Abstract
In the last decades, we have learned some critical lessons about the relationship between the human body and its interaction with many infectious diseases, where regularly, the immune system has a major role in protection. We learned to differentiate between the immune response occurring in either an intracellular or extracellular parasitic infection, between innate and adaptive immune response, between either inflammatory or anti-inflammatory responses, and finally, we learned to recognize very particular mechanisms, such as the inability of the immune system to respond during very particular scenarios, such as the inability of T cells to both proliferate and produce cytokines even after their exposure to mitogens or specific-antigens. Along with our increase in the knowledge in immunology, we figured out that immunoregulation and immunosuppression are processes used by many parasites to reduce the capacity of the immune system to eliminate them, and to persist in the host favoring their transmission and also to complete their life cycles. Immunoregulation involves several mechanisms such as anergy, apoptosis, induction of both suppressive cytokines and membrane-bound molecules, as well as specialized cell populations of the immune system like regulatory T cells, Alternative Activated Macrophages, or Myeloid-derived Suppressor Cells, that together modify the outcome of the immune response. In this chapter we will review the general differences between the different types of immunoregulation, the kind of cellular populations of the immune system used by the helminths Taenia solium and Taenia crassiceps to induce immunoregulation and immunosuppression and also, the mechanisms used by these parasites such as mimicking molecules of the immune system to replace directly these mechanisms. Understanding and deciphering all these regulatory mechanisms could be useful to develop new tools to control this infection.
Keywords
- Cysticercosis
- Immunoregulation
- Immunosuppression
- Taenia solium
- Taenia crassiceps
- Regulatory T cells (Treg cells)
- Alternative Activated Macrophages (AAM)
- Myeloid-derived Suppressor Cells (MDSC)
1. Introduction
Taeniasis and cysticercosis, both neglected diseases, are two kinds of infections caused by the same parasite,
Because taeniasis remains asymptomatic, there are no symptoms directly associated with the disease, only general symptoms like abdominal bloating and abdominal pain [1, 5]. For this reason, a model to understand the immunological interactions between the host and the parasite and also, to understand the evolutionary capacity of
2. General aspects of the immune response during NCC and Taeniasis
The immune response against
On the other hand, evidence from subcutaneous, visceral, muscle, lung and cardiac tissue infected with
The immune response described in the
3. Immunoregulation during cysticercosis
An inflammatory response during the initial infection process is necessary to induce immunity, to reduce parasite load and finally to have protection in cysticercosis. However, since basic science started to clarify the role of the immune response during cysticercosis, some special discoveries have been observed only in this helminth infection, suggesting a process of transformation from inflammation to an anti-inflammatory response, tipping the balance towards the parasite survival. Is necessary to pay attention in the fact that, during some helminth infections, the Th1 to Th2 switch is caused to keep the balance between immunity in the host with tissue repairing, and for the survival of the parasite o for its expulsion from the host, example of that are
3.1 Immunoregulation mediated by T-cells
During some intracellular parasitic infections, like toxoplasmosis, trypanosomiasis and leishmaniasis, an incapacity of T lymphocytes to proliferate in response to antigen-specific or polyclonal mitogens has been described, mainly during acute infection [23, 24, 25, 26]. Although the general observation is that the process of immunosuppression starts at the beginning of the chronic
As well as in
3.2 Immune-regulatory myeloid-derived mechanisms
The generation of an immune-regulatory environment could have an effect not exclusively in T cells, but in all immune cells, including all myeloid-derived lineages such as macrophages, dendritic cells (DCs) and PMNs. Thus, myeloid cells are key players in the immune response against cysticercosis. In fact, there is evidence suggesting an increased profile of alternative activated macrophages or M2 macrophages involved in parasite expulsion and tissue repair during helminth infections, which induce protection to the host [36]. However, in cysticercosis, the scenario appears to be different.
During
On the other hand, monocyte-derived DCs co-cultured with CD4 naïve cells in presence of
4. Regulatory mechanisms mediated by cytokines, antibodies, and soluble immune factors
4.1 IL-10
IL-10 is produced by innate cells like myeloid and plasmacytoid DCs and macrophages, and is also produced by Breg cells, Th2, Th17 and Treg cells from the adaptive immune response. This capacity to be produced from several immune cell lineages, depends on the signal pathways activated like ERK, and also from transcription factors like STAT3, STAT4, STAT6 and cytokines like TGF-
4.2 Transforming growth factor beta (TGF-β)
TGF-β is a cytokine involved in some situations during immune and not immune phenomena. It has a role in the control of cell proliferation and differentiation of some cell types like either Treg or Th17 cells [43, 44]. Also, by itself, it has the capacity to induce a suppressive environment in scenarios where required, like mucosal immune reactions. Dysregulation of TGF-β generates inflammatory disorders such as spontaneous colitis [45]. In the
4.3 Osteopontin
Osteopontin (OPN) is a Th1 type cytokine upstream of IL-12 that has a role in the granuloma formation in inflamed tissues [47]. It was shown that blood cells co-cultured with TsES or viable cysticerci from
4.4 Antibodies
Humoral immune response has been described for its essential role against helminth infections, being IgE antibody isotype a cornerstone to induce protection [49]. However, during taeniasis and cysticercosis, little information about the role of B cells has been described. It was shown that an antibody called anti-GK-1 (IgG) obtained from the serum of pigs infected with
4.5 Prostaglandin E2
Some lipids from eicosanoid family derivatives from arachidonic acid, like prostaglandin E2 (PGE2), have been described as potent immunosuppressant molecules [53]. It has been described that administration
5. Immunoregulation mediated by Taenia-derived products
5.1 Paramyosin
Paramyosin is an α-helical coiled coil 100 KDa protein that is present in muscle and tegument of the larval stage of
5.2 Glutathione transferase
Glutathione transferase (GST) is an essential enzyme in the metabolism of cestodes, mainly for the detoxification of xenobiotics, it is localized on the cysticerci tegument of
5.3 TcES or TsES antigens
Analysis of
Studies in our laboratory demonstrated that TcES products have the capacity to block TLR4 and TLR9 initial signaling pathway in DCs, which has a negative effect over their maturation, their production of pro-inflammatory cytokines and also, to induce alloreactive T cell proliferation, but in an IL-10 independent pathway. All these regulatory effects were carbohydrate-dependent in the TcES, because the chemical alteration of glycans switch this tolerogenic environment to one favoring DCs maturation and secretion of pro-inflammatory cytokines (Figure 1) such as IL-12 and TNF-α [62]. Moreover, it was shown that the
Also, it was shown that the nature of antigens of
6. Conclusions
It has been largely known that helminthic infections induce strong Th2-mediated immune responses associated with regulation of inflammatory responses. Here, it has been described the different molecules and pathways altered by
The anti-inflammatory activities and immunoregulatory properties found in both
Lately, we have observed that the mechanisms used by the parasites that cause infectious diseases, such as taeniasis and cysticercosis, are very similar processes, and we dare to suggest that they are the same, to those occurring during the main oncological (solid) pathologies. The fact that a carcinogenic transformed cell induces an immunosuppressive process through immune-checkpoints such as PD1, CTLA-4 or Tim3, is a mechanism that had already been described in the past, during cysticercosis. So, immunoregulation and immunosuppression are natural selection mechanisms that pathogens take advantage of to be able to survive in a hostile environment and turn it to favor them, to face a variety of processes of continuous and varied attack of the immune response. Therefore, understanding and deciphering the why, how, and when these natural selection processes occur, we will be able to apply the lesson obtained during infectious diseases in processes affecting the current public health, like the main oncological pathologies.
Acknowledgments
“This work was supported by CONACYT grant number A1-S-37879 and DGAPA-PAPIIT-UNAM grants numbers IA209720 and IN226519.
AAM | Alternatively activated macrophages |
ConA | Concanavalin A |
CTLA-4 | Cytotoxic T-Lymphocyte Antigen 4 |
DCs | Dendritic cells |
DPI | Days post-infection |
EAE | Experimental autoimmune encephalomyelitis |
ELISA | Enzyme-linked Immuno Assay |
ERK | Extracellular signal regulated kinases |
Foxp3 | Forkhead box P3 transcription factor |
FIZZ1 | Found in inflammatory zone 1 gene |
Gal-9 | Galectin-9 |
Gal-7 | Galectin-7 |
IFN-γ | Interferon-gamma |
IgE | Immunoglobulin E |
IgG | Immunoglobulin G |
IL-2 | Interleukin-2 |
IL-4 | Interleukin-4 |
IL4Rα | Interleukin4 receptor α |
IL-6 | Interleukin-6 |
IL-10 | Interleukin-10 |
IL-12 | Interleukin-12 |
IL-13 | Interleukin-13 |
IP | Intraperitoneal |
MDSC | Myeloid-derived suppressor cells |
NCC | Neurocysticercosis |
NCS | Nervous Central System |
NO | Nitric oxide |
OPN | Osteopontin |
PD1 | Programmed death 1 |
PDL1 | Programmed Death-ligand 1 |
PDL2 | Programmed Death-ligand 2 |
PGE2 | Prostaglandin E2 |
PHA | phytohaemagglutinin |
PMN | Polymorphonuclear cells |
RT-PCR | Real time polymerase chain reaction |
SLAMF1 | Signaling Lymphocytic Activation Molecule 1 |
STAT3 | Signal transducer and activator of transcription 3 |
STAT4 | Signal transducer and activator of transcription 4 |
STAT6 | Signal transducer and activator of transcription 6 |
TcES | Taenia crassiceps excreted/secreted antigens |
TGF-β | Tumor growth factor beta |
TNF-α | Tumor Necrosis Factor Alpha |
Th1 | T helper cells 1 |
Th2 | T helper cells 2 |
Th17 | T helper cells 17 |
Tim3 | T-cell Immunoglobulin domain and Mucin domain 3 |
TLR4 | Toll-like receptor 4 |
TLR9 | Toll-like receptor 4 |
Treg | Regulatory T cells |
Tr1 | T regulatory Type 1 population |
TsES | Taenia solium excreted/secreted antigens |
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