Download Chagas disease: a role for autoimmunity?

Opinion
TRENDS in Parasitology
Vol.19 No.10 October 2003
447
Chagas disease: a role for
autoimmunity?
Rick L. Tarleton
Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
Despite many years of investigation and discussion, the
cause of disease in chronic Trypanosoma cruzi infection
remains a hotly debated topic. The primary point of contention is whether Chagas disease is an autoimmune disease resulting from inappropriate immune responses to
self antigens that are induced and perhaps perpetuated
by T. cruzi infection, or whether this disease is a result of
the inability to adequately, and without significant
cumulative damage, control T. cruzi infection on the part
of some hosts, including the 30-40% of infected individuals who develop clinical disease. This review updates
some of the data applicable to this debate with emphasis
on the role of parasite persistence in Chagas disease.
Several recent reviews [1– 3], including the Opinion by
Girones and Fresno [4] in Trends in Parasitology, outlined
many of the data supporting an autoimmune etiology for
Chagas disease. These reviews pose soe questions for
proponents of alternative views, which will be addressed
here. But, before dealing directly with the experimental
data on Chagas disease, it is instructive to consider how
autoimmunity became enshrined as the causative factor in
chronic T. cruzi infection. Chagas disease is the manifestation of tissue damage resulting from infection with
the protozoan parasite, Trypanosoma cruzi. Despite the
obvious connection between infection and disease, T. cruzi
infection and Chagas disease are often considered as
separate entities. The infection is usually viewed as an
acute event with any resulting symptoms being a direct
result of parasite invasion and the immune response to
this invasion. The acute infection is normally controlled,
although not cleared, and acute symptoms are alleviated
by a competent host immune response. By contrast,
Chagas disease is clearly uncoupled from the initial
infection in time (by several decades in humans), and
chronic disease symptoms are generally considered to
result from different mechanisms than those that are
operative in the acute infection. However, even some of
the earliest and most vocal proponents of autoimmunity as
the cause of Chagas disease realized that the separation of
acute infection from chronic disease was probably an
artificial one (see, for example, Ref. [5]).
Historical perspective
Autoimmunity rose to the forefront as a proposed cause of
Chagas disease for one simple reason – parasites are
Corresponding author: Rick L. Tarleton ([email protected]).
difficult to detect at sites of the most severe pathological
damage in chronically infected hosts. Observers of this fact
cast about for an explanation and, as early as the 1940s,
the idea of a role for ‘allergic’ mechanisms in Chagas
disease was proposed (reviewed in Ref. [6]). Various
technical advances helped to further explore the role of
immune dysfunction in Chagas disease, resulting in the
evolution of hypotheses on the mechanisms by which antiself immune responses could be generated, including
polyclonal activation, molecular mimicry and bystander
activation [1]. This evolution was coincident with the
investigation of autoimmune diseases in general, including those linked to infectious diseases, resulting in a set of
postulates by which one could attempt to assess the
contribution of autoimmune responses to disease [7,8].
These developments also took place within the context of
an explosion in the understanding of the immune system,
the generation of diversity within it and the mechanisms
that regulate host immune responses.
The artificial uncoupling of T. cruzi infection from
Chagas disease made it relatively easy to discount the
contribution of persistent parasitic infection to disease
severity in T. cruzi infection. The supposed absence of
parasites at or near sites of disease is still cited as proof of a
dissociation between active infection and disease, and in
support of an autoimmune etiology for Chagas disease
[1,9,10]. However, even ardent supporters of autoimmunity as the cause of disease in T. cruzi infection now largely
concede that parasite persistence is a co-requisite, if not a
prerequisite, for pathology [3,4]. This conclusion is based
on the overwhelming evidence for parasite persistence in
chronic T. cruzi infection and for a linkage between the
sites of parasite persistence and the presence of disease in
that tissue. Much of the data in support of this point,
including the detection of parasite DNA, parasite protein
and even intact parasites using various techniques, has
been previously reviewed in detail [11,12], and additional
support not included in these reviews continues to mount
[13,14]. Not only is parasite persistence being nearly
uniformly documented in linkage with severe disease,
there is also emerging evidence in human cases and in
experimental models that re-infection or continued
exposure (due to continued residence in areas of active
transmission) increases parasite load, in addition to
disease severity [15 – 17].
Cumulatively, these data demonstrate that the initial
suggestions of a disjunction between T. cruzi infection and
Chagas disease was a problem of the insensitivity of
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448
Opinion
TRENDS in Parasitology
techniques, rather than a true absence of parasites at sites
of disease in chagasic patients. Given this conclusion, it is
interesting to consider whether or not Chagas disease
would ever have been considered an autoimmune disease
if these more sensitive techniques had been available to
some of the early investigators of chronic Chagas disease.
However, despite the general agreement that parasite
persistence is a crucial causative factor in chronic Chagas
disease, autoimmunity still has strong advocates, as
recent reviews document [1– 4]. Among the questions
posed by these reviews are: (1) why do lesions develop
primarily in the heart and not at other sites of parasite
persistence? (2) why does parasite burden not always
correlate with disease severity? and (3) how does one
exclude the possibility that autoimmune pathogenesis is
fundamental to Chagas disease?
The heart of the matter?
Whereas it is true that Chagas disease is a clinical
syndrome primarily involving the heart, other tissues
are affected as well. The most studied other site for human
disease is the gut and it was appreciated very early in the
discovery of the parasite and the description of Chagas
disease that gut pathology occurred in a variable, but
significant proportion (generally estimated at , 10%) of
infected individuals [18]. The timing of occurrence
(i.e. decades after the initial infection), the type of tissue
affected (e.g. muscle) and the type of damage (inflammation, scaring, loss of nervous function and elasticity) are
all similar to what is observed in the heart. These
similarities strongly suggest a common etiology. In
experimental hosts, disease is also evident in the skeletal
muscle, again with the same characteristics of delayed
onset, inflammation and loss of muscle function. Skeletal
muscle disease also exists, but is less well documented, in
human infections [19,20]. Persistence of T. cruzi has been
documented in several other sites, including the bladder
[21], adrenal gland [22,23], skin [24] and central nervous
system [25]. Thus, parasite persistence in the heart and
at other sites of disease in chronic T. cruzi infection is
firmly established.
Perhaps, rather than asking why the heart is the only
tissue affected in Chagas disease, we should question why
disease is primarily focused in muscle tissue. If disease is
similar in these various muscle sites, how does this mesh
with the idea of cardiac-based autoimmunity? The answer
to the first question is that muscle appears to be one of the
main tissues where T. cruzi has the ability to persist for
decades. The tissue specificity of disease in different hosts
correlates well with parasite persistence in those tissues.
For example, in different mouse models of the chronic
disease, the persistence of parasites in skeletal muscle
correlates with disease development in that tissue,
whereas persistence in heart is linked to inflammatory
disease there [26]. In humans, the link between tissuespecific persistence of T. cruzi and clinical disease is
demonstrated by: (1) the detection of parasite DNA in the
hearts, but not in the esophageal tissue, of individuals
with cardiac disease; and (2) the detection of parasite DNA
in the esophageal tissue, but not the hearts, of those with
esophageal disease [27,28].
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Parasite burden and disease
The lack of a direct quantitative correlation between
parasites and parasite components and sites of disease is
often cited as supporting autoimmunity as the cause of
Chagas disease [1,3,4,10]. For example, Palomino et al.
[10] report the presence of parasite antigens in 12 out of 12,
and parasite-filled pseudocysts in 9 out of 12 chagasic
hearts submitted to extensive immunohistochemical
analysis. However, this investigation did not document a
quantitative link between parasite antigen and tissuespecific lesions, prompting the authors to conclude that
autoimmunity must be at work in the development of these
lesions. These are difficult experiments, and Palomino
et al. are to be commended for the exhaustive and high
quality analysis of the tissues. However, like earlier
investigations that failed to detect T. cruzi in chagasic
hearts, these types of studies are also limited by available
techniques. Immunohistochemistry cannot provide quantitative data easily and it is not possible to know the
evolutionary history of a lesion from the ‘snapshot’ of
that process provided by tissue sections. An equally (if not
more) plausible conclusion from these studies is that some
lesions are more active, more recent, or maybe even just
happened to be sectioned through areas of current or
recent infection (and thus have intact parasites or parasite
antigen associated with them), whereas other lesions lack
parasites or parasite antigens because of the effective
clearance of parasites from this site, or because of the
angle or depth of the section. If the presence or absence of
parasites is not responsible for the focal nature of lesions in
Chagas disease, then what is? What is distinctive about
cardiomyocytes in one area of the heart that makes them
susceptible to autoimmune damage, whereas adjacent
cells are resistant? Until technical advances provide the
means to follow the evolution of a lesion over time, it is
difficult to determine exactly how lesions arrive at the
point that one observes in histological sections.
Another set of data that addresses the issues of parasite
levels and disease severity comes from studies of the effect
of drug treatment during the chronic phase of infection on
the progression of disease. Viotti et al.’s studies on the
effectiveness of chemotherapeutic treatment in reducing
the incidence of disease progression in long-term follow-up
studies are seminal [29]. These studies have been extended
to a larger group of patients with similar results (R. Viotti
et al., unpublished). The most remarkable study is that by
Apt et al., who conducted a nine-year follow-up study on
299 chronically infected patients treated with either
itraconazole or allopurinol during the chronic stages of
infection [30]. These authors reported that the frequency
of new electrocardiogram (ECG) abnormalities was significantly lower in the itraconazole-treated group when
compared with that in the untreated group and that 50% of
the patients who exhibited ECG abnormalities before
treatment became electrocardiographically normal during
the follow-up. These results suggest that disease can be
arrested and even reversed with aggressive treatment to
reduce the parasite burden.
Unfortunately, not all studies have yielded such
encouraging results (for review, see Ref. [31]). In addition
to problems of experimental design, low numbers of
Opinion
TRENDS in Parasitology
individuals in the study groups and short follow-up
periods, the poor efficacy of existing drugs in reducing
parasite load contributes to the variable results in longterm follow-up studies. For example, Braga et al. found no
difference with respect to numbers of circulating parasites
detected by PCR between patients treated during the
chronic stage of the infection and those left untreated [32].
In cases where chemotherapy fails to alter the prevalence
of infection or the parasite load in a group of chronically
infected individuals, there is likewise a failure to achieve
an improvement in the clinical picture following this
treatment [33]. Alternatively, therapies that are effective
in reducing or eliminating T. cruzi infection in chronic
patients result in significant improvements in clinical
status [30] (R. Viotti et al., unpublished). Apt et al. and
Viotti et al.’s studies also substantiate the conclusion that
individuals who become spontaneously seronegative without treatment (presumably self-cured) also do not show
progression toward severe disease. In addition to parasite
load and location being tightly linked to disease severity
and its location, there is evidence that Chagas disease is
not self-perpetuating and does not occur in the absence of
infection [26,34]. Thus, Chagas disease fails to meet the
most crucial criteria for being considered an autoimmune
disease [8].
A substantial body of work shows that Chagas disease
progresses in the presence of higher parasite burden and is
reduced when parasite burden is reduced. Although a
uniformly effective treatment does not exist yet, it is
encouraging that therapies capable of reducing parasite
burden have an excellent chance of reducing disease
development or preventing progression of clinical disease,
irrespective of the presence of possible autoimmune
responses.
If not autoimmunity, then what is it?
There seems little doubt that anti-self responses exist in
T. cruzi infection. This should not be surprising, considering that all individuals have autoreactive T cells and B
cells that can be activated under the appropriate set of
circumstances. All chronic infections provide these circumstances, for example, a pro-inflammatory milieu,
tissue damage and the release of cryptic epitopes enhanced
antigen presentation as a result of upregulation of
co-stimulatory molecules, all of which are associated
with persistence of a pathogen. What is it about Chagas
disease that distinguishes it from other persistent infections and turns it into an autoimmune disease? Some
propose that it is the target(s) of the autoimmune
responses that the makes T. cruzi infection different.
Indeed, several potentially mimicked antigens have been
described in T. cruzi – ‘perhaps too many’ in the estimation
of Girones and Fresno [4]. Some limited data have
suggested that the responses to the mimicked antigens
can be pathogenic [35 – 38]. Others suggest that polyclonal
activation is the key in T. cruzi-induced autoimmunity
[39]. However, in sum, the evidence supporting either
molecular mimicry or polyclonal activation directly in the
pathogenesis of T. cruzi infection is sparse. With respect to
mimicry, it is clear that T. cruzi infection meets only one of
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449
the five criteria deemed necessary to call this an
autoimmune disease (see those outlined in Ref. [8]).
If Chagas disease is not caused by autoimmune
reactivity, then why does it occur and how does one
account for the latency and spectral nature of the disease,
characteristics normally associated with autoimmune
diseases. More importantly with respect to treatment
and prevention, why do a subset of T. cruzi-infected
individuals develop disease, whereas the majority do not?
Two interacting factors are associated with the development (or not) of severe disease: (1) parasite burden; and
(2) the effectiveness of the host immune response in
controlling parasites in specific tissues. The link between
parasite burden and disease has been reviewed in depth
above. Parasite burden is, in turn, largely dependent on
how effective the host immune response is in killing
parasites or limiting parasite replication. Variations in the
parasite strain(s) infecting an individual help determine
parasite burden, but so too does the effectiveness of the
immune response, which is highly variable between
individuals. When immune control is inefficient, parasite
load and inflammation, and thus the potential for tissue
damage, increases. Increased inflammation with poor
immune control might seem counterintuitive. But, the
immune system is generally self-regulating – a wellexecuted response that achieves clearance (or perhaps
more often, ‘near’ clearance) of a pathogen results in less
tissue damage than does an ineffective response that
allows for persistence of the pathogen in greater numbers.
The evidence that the quality of the immune response to
T. cruzi correlates with disease severity comes from
several types of studies. First, the effect of immunosuppression or of genetic deficiencies in the immune response
on disease severity is well documented in humans and in
animal models with T. cruzi infection [11,12,40]. In all
cases, the compromise of one or more of the immune
mechanisms that are known to be important in the control
of T. cruzi infection results in increased parasite load and
increased incidence of chronic-stage disease. This is most
clearly seen in humans with respect to co-infection with
HIV [40]. Second, treatments that boost immune
responses decrease the severity of disease. Prophylactic
vaccination of mice with genes of the T. cruzi transsialidase family results in substantially less chronic-stage
disease [41]. Third, there are emerging (although still
limited) data from immunological studies in animal
models and in humans that support a link between the
strength and nature of the antiparasite response and
the severity of chronic stage disease. For example,
Laucella et al. have found a higher frequency of T. cruzispecific interferon g (IFN-g)-producing memory T cells in
individuals without clinical symptoms when compared
with those with severe disease (S. Laucella et al.,
unpublished). In addition, there continue to be reports of
infected individuals who become seronegative over time
(i.e. they appear to cure spontaneously, almost certainly as
a result of a particularly effective immune response). None
of these individuals exhibit progressive disease following
conversion to seronegative [29,42] (R. Viotti et al. unpublished), which argues strongly in favor of the participation
of an effective antiparasite response in preventing disease
450
Opinion
Chagasic
TRENDS in Parasitology
Asymptomatic
(a)
Vol.19 No.10 October 2003
development. If autoimmunity was important in disease,
then an occasional previously infected seronegative would
be expected to have progressive disease.
Perspective
The controversy over the etiology of Chagas disease will
continue for some time. There are no data that can
absolutely rule out autoimmunity as having any role in
disease development, and the support for autoimmunity as
a primary cause of pathology in this, or for any other
infectious disease, is far from definitive [8]. One area of
agreement that has emerged in recent years is that
parasite persistence is required for disease. However, the
evolution of disease as a result of this persistence is still
unclear. Girones and Fresno propose that a ‘trigger’ might
be required to initiate the disease process, although the
nature of this trigger is still unclear [4]. Figure 1
illustrates how disease might occur in the absence of
autoimmunity, highlighting the ability of a competent
immune response to limit parasite load and thus tissue
damage (see animation of this process on: http://tango.
ctegd.uga.edu/chagas.htm). Further studies and better
tools are needed to test the validity of the mechanism
illustrated in Fig. 1.
Whatever the mechanism for disease, one goal seems
clear: patients will benefit from a reduced parasite burden.
This cannot be achieved by targeting autoimmunity as
the problem in Chagas disease. Global suppression of
immune responses in chagasic patients is out of the
question, and suppression of responses to one or more of
the proposed autoantigens is also problematic (J.S. Leon
and D.M. Engman, unpublished). A reduction in parasite
burden can be achieved not only through the discovery of
better chemotherapeutics, but also with the use of
immunologicals, potentially including therapeutic vaccines, to enhance host immune control of the infection.
Effective chemotherapy could enhance anti-T. cruzi
immunity [43]. Driving the immune response toward an
appropriate, efficient control of the parasite burden –
something that happens in the majority of individuals – is
an approach which has not until now been pursued with
sufficient vigor.
(b)
(c)
(d)
Acknowledgements
TRENDS in Parasitology
Fig. 1. Proposed model for lesion progression in symptomatic (chagasic) and
asymptomatic Trypanosoma cruzi infection. (a) Lesions originate from a single
infected cell. (b) Parasites (indicated in brown) released from infected cells invade
adjacent cells or circulate to other sites. Immune recognition results in inflammation (lymphocytes indicated in blue), which regulates the spread of parasites to
varying degrees in different patients, depending on the quality (i.e. type and intensity) of the immune response. (c) Tissue destruction occurs as a result of parasite
destruction, killing of infected cells by immune effectors (represented by blue
cells), and peripheral damage to noninfected cells. Efficient immune control results
in less tissue damage in asymptomatic patients. (d) When immune control is not
efficient, the lesion size increases and fibrosis is extensive (chagasic). By contrast,
efficient control of parasite replication results in less tissue damage and a selfhealing lesion (asymptomatic). For an animated version of this process, go to:
http://tango.ctegd.uga.edu/chagas.htm
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Thanks to David Engman and Rodolfo Viotti for sharing data from
unpublished works, and to the past and present members of the Tarleton
laboratory for their contributions to the data and ideas expressed in this
review. R.L.T.’s laboratory is supported by grants from the National
Institutes of Health. R.L.T. is a Burroughs Wellcome Fund Scholar in
Molecular Parasitology.
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