**6.2 Immune system activation by parasitic helminth infection**

More than two billion people around the world are infected with helminth parasites. Parasitic helminth infections are a major public health problem worldwide due to their ability to cause great morbidity and socioeconomic loss [141, 142].

The immune response against helminth parasites is characterized by the induction of an early Th1-type immune response, with the subsequent predominance of a Th2 type immune response, resulting in a mixture of both Th1/Th2 immune responses [143, 144], which depend on the CD4+ T cells [145]. The CD4<sup>+</sup> T cells have a key role in the establishment of the cytokine environment during helminth parasite infection, thus directing their differentiation either by suppressing or favoring the inflammatory response at the intestinal level, which is crucial for the elimination of the parasite [146] (**Figure 5**).

PAMPs derived from helminth parasites induce the activation and maturation of dendritic cells [147, 148], promoting the development of the Th1 immune response [149], which results in a significant increase of Th1 cytokines such as IL-12 [150–152], INF-γ [149–153], IL-1β [152, 154], and TNF-α [150–152, 155] (**Figure 5**). However, in recent years, several studies have shown that this immune response of Th1 type favors infection by helminth parasites. On the one hand, IL-12 and INF-γ are two important cytokines against infection by helminth parasites, since they participate in the polarization of the Th1 type immune response [149–151, 153]. However, exogenous IL-12 is capable of suppressing intestinal mastocytosis, delaying the parasite expulsion, and increasing the parasite burden at the muscular level [156]. INF-γ induces the expression of iNOS, activates transcription factors such as NF-κB [157], and regulates the production of pro-inflammatory cytokines such as TNF-α [158]. Studies have shown that TNF-α is a cytokine that is produced during

#### **Figure 5.**

*Immune Response Activation and Immunomodulation*

induction of adaptive immunity [119].

cytokine-activated macrophages are central to the innate response to intracellular parasites. Innate cytokine and dendritic cell responses also play a critical role in the

During the initial stage of parasitic protozoan infections, intestinal epithelial cells (IECs) bind and recognize PAMPs through PRRs [120] such as TLR-2 and TLR-4 [121], which activates NF-κB and leads to the production of proinflammatory cytokines [122], including IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α [123, 124], which induces the activation of a Th1 type response [125]. IFN-γ is involved in clearance of infection, through the activation of neutrophils and macrophages

are involved protection in vaccinated mice [133]. Several studies suggest a role for IFN-γ in the pathogenesis of parasitic protozoan infections. In both humans and animal models, the production of high levels of IFN-γ is associated with resistance to infection [134–136], while low levels of IFN-γ are associated with an increased susceptibility to infection. Therefore, it is considered highly probable that IFN-γ provides protection against infection by activation of neutrophils and/or macrophages [125]. The production of reactive oxygen species (ROS) and NO through the complex of NADPH oxidase and iNOS, respectively, plays a critical role in the elimination of protozoan parasites [131, 132]. In experimental studies, infection protection was mediated by IFN-γ from NK T cells (NKT), while TNF-α is produced by increased tissue damage [137, 138], together with IL-1 and IL-8 [139] (**Figure 4**). On the other hand, the antigenic exposure of protozoan parasites activates a Th2-type immune response by the host, inducing the production of anti-inflammatory cytokines such as IL-4, IL-10 [125], IL-5 and IL-13, which try to attenuate the Th1 type response characterized also by the INF-γ production, leading to upregulation of Th2 cytokine responses (IL-4, IL-5, and IL-13) and Th17 (IL-17), suppressing the production of Th1 cytokines [140] (**Figure 4**). In addition, another cytokine of anti-inflammatory importance is TGF-β, which acts in a synergistic manner to counteract this Th1 type response, activating macrophages which produce

*Cytokines profile in parasitic protozoan infections. The immune defense mechanisms against protozoan parasites involve several immune cells such as neutrophils, macrophages, NK cells, and CD4+*

*cells are capable to produce proinflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, promoting type 1 immune response. Likewise, protozoan parasites activate a Th2-type immune response, producing anti-inflammatory cytokines such as IL-4, IL-10, IL-5, and IL-13, suppressing the production of Th1* 

T cells

 *T cells. These* 

(**Figure 4**) [126–132]. It has been also shown that IFN-γ-producing CD4+

**22**

**Figure 4.**

*cytokines.*

*Cytokines profile in parasitic helminth infection. The immune response against helminth parasites is characterized by the induction of an early Th1 type immune response, which results in a significant increase of Th1 cytokines such as IL-12, INF-γ, IL-1β, and TNF-α. Then, there is a subsequent predominance of a Th2 type immune response characterized by the release of IL-4, IL-5, IL-10, and IL-13 favoring helminth parasites expulsion.*

intestinal infection by helminth parasites [150, 151, 159], which is necessary in the protection against the parasite through the Th2 immune response [160]. However, several studies have associated the production of TNF-α with the development of intestinal pathology during infection by helminth parasites [155, 161, 162]. One of the effects of TNF-α is the iNOS expression and consequently the NO production [163–165]. Helminth parasite antigens are capable to induce the expression of iNOS, with the subsequent production of NO [166], which acts mainly as an effector molecule against both extracellular and intracellular parasites [167]. Studies in iNOS knockout mice infected with helminth parasites, showed a reduction in the expression of Th2 cytokines (IL-4, IL-5), a reduced humoral response (IgG and IgE), with a decrease in mastocytosis. However, no significant difference was observed in the helminth parasite expulsion, although iNOS knockout mice showed a decrease in intestinal pathology compared to wild-type animals. These results suggest that NO is not required for the helminth parasite expulsion, but its production is responsible for the intestinal pathology [155, 168]. With respect to IL-1β, it is well known that it participates in the intestinal inflammatory response in the helminth parasites infection, observing high levels during intestinal infection. However, until now, the role of IL-1β is not well understood [159].

With respect to the Th2 type immune response, in vitro studies have shown that helminth parasite antigens are capable of dendritic cells activating, inducing the synthesis of Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13 [147, 149, 153, 169]. Likewise, studies in in vivo models have shown that helminth parasites infection is a significant increase in the synthesis of IL-4, IL-5, IL-10, and IL-13 [150, 151, 159, 170] (**Figure 5**). IL-10 may suppress antigen presentation by dendritic cells and inhibition of IL-12 secretion. In addition, helminth parasite antigens increased both IL-4 and IL-10 production derived from Th2 cells with a decrease in INF-γ production, polarizing the immune response to a strong Th2 cellular immune response, protective and responsible for the helminth parasite expulsion [143]. IL-10 is a Th2 cytokine, which is necessary for a successful intestinal immune response. This is because the absence or decrease of IL-10 causes a significant delay in the helminth parasite expulsion and an increase in the parasite burden [171]. IL-4 and IL-13 induce muscle cells hypercontractility of the jejunum and intestinal mastocytosis, promoting the helminth parasite expulsion [161, 172]. In IL-4/IL-13 mice deficient, a reduction in the helminth parasite expulsion, mastocytosis, and development of intestinal pathology was observed [161, 162, 173, 174]. Therefore, these studies suggest that IL-4 and IL-13 can regulate the induction of the protective Th2 immune response and intestinal inflammation, both associated with the helminth parasite expulsion [162]. During the Th2 immune response, the cytokines such as IL-4, IL-5, and IL-13 stimulate IgE synthesis [175], inducing mast cell and eosinophil hyperplasia [176], triggering immediate hypersensitivity reactions, and promoting the helminth parasite expulsion from the intestine [177]. However, mast cells and eosinophils are involved in tissue damage, thus promoting the inflammatory response. It suggests that the protective role of the Th2 type immune response is not sufficient facing the challenge against helminth parasite infections, as it contributes to the development of immunopathology [178] (**Figure 5**).

### **7. Conclusion**

Although cytokines are produced with the purpose of modulating the immune response against infections caused by microorganisms, such as bacteria, fungi, viruses, and parasites, there is evidence that these microorganisms can induce cytokine production with bad prognostic to host recovery. In this sense, overproduction

**25**

provided the original work is properly cited.

Aguascalientes, Aguascalientes, Mexico

\*Address all correspondence to: mcbjlmc@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens*

of inflammatory cytokines may be responsible for the severe damage observed in many microorganism infections. For this reason, a better understanding over the cytokine balance related to diseases by microorganisms is required to avoid severe damage against the organism caused by overreaction of the immune system.

We thank the authors who collaborated in the writing of this chapter: Dr. José Luis Muñoz, Dr. Juan Francisco Contreras, Dr. Oscar Gutiérrez, Dra. Paola Trinidad Villalobos, Dra. Viridiana Elizabeth Hernández and Luis Guillermo; as well as the Universities involved: Cuauhtémoc University Aguascalientes, Autonomous University of Nuevo Leon, and University of Guadalajara. We also thank the finan-

\*, Juan Francisco Contreras-Cordero2

1 Faculty of Odontology, School of Biomedical Sciences of the Cuauhtémoc

2 Laboratory of Immunology and Virology, Faculty of Biological Sciences of the Autonomous University of Nuevo Leon, San Nicolás de Los Garza, Nuevo León,

3 Laboratory of Immunology, Department of Earth and Life Sciences, University Center of Lagos de Moreno of the University of Guadalajara, Lagos de Moreno,

4 Faculty of Medicine, School of Biomedical Sciences of the Cuauhtémoc University

, Paola Trinidad Villalobos-Gutiérrez<sup>3</sup>

and Viridiana Elizabeth Hernández-Reyes1

,

,

*DOI: http://dx.doi.org/10.5772/intechopen.80843*

**Acknowledgements**

**Conflict of interest**

**Author details**

Mexico

Jalisco, Mexico

José Luis Muñoz-Carrillo1

Oscar Gutiérrez-Coronado3

Luis Guillermo Ramos-Gracia4

cial support for chapter publication.

We have no conflict of interest related to this work.

University Aguascalientes, Aguascalientes, Mexico

*Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens DOI: http://dx.doi.org/10.5772/intechopen.80843*

of inflammatory cytokines may be responsible for the severe damage observed in many microorganism infections. For this reason, a better understanding over the cytokine balance related to diseases by microorganisms is required to avoid severe damage against the organism caused by overreaction of the immune system.
