Abstract
Infectious pathologies are a group of diseases that contribute with great impact on public health worldwide. Among the various diseases, some have a higher epidemiological importance, since their morbidity and mortality are very significant. In addition to the usual immune response, mounted against noxious agents, there is still the concept of infection-induced autoimmunity. Autoimmune diseases are defined as illnesses in which the evolution from benign to pathogenic autoimmunity takes place. However, proving a disease to be of autoimmune etiology is not a simple task. It is well known that both genetic influences and environmental factors trigger autoimmune disorders. However, some theories are still under great discussion. One of the most intriguing self-induced disorders is the hypothesis of autoimmunity during Chagas disease. Since the mid-1970s, the Chagas autoimmunity hypothesis has been considered an important contributor to the complex immune response developed by the host and triggered by Trypanosoma cruzi. New ideas and findings have strengthened this hypothesis, which has been reported in a series of publications from different groups around the world. The aim of this chapter is to discuss the mechanisms involving autoimmunity development during Chagas disease.
Keywords
- Chagas disease
- autoimmunity
- T. cruzi
- autoantibodies
- immunology
- cardiomyopathy
1. Introduction
Autoimmune diseases are chronic disabling disorders described as immune responses against self-antigens that comprise cells, tissues, and organs, resulting in devastating consequences for patients [1]. For over decades, the concept of autoimmune disease has been studied, and the relationship between infectious diseases and autoimmunity has been established. Among all illnesses, Chagas disease has caught the attention of many researchers worldwide. Along with all the possible pathogenic mechanisms involved in
2. Autoimmunity: an obscure immunological path
In order to understand autoimmunity, it is essential to go back into the first steps of T- and B-cell development, differentiation, and maturation. During the process of generation of new lymphocytic clones derived from a stem cell, a novel lymphocyte carrying a specific pattern of B-cell receptor (BCR) or T-cell receptor (TCR) is formed as revised recently [2, 3]. While B-lymphocytes may undergo full maturation in the bone marrow, T lymphocytes need thymic education, as can be observed in Figure 1.
After egressing the bone marrow, T lymphocytes undergo differentiation and maturation in the thymus in which they pass through a process called negative and positive selection [4, 5].
Positive selection occurs during classical thymic differentiation, in which thymocytes may generate naive conventional T lymphocytes. These cells migrate to peripheral tissues and further differentiate in response to encounter with nonself-antigens. The negative selection is based on the elimination or inhibition of “self-reactive” cells. Nevertheless, some of these self-reactive T cells could escape negative selection and might become activated during the inflammatory process. On the other hand, a second or agonist-driven thymic selection, was proposed in which specialized T-cell subsets are generated from thymocytes that bind with high avidity to self-antigens. In this case, these cells leave the thymus as antigen-experienced activated T cells, such as double-negative TCRαβ+ intestinal T cells, CD8αα+, invariant iNKT, Foxp3+ nTreg cells, TH17 cells [6] and possibly mucosal associated invariant T cells (MAIT) [7]. Two barriers for self-reactive cells exist, which are the central and peripheral tolerance [5]. Failure in these processes may allow the proliferation of self-reactive clones, thus establishing an autoimmune pathogenic disease. Genetic disorders as well as environmental conditions can trigger the failure on central or peripheral tolerance, [8–12]. In addition, other pathways can lead to autoimmunity such as molecular similarity or mimicry, specific epitope spreading, indirect or bystander activation, B- and T-cell polyclonal activation, infections, and self-inflammatory activation that trigger innate immunity [8, 13].
3. Chagas disease: an outburst of inflammatory events that may lead to autoimmunity
Since
In this regard, the functional role of peripheral blood leukocytes in patients infected by
4. The autoimmunity during Chagas disease: theories, concepts, and mechanisms triggered by Trypanosoma cruzi
Starting from the innate response, the human organism defends itself in a variety of ways. Physical barriers, phagocytic cells, (such as macrophages and dentritic cells), natural killer cells, neutrophils and the complement system are just a few examples of how precise and efficient our body reacts. Besides the innate response, the immune system is comprised of the adaptive response, a complex compartment of defense. Leucocytes (T and B lymphocytes), antibodies, and many other molecules are constantly working in order to keep the homeostasis. Furthermore, another important mechanism that is part of the immunological system is the autoimmunity concept. The autoimmunity concept started when researchers proposed that
The debate about a role for autoimmunity in Chagas disease continued. Autoreactive T cells and antibodies were identified in individuals with chronic Chagas disease, and several specific antigens abundant in the myocardium were identified as targets of autoreactive responses [22, 45, 46]. Inflammatory factors present in the local environment, such as cytokines and nitric oxide, were also found to promote the activation of potentially autoreactive T cells encountering major histocompatibility complex-bound cognate antigen [21, 47, 48]. In this context, the autoimmune hypothesis plays a crucial role in the pathogenesis of many infectious diseases, including Chagas. The mechanisms proposed in this section for the generation of autoimmunity during Chagas disease are mimicry, indirect or bystander activation, and epitope spreading.
Mimicry is defined by the development of immune responses against foreign antigens that share sequence or structural similarities with self-antigens. This is due to the fact that immune responses can be directed against peptides with similar charge distribution and shape [8]. This mechanism suggests that
In addition, other host antigens have been studied and proved to cross-react with
An additional concept of great discussion is the bystander activation. During microbial infection, toll-like receptors (TLRs) and pattern recognition receptors present on antigen-presenting cells (APCs) are stimulated leading to the synthesis and release of proinflammatory mediators. Together with self-antigens, coming from tissue destruction and creating a milieu of proinflammatory factors, all of these mediators may defeat self-tolerance by decreasing the threshold of activation enough to activate potentially autoreactive T cells and trigger autoimmunity. Furthermore, CD8+ T cells may also initiate bystander activation by proliferating in response to self-antigen presented by APCs [21, 49, 60]. Hyland et al. [61] have shown that a reduction in parasitemia via treatment with Benznidazole, decreased or eliminated myosin-specific autoimmunity. They hypothesized that reduction of parasitemia consequently reduces release of host antigens and also dampens the inflammatory environment lessening bystander activation. Altogether, these data bring great perspectives to elucidate the autoimmune hypothesis of Chagas disease.
Subsequent to bystander activation, there is the development of autoimmune responses to endogenous epitopes secondary to the release of self-antigens, the so-called epitope spreading. It results from a change in protein structure, for example, changing of an amino acid from arginine to citrulline, which may succumb in an immune reaction against either the original protein or the citrullinated protein. Some of the mechanisms involved in epitope spreading are endocytic processing, antigen presentation, and somatic hypermutation, all culminating in broadening the immune response in autoimmune pathologies. Several authors have demonstrated the epitope spreading against many cardiac proteins, such as myosin, Cha protein, desmin, actin, myoglobin, tubulin, and B1 adrenergic receptor [49, 55, 62]. Still, more studies must be conducted in order to prove that this mechanism fully contributes to the propagation of autoimmunity in Chagas disease.
5. Final remarks
Chagas disease afflicts millions of people each year worldwide. Some individuals present mild to moderate symptoms during the chronic phase, while others develop severe and life-threatening cardiac and digestive conditions. There have been great advances in understanding the physiopathology of Chagas heart disease, which may contribute to the evolution in the field of drug development and therapy approaches. Apparently the auto-reactive cells are great responsible for destruction of the cardiac tissue leading to cardiac failure, the most severe consequence of the disease. Although the data describing the existence of
Acknowledgments
OAMF and ATC received fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). JGCdR received fellowship from Programa Nacional de Pós-Doutorado funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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