Harnessing the Helminth Secretome for Therapeutic Immunomodulators
Figure 1
Cellular interactions in the immune response against helminths. Helminth-secreted excretory/secretory (ES) products are capable of inhibiting in vitro generated dendritic cells (DCs). They can inhibit the maturation of DCs and induce the expansion of functional Tregs [35, 36]. The helminth-induced TH2 response starts with the recognition of parasitic pathogen-associated molecular patterns (PAMPs) by certain pattern recognition receptors (PRRs) that are expressed on the DCs of the host [13, 37]. Through contact with the antigen, the DCs become activated, allowing them to act as antigen-presenting cells (APC) after the migration to the adjacent lymph nodes, with the ability of processing and presenting the antigen to T cells to initiate an immune response [16]. The helminth-induced host immune response is focused on the protection of the host organism and is mediated by TH2 cells. This response includes IL-4, IL-5, IL-13, and IL-10 secretion and production of IgG4 and IgE by B cells, as well as the activation of effector cells such as mast cells, eosinophils, and basophils [35]. Affected by IL-4 and IL-13 occurs the differentiation of alternatively activated macrophages (AAMs) which can inhibit the proliferation of other cells like TH1, TH2, and TH17 cells. Thus, these cells have strong anti-inflammatory properties, which are manifested by the secretion of IL-10 and TGF-β as well as the expression of additional genes [13, 16, 32]. Furthermore, IL-4 and IL-13 lead to an increased contractility of smooth muscle cells and a hypersecretion of mucus for expulsion of intestinal helminths [38]. Immune complexes of IgE bind to high affinity IgE receptors (FcRI) on mast cells and basophils; this leads to an activation of these cells and a secretion of inflammatory mediators like histamine, heparin, leukotrienes, and prostaglandin D2 [16, 38–40]. PAMPs: pathogen-associated molecular patterns; PRRs: pattern recognition receptors; ES: excretory/secretory; IL: interleukin; Ig: immunoglobulin; AAM alternatively activated macrophages; TH: T helper cells; TGF-: transforming growth factor-; ADCC: antibody dependent cellular cytotoxicity; EDN: eosinophil derived neurotoxin; DC: dendritic cell; APC: antigen-presenting cell; Treg: regulatory T cell.
