration of the mucosa. In the
mucosa so ulcerated begins a secondary inflammatory process
and independent of the inflammation induced by Chagas’ disease
itself. This inflammatory process reaches my enteric plexus
already previously damaged by T. cruzi, further aggravating the
destruction of the enteric nervous system (SNE). In turn, the
sub mucosal plexus suffers the consequences of the lesions of
my enteric plexus, due to the synaptic relations between them.
Inflammation secondary to stasis added to destruction of the
plexus and interstitial components evolves into interstitial
fibrosis of the sub mucosa and inter muscular conjunctiva. In
turn, increasing the resistance of the medium requires more
effort in the muscle fibers for contraction. Over time, hypertrophy
and regressive changes in muscle fibers occur. The latter is
consequence of disorders of metabolic changes of muscle cells
and the interstitium induced by inflammation itself (vascular
changes, edema, cellular infiltrate and fibrosis) that interposes
between them. Because the sub mucosal plexus is closely related
to muscle cells, it is easy to understand how myositis and its
squeal can further damage the lymph nodes [5]. The scarcity of
parasites in relation to the intensity and extent of the lesions in
the chronic phase of the disease led several authors to evaluate
the involvement in autoimmune factors of the pathogenesis of the
chagasic lesion. Some authors point in the existence of a crossreaction
between autologous components and T. cruzi antigens.
Studies using an experimental infection model by T. cruzi
suggest that during the acute phase of infection there would be a
polyclonal activation responsible for the release of self-reactive
clones that would persist for long periods in the host, leading to
the appearance of lesions [6]. Although parasitism is scarce in
relation to the intensity and extent of the lesions, several studies
leave no doubt as to the presence of the parasite in the tissues
of chagasic patients [7], found that the cardiac inflammatory
process was particularly evident in parasitized muscle cells.
Barbosa et al. [8] demonstrated, through autopsies of patients
with diffuse chagasic myocarditis, the presence of T. cruzi
amastigote forms into heart samples as well as extra-cardiac
tissues. In the last decade, using polyclonal anti- T. cruzi to detect
parasite antigens in heart tissues of patients with chagasic
cardiopathy, Higuchi et al. [9] have shown a close correlation
between the presence of parasite antigens and the intensity of
the inflammatory infiltrates. Another methodology used is the
polymerase chain reaction (PCR) technique, through which T.
cruzi DNA is detected in inflammatory lesions in patients with
Chagas’ and Chagas’ cardiomyopathy with megaesophagus
[10,11].
The inflammatory process of the chronic phase of Chagas
disease always shows signs of cellular activity. In the chagasic
megaesophagus, inflammatory infiltrates are composed of 72-
93% of CD3-IR T lymphocytes, 6-29% of CD68-IR macrophages
and 1-4% of CD20-IR B lymphocytes. About 1-35% of the
inflammatory infiltrate cells in the muscle layers express TIA- 1 (T-cell intracellular antigen) a protein found in cytotoxic
lymphocytes and Natural Killer cells. Natural Killer CD57-
IR cells were rarely observed. These findings suggest that
cytotoxic T lymphocytes may be involved in the pathogenesis
of chagasic megaesophagus as well as in the development of
heart disease present in some individuals with chronic infection
[12]. Corbett et al. [13] analyzing tissues of chagasic patients
with megacolon demonstrated the presence of Natural Killer
cells, thus suggesting their participation in the continuation of
the chronic phase inflammatory process of the megacolon of
chagasic patients. Lemos et al. [14], studying patients with the
digestive tract of Chagas disease, performed peripheral blood
analysis of these individuals to verify the circulating lymphocyte
phenotype. A significant decrease in the number of CD3/CD4-
IR T lymphocytes and CD19-IR B lymphocytes was observed.
The number of CD4-IR T lymphocytes / number of CD8-IR T
lymphocytes was decreased from individuals with advanced
megaesophagus, thus demonstrating a more significant decrease
in the number of CD4-IR T lymphocytes, which is not observed
in cardiac non-mega-chagasic patients [15]. As a marker for
activation of T lymphocytes in mega-bearing patients, an anti-
HLA-DR antibody was used and in this way elevated levels of
activated T lymphocytes were demonstrated, which had already
been observed in patients with Chagasic or even asymptomatic
heart disease. Still in mega-bearing patients, there was also a
decrease in the percentage of CD4/CD28-IR cells, which initially
suggested that the lack of the CD28 co-stimulation molecule
could in some way lead to failures of immune resistance
mechanisms and contribute to progression of the disease. This
hypothesis is in part corroborated by the studies of Miyahira
et al. [16] that evaluated the role of the CD28-CD80/CD86
co-stimulation pathway to the resistance of mice to T cruzi
infection. This study concluded that this pathway is essential
for the organism to develop resistance to T cruzi, since the
abolition of this pathway led to a decrease in the production of
interferon and the activation of CD8-IR lymphocytes, resulting in
an exacerbation of parasitemia.
Eosinophils are important cells in resistance to T. cruzi
infection and their role in chronic phase pathology has been
considered by several authors [17,18]. Eosinophils synthesizes
and release several bioactive mediators and are important
to both intestinal physiology and defense against various
pathologies [19,20]. These cells have intra-cytoplasmic granules
that may vary due to the degree of maturation and activation
of the cell. These granules have four main substances: primary
basic protein (MBP), cationic eosinophilic protein (ECP),
eosinophil peroxidase (EPO) and eosinophil-derived neurotoxin
(EDN). These proteins give the eosinophil a high capacity for cell
destruction. For many years eosinophils have been believed to
possess only pro-inflammatory action, but it is now known that
these cells are also capable of secret immuno-mediators that
may participate in the modulation of the inflammatory process.
In the intestine, eosinophils are found mainly associated with
observed lesions and acute and chronic inflammatory processes, and their role in defense against parasites is well known [21-
24], using mice infected with T cruzi, evaluated the kinetics of
eosinophil release by bone marrow, suggesting a role as these
cells in the parasite resistance process. Molina and Kierszenbaum
performed a series of studies in which associations between
eosinophils and the pathological changes induced by T. cruzi
were demonstrated. In myocardial studies of chagasic patients,
deposits of a neurotoxin derived from eosinophils in the
myocardium of chagasic patients were observed, as well as
the presence of activated eosinophils. A correlation between
eosinophil concentration and severity of inflammatory lesions
in the myocardium and skeletal muscles was also demonstrated.
Later these same authors, using cultures of cardio my ocytes
infected with T. cruzi, showed that eosinophils and neutrophils
play an important role in the destruction of T. cruzi in myocardial
cells [19,25,26].
Another cell of the immune system that plays an important
role in the evolution of Chagas’ disease is the mast cell. Mast cells
are multi-functional cells, being important both in intestinal
physiology and in defense against pathological processes. These
cells release pro inflammatory molecules, such as histamine and
tumor necrosis factor alpha (TNF-α). Mast cells are also capable
of increasing the permeability of the intestinal epithelium in
situations of chronic stress, inflammatory processes and parasitic
infections through mechanisms not yet known [27]. Mast cells
function as the main link between the immune system and the
enteric nervous system, detecting, encoding and transmitting
information about these systems. Signals sent by mast cells in
response to an invading agent act both on the immune system
and on sensory neurons [22,28,29]. The evaluation of the role
of mast cells in the pathology induced by T. cruzi infection
has already been the subject of several studies. Almeida et al.
[30], working with mice infected with T. cruzi, showed in the
stomach of these animals a reduction of acetylcholine levels
and an increase in histamine levels, probably due to the large
number of mast cells in the gastric wall. Postan et al. [31]
through in-vitro studies have suggested that the presence of
mast cells is directly related to the development of fibrosis in
cardiomyocytes infected by T. cruzi. Recently, Freitas et al. [28]
demonstrated that the presence of serotonin is closely related to
the concentration of mast cells in the colon of chagasic patients
and that this would represent the main form of communication
between the immune system and the enteric nervous system.
This would represent a great possibility of pharmacological
intervention in inflammatory bowel diseases where intestinal
transit is compromised due to an intense inflammatory reaction.
Conclusion
We believe in the existence of an interconnection
between the
immune and neuro endocrine systems. This link would promote
a bi-directional information exchange about the immune system
and the enteric nervous system. Mast cell activation, besides
performing roles in gastrointestinal physiology, plays a crucial role in
the inflammatory process, being one of the main encoders
of intestinal signs that will culminate in motor responses,
visceral perceptions and activation of cells of the immune system
in gastrointestinal pathologies.
Acknowledgement
This work was supported by funds from CNPq (Conselho
Nacional de Desenvolvimento Científicoe Tecnológico) Grant
404718/2016-7, Brazil.
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