**4.2 Parasitic helminth infections**

Helminth parasites, like protozoan parasites, have significant differences in their biological life cycles, which are reflected in the differences in clinical outcomes seen among helminth parasites. Pathological consequences of most helminth infections have been associated with both with the parasite intensity (or burden) and the relative acuteness or chronicity of the infection, because the helminth parasites modulate/regulate the host response to themselves (parasite-specific immunoregulation) [84].

The immune response against helminths is characterized by the induction of an early immune response of type Th1, with subsequent predominance of a Th2 type

immune response, resulting in a mixture of both Th1/Th2 responses [85, 86], which are dependent on the immune responses mediated by CD4+ T cells [87]. These CD4<sup>+</sup> T cells can function as APCs and play a key role in establishment the cytokine environment, thus directing their differentiation either by suppressing or favoring the inflammatory response at the intestinal level, which is crucial for the expulsion and elimination of the parasite (see **Figure 4**) [88].

This implies that the helminths have developed strategies, such as the evasion or suppression of the host immune response, which prevent their expulsion and allow their long-term survival. It is believed that the modulating effects of the immune system arise from the ability of the helminth to regulate the host immune response, developing mechanisms for the modulation of DCs as key players in the initiation and polarization of adaptive immune responses [89–91].

During the intestinal infection by helminths, the polarization of the cellular immune response to a Th1 type immune response depends on the type of signal derived from DCs. For example, *Trichinella spiralis* larvae group (TSL-1) antigens induce the DCs maturation [92], leading to the expression of MHC II [93, 94], promoting the development of a Th1 type cellular immune response [95]. Several studies, both *in vitro* and *in vivo*, have shown that during the early stage of intestinal infection by *T. spiralis* there is a significant increase of Th1 cytokines such as IL-12 [96, 97], INF-γ [95–98], IL-1β [97–99] and TNF-α [96, 97, 100]. It is possible that this Th1 response is mediated through the TLR-4 activation in DCs by TSL-1, through the signaling pathway TLR4/MyD88/NF-κB [101, 102]. Another example is double-stranded RNA from schistosome eggs has been implicated in the activation of DCs *via* TLR-3, resulting in a Th1-polarized response [103, 104].

Intestinal DCs are classified according to their unique or combined expression of CD11b and CD103, as well as the dependence on either interferon regulatory factor 4 or 8 (IRF4 or IRF8) for their development and/or survival. The intestinal DCs are

#### **Figure 4.**

*Role of DCs in helminth infections. The immune response against helminths is characterized by the induction of an early immune response of type Th1, with subsequent predominance of a Th2 type immune response, resulting in a mixture of both Th1/Th2 responses. The polarization of the cellular immune response to a Th1/Th2 type immune response depends on the type of signal derived from DCs. Description in the text. (figure created by Muñoz-Carrillo* et al*., with BioRender.com).*

*Role of Dendritic Cells in Pathogen Infections: A Current Perspective DOI: http://dx.doi.org/10.5772/intechopen.95551*

capable of process antigens, migrating to mesenteric lymph nodes upon activation, and priming naive T cells. However, IRF8-dependent CD103+ DCs are important for the generation of type 1 responses of both helper and cytotoxic T cells, thus promoting *Trichuris muris* and *Heligmosomoides polygyrus* chronicity. In contrast, IRF4-dependent CD11b+ DCs in the induction of Th2 immunity, notably during infection with *Nippostrongylus brasiliensis*, *T. muris*, and the parasitic trematode *Schistosoma mansoni* [105].

On the other hand, the PRRs from helminths can also activate the DCs for the induction of the Th2 response by interacting with the TLR and CLR. This interaction may promote Th2 responses by suppressing antigen presentation, co-stimulation and/or expression of Th1-promoting cytokines by directly interfering with these pathways. DCs that drive Th2 responses typically exhibit specialized markers, such as CD301b, PDL2, and CD11b, and several receptors for the Th2-related cytokines IL-4R, IL-13R, IL-25R, TSLP-R, and IL-33R. Additionally, the extracellular signalregulated kinase (ERK) and signal transducer and activator of transcription 4 (STAT4) pathway upregulates the costimulatory molecules, CD40, OX40L, and Jagged. Activation of the major transcription factors interferon regulatory factor 4 (IRF4) and KLF4 inhibits IL-12 production and increased IL-10 secretion. These factors typically act individually or in concert to orchestrate Th2 responses in helminth infections [106–108].

In *T. spiralis* infection, the initial exposure of TSL-1 antigens of *T. spiralis* activated CD4+ T cells, as well as DCs, leading to the secretion of large amounts of IL-10. IL-10 suppress cell markers, the proliferation and antigen presentation by DCs and inhibition of IL-12 secretion. In addition, TSL-1 increased the 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 *T. spiralis* expulsion [109]. In addition, it has been shown that phosphatidylserine (PS) lipids derived from schistosomes and ascaris worms, which carry TLR2-activating molecules, promote Th2 responses through DCs [110]. Further, it was found that antigens of *Toxocara canis* were recognized by DC-SIGN expressed on DCs [111], and the induction of a Th2 response *in vivo* by antigens of the parasitic nematode *Brugia malayi*, as well as the free-living nematode *Caenorhabditis elegans*, was found to be dependent on intact glycans [112]. These findings together suggest that certain helminth glycans can serve as PAMPs that instruct DCs through CLR to boost polarized Th2 responses [113].
