Host responses to intestinal nematodes

Host responses to intestinal nematodes Abstract Helminth infection remains common in developing countries, where residents who suffer from the consequences of such infections can develop serious physical and mental disorders and often persist in the face of serious economic problems. Intestinal nematode infection induces the development of Th2-type immune responses including the B-cell IgE response; additionally, this infection induces an increase in the numbers and activation of various types of effector cells, such as mast cells, eosinophils and basophils, as well as the induction of goblet cell hyperplasia, anti-microbial peptide production and smooth-muscle contraction, all of which contribute to expel nematodes. Innate immunity is important in efforts to eliminate helminth infection; cytokines, including IL-25, IL-33 and thymic stromal lymphopoietin, which are products of epithelial cells and mast cells, induce Th2 cells and group 2 innate lymphoid cells to proliferate and produce Th2 cytokines. Nematodes also facilitate chronic infection by suppression of immune reactions through an increased number of Treg cells. Immunosuppression by parasite infection may ultimately be beneficial for the host animals; indeed, a negative correlation has been found between parasite infection and the prevalence of inflammatory disease in humans. helminths, IgE, IL-13, mast cells, Th2 Introduction The 2015 Nobel Prize in Physiology or Medicine was awarded to Satoshi Omura, William Campbell and Youyou Tu (1, 2). Omura and Campbell developed the revolutionary therapeutic drug, ivermectin (3, 4), to cure both onchocerciasis (river blindness) and lymphatic filariasis; Tu developed a new malaria treatment, artemisinin (5). Awarding the Nobel Prize for development of anti-parasitic drugs indicates that parasitic infections remain highly important targets for medical research. Indeed, according to a World Health Organization (WHO) survey, >1 billion people worldwide are currently infected with intestinal parasites (6). When infected with parasites, many individuals develop a chronic infection, which often manifests as severe anaemia and malnutrition and is dependent on the type and number of parasites (7). The infection of children with parasites may induce developmental disorders and delay cognitive development; for some children, these infections may become lethal. Parasites include the unicellular eukaryotes, protozoa (e.g. malaria, toxoplasma, amoeba) and the multicellular helminths, which are classified as trematodes, cestodes and nematodes (nematodes include trichinella, hookworm, ascarid, filaria) (8). There is a wide variety of methods and sites of parasitic infections; similarly, there is a wide variety of host immune responses that are dependent upon the nature of the infecting parasite. However, there are some general trends within parasitic infections: Th1-type immune responses develop in response to protozoan infections (9), whereas Th2-type immune responses develop in response to helminthic infections (10). Th2 immune cells aid the immune response through production of Th2 cytokines. These Th2 cytokines induce the production of antibodies, particularly IgE, and promote an increase in the number of eosinophils and basophils in blood and tissues (11). Furthermore, in mucosal tissues, such as the gastrointestinal tract, Th2 cytokines induce goblet cell hyperplasia and mucin production, as well as the accumulation of mast cells (12, 13). In addition to the immune response induced by Th2 cells, the broader mechanism of anti-helminthic innate immunity is under active investigation. Notably, group 2 innate lymphoid cells (ILC2s), activated by cytokines from epithelial cells, have received much attention as a powerful source of Th2 cytokines (14, 15). Moreover, various immune responses have developed to attack infecting parasites, but many helminths acquire the ability to escape these immune responses (16); thus, the infection becomes chronic (17). This recent knowledge of innate type and acquired type immune responses against helminths was largely obtained by intensive studies on intestinal nematode infections. Thus, in this article, we focus on immune responses to common intestinal nematodes of experimental animals. Intestinal nematodes strongly induce a Th2-type immune response The importance of T cells in the anti-parasitic response was originally demonstrated in classical experiments where nude mice infected with various helminths showed their inability to expel infected parasites normally (18–20). In normal hosts infected with helminths, naive T cells differentiate into Th2 cells. During infection by Trichuris muris (T. muris), mice with a dominant Th2-type immune response are resistant to the infection, whereas mice with a dominant Th1-type immune response are susceptible to the infection (21). This indicates that Th2 cell differentiation is important for protection against helminths (Fig. 1). Fig. 1. View largeDownload slide Th2-dominant immune responses protect host animals from nematode infection. When nematode larvae infect host animals, the worms stimulate or damage epithelial cells, which then produce epithelial cell-derived cytokines. Parasites release ES products, including PGE2, which suppresses the induction of IL-12 from dendritic cells (DCs). ES products also stimulate the release of NMU from neurons. Epithelial cell-derived cytokines and NMU cooperatively activate ILC2s to produce Th2 cytokines. Antigen-captured DCs induce development of Th2 cells, which can then produce Th2 cytokines. Th2 cytokines activate multiple effector cells including mast cells, basophils (Baso), eosinophils (Eo), goblet cells, M2 macrophages (M2Mϕ) and B cells; some of these effector cells contribute to expulsion of the helminths dependently on the type of helminths, for instance goblet cells induce expulsion of N. brasiliensis and mast cells are important in expulsion of S. venezuelensis. Fig. 1. View largeDownload slide Th2-dominant immune responses protect host animals from nematode infection. When nematode larvae infect host animals, the worms stimulate or damage epithelial cells, which then produce epithelial cell-derived cytokines. Parasites release ES products, including PGE2, which suppresses the induction of IL-12 from dendritic cells (DCs). ES products also stimulate the release of NMU from neurons. Epithelial cell-derived cytokines and NMU cooperatively activate ILC2s to produce Th2 cytokines. Antigen-captured DCs induce development of Th2 cells, which can then produce Th2 cytokines. Th2 cytokines activate multiple effector cells including mast cells, basophils (Baso), eosinophils (Eo), goblet cells, M2 macrophages (M2Mϕ) and B cells; some of these effector cells contribute to expulsion of the helminths dependently on the type of helminths, for instance goblet cells induce expulsion of N. brasiliensis and mast cells are important in expulsion of S. venezuelensis. Th2 cells are induced by parasitic infection and produce Th2 cytokines, including IL-3, IL-4, IL-5, IL-9 and IL-13, which activate effector mechanisms that are necessary to eliminate parasitic intestinal helminths (22–26). Mice that lack IL-4 and IL-13 production develop chronic infections, even when the mice are genetically resistant to infection (27). Conversely, administration of an antibody that neutralizes IFN-γ and thus enhances the Th2-type immune response, to mice with a susceptible genetic background causes consistent expulsion of the worms (21). Although it is unclear why naive T cells differentiate into Th2 cells in hosts infected by helminths, there are several possible reasons. First, helminths exhibit very few TLR ligands that induce dendritic cells to produce IL-12, which is important for differentiation of Th1 cells. Second, parasites might produce excretory/secretory (ES) molecules that suppress IL-12 production while enhancing production of cytokines that inducing Th2 cells [e.g. thymic stromal lymphopoietin (TSLP), IL-25 and IL-33] from non-hematopoietic epithelial cells (28–30). Under these circumstances, Th2 cells and Th2 cytokines work to induce the activation of many cell types with anti-helminthic functions, including mast cells, eosinophils, basophils and epithelial cells (discussed below). Furthermore, IL-4 induces B cells to produce antibodies, including IgE. These effector cells and molecules act synergistically to expel infected helminths. We note that ILC2s are an important source of Th2 cytokines, inducing substantial production of IL-5, IL-9 and IL-13 in response to the IL-33 released from nematode-damaged epithelial cells. Recently, Cardoso et al. (31) reported that a neuropeptide, neuromedin U (NMU), is produced by mucosal neurons stimulated either by IL-33 or by Nippostrongylus brasiliensis (N. brasiliensis) ES products. NMU strongly stimulates activation of ILC2s, inducing Th2 cytokine production (32), and contributes to protection against N. brasiliensis infection (33) (Fig. 1). Functions of mast cells IL-3 and IL-9, products of activated Th2 cells, synergistically induce the accumulation of mucosal mast cells (MMCs) in the mucosa of the small intestine (34). These IL-3- and IL-9-stimulated MMCs release chondroitin sulfate, preventing nematode adhesion to, and penetration of, the mucous membrane (Fig. 2A) (35). Strongyloides spp. are expelled by this mechanism (36–38). Strongyloides venezuelensis (S. venezuelensis) is a convenient infection model of human Strongyloides; its adult worms invade the intestinal mucosa and excrete large amounts of eggs into the intestinal lumen (39). However, when a Th2-type immune response is induced, these adult worms are expelled from the intestinal tract after ~12 days of infection, largely by action of MMCs (38). However, even when MMCs are present, clearance of the infection is delayed in Fc receptor γchain (FcRγ)-deficient mice (37). This indicates that antibodies are necessary for parasite expulsion by MMCs; however, the critical antibody isotype remains unknown. Fig. 2. View largeDownload slide Role of mast cells in the expulsion of nematode infection. (A) Th2 cells produce IL-3 and IL-9, which induce proliferation and differentiation of MMCs. MMCs express both FcεRI and FcγRIII, which can bind nematode ES antigen (ES-Ag) using IgE and IgG1, respectively, resulting in activation of the MMCs to release granule contents and expel S. venezuelensis. (B) MMCs produce IL-33 upon activation of P2X7R by ATP from damaged epithelial cells; this IL-33 activates ILC2s to produce IL-13 resulting in induction of goblet cell hyperplasia to protect against H. polygyrus infection. Fig. 2. View largeDownload slide Role of mast cells in the expulsion of nematode infection. (A) Th2 cells produce IL-3 and IL-9, which induce proliferation and differentiation of MMCs. MMCs express both FcεRI and FcγRIII, which can bind nematode ES antigen (ES-Ag) using IgE and IgG1, respectively, resulting in activation of the MMCs to release granule contents and expel S. venezuelensis. (B) MMCs produce IL-33 upon activation of P2X7R by ATP from damaged epithelial cells; this IL-33 activates ILC2s to produce IL-13 resulting in induction of goblet cell hyperplasia to protect against H. polygyrus infection. Recently, we investigated this aspect, using mice deficient in activation-induced cytidine deaminase (AID), who have no capacity to switch immunoglobulin classes during infection (40). Thus, they can produce IgM, but not IgG, IgA or IgE, when infected with S. venezuelensis. Further, they required a longer period (>9 additional days) for parasite expulsion, compared with wild-type mice. Th2 cells and MMCs exhibit normal development in both wild-type and AID-deficient mice (41). Additionally, during infection with N. brasiliensis, AID-deficient mice are able to expel N. brasiliensis, suggesting that their goblet cell development remains intact. Therefore, we purified IgG1 and/or IgE from the sera of normal mice that had been infected twice with S. venezuelensis; we administered these purified antisera to AID-deficient mice. Both isotypes promoted expulsion of parasites in a dose-dependent manner (41). Furthermore, a combination of IgG1 and IgE collaboratively augments the capacity of AID-deficient mice to expel S. venezuelensis (41). IgE constitutes a trace (~1/200) compared with the concentration of IgG in blood, but demonstrates a strong effect; in normal mice, both IgG and IgE work together to eliminate S. venezuelensis. Thus, the FcRγ-mediated activation of MMCs by cooperative efforts of IgG1 and IgE is important for elimination of S. venezuelensis. We previously reported that C57BL/6 mice, after treatment with IL-18 and IL-2, are able to promptly expel surgically implanted adult S. venezuelensis worms (38). These mice developed mucosal mastocytosis and exhibited high levels of serum mMCP1, a marker of MMC activation. These results revealed that proper activation of MMCs is important for expulsion of S. venezuelensis. Notably, the protective function of mast cells is observed in the late stages of infection, where Th2 cells stimulate various cell types through the activity of Th2 cytokines (42). In contrast, during defence against the rodent nematode Heligmosomoides polygyrus (H. polygyrus), mast cells are required for the early Th2 immune response (43, 44). KitW/KitW-v mice lacking mast cells cannot sufficiently induce Th2 immune responses against H. polygyrus. These studies also demonstrated the importance of IL-25, IL-33 and TSLP from mast cells. Shimokawa et al. also reported the importance of IL-33 production from mast cells, and further noted that Spi-B-deficient mice possess an increased number of mast cells and are thereby resistant to H. polygyrus (45). These mast cells utilize ATP stimulation to produce IL-33, which activates ILC2s to produce IL-13 and goblet cell hyperplasia (Fig. 2B). Parasite infection and eosinophils The accumulation of eosinophils in nematode-infected sites was shown in classical experiments (46). Later, investigators discovered the relationship between parasitic infection and pulmonary eosinophilia (Löffler’s syndrome) (47). Although the mechanism of this eosinophil accumulation was unknown for many years, we described this mechanism using an S. venezuelensis infection model. First, we demonstrated that nasal administration of IL-33 could induce pulmonary eosinophilia, even in Rag2-deficient mice (48). Next, we examined whether S. venezuelensis could induce pulmonary eosinophilia in wild-type and Rag2-deficient mice (49). Some parasitic intestinal nematode larvae, including S. venezuelensis and N. brasiliensis, do not travel directly to the intestinal tract upon percutaneous or oral infection; instead, they arrive at the lung via the bloodstream, then penetrate the alveolar cavity and ascend to the throat, where they are swallowed with sputum. Finally, they reach the small intestine and begin maturation (50, 51). Thus, injury of the lung tissue is induced by parasitic larvae, stimulating release of IL-33 from type II alveolar epithelial cells (ATIIs). This IL-33 induces ILC2s to accumulate, proliferate and produce IL-5 and IL-13, which combine to induce pulmonary eosinophilic inflammation (Löffler’s syndrome) (Fig. 3) (49). Fig. 3. View largeDownload slide Mechanism of Löffler’s syndrome. Strongyloides venezuelensis larvae infect host animals through the skin, then migrate to the lung via the bloodstream (shown at the bottom of the figure). When the larvae reach the lung, they penetrate blood vessels and alveolar walls by disrupting the endothelial and epithelial cell layers. The dead cells release damage-associated molecular patterns such as IL-33, which stimulates ILC2s to proliferate and produce Th2 cytokines. IL-5 and IL-13 cooperatively induce eosinophilia in the lung. AM, alveolar macrophage; ATI, type I alveolar epithelial cell; ATII, type II alveolar epithelial cell. Fig. 3. View largeDownload slide Mechanism of Löffler’s syndrome. Strongyloides venezuelensis larvae infect host animals through the skin, then migrate to the lung via the bloodstream (shown at the bottom of the figure). When the larvae reach the lung, they penetrate blood vessels and alveolar walls by disrupting the endothelial and epithelial cell layers. The dead cells release damage-associated molecular patterns such as IL-33, which stimulates ILC2s to proliferate and produce Th2 cytokines. IL-5 and IL-13 cooperatively induce eosinophilia in the lung. AM, alveolar macrophage; ATI, type I alveolar epithelial cell; ATII, type II alveolar epithelial cell. In vitro experiments demonstrated that eosinophils have the ability to kill schistosomula in combination with antibodies and complement (52, 53). Importantly, IgE and eosinophil cytotoxicity (antibody-dependent cellular cytotoxicity) has been widely reported as a mechanism for helminth exclusion (54). However, the in vivo role for IgE and eosinophils is not yet clear because expression of high-affinity FcεRIα is not often found in murine eosinophils, the most common experiment animal model. During N. brasiliensis infection of eosinophil-deficient mice and normal wild-type mice, comparable numbers of adult worms harboured in the intestinal tract are detected in both types of mice; however, increased number of eggs are detected only in faeces of the eosinophil-deficient mice (55). During H. polygyrus infection, eosinophil-deficient mice harbour more worms than wild-type mice do (56). In microfilarial infection achieved by intravenous administration of Brugia malayi, the population of microfilaria decreases shortly after infection in wild-type mice, whereas the population remains stable after infection in eosinophil-deficient mice (57). Thus, eosinophils contribute in a limited manner to host defence, as shown by the lack of effect in infectious models of Schistosoma mansoni (58), Strongyloides stercoralis larvae (59) and T. muris (60), though eosinophils are able to kill the larvae of all these species in vitro. Conversely, it has been reported that eosinophils may promote infection (61). New larvae of Trichinella spiralis (T. spiralis) formed in the intestinal tract migrate to muscles, where they invade muscle fibres and become capsular larvae (62). Here, Treg cells are induced by eosinophil-produced IL-10; larvae can thus survive because IL-10 suppresses production of nitric oxide (NO). However, eosinophil-deficient mice exhibit insufficient Treg cell differentiation, enhanced IFN-γ expression, enhanced NO production and a reduced cystic larvae population (63). Furthermore, larvae of Litomosoides sigmodontis (L. sigmodontis), a rodent filaria, grow more rapidly in the presence of eosinophils, suggesting that eosinophils support the growth of larvae (64). Once a host is infected by a parasite, it can gain immunity against the parasite, and thus become resistant to re-infection by the same parasite (65, 66). When wild-type mice are re-infected with N. brasiliensis, parasite larvae are captured in the skin and fewer larvae are able to reach the lung, whereas eosinophil-deficient mice allow many larvae to reach the lung (55). Eosinophils may support parasitism of T. spiralis during primary infection; however, eosinophils work during re-infection to inhibit migration of new larvae and proliferation of intramuscular larvae (61). Parasite-specific antibodies support eosinophil-mediated infection resistance. Antibodies support in vitro activities of eosinophils against T. spiralis larvae: binding, degranulation and killing (67). Antibodies have also been shown to synergize with basophils and M2 macrophages to inhibit movement of N. brasiliensis and H. polygyrus (68); eosinophils may function similarly to control parasites. Eosinophils can release DNA to capture antigens (similar to neutrophils); this has been demonstrated in vitro during capture of Haemonchus contortus larvae (69). Protective immunity of basophils to parasitic infection Min et al. (70) reported an ~50-fold increase in number of IL-4-producing basophils in the liver and lungs of mice infected with N. brasiliensis, as well as a focused role of basophils in the host response. In order to clarify the in vivo function of basophils, the basophils were removed using antibodies for FcεRIα chain (MAR-1) (71) or for CD200R3 (Ba103) (72); this was used in some parasite infection models. Oral administration of whipworm eggs (T. muris) in a resistant murine model leads to goblet cell hyperplasia in the intestinal epithelium at 21 days post-infection; it also causes development of Th2 cells in mesenteric lymph nodes, thus expelling the worms (21). In this model, basophils also increase in a TSLP-dependent manner. However, depletion of basophils through MAR-1 antibody administration shifts the dominant cell balance in normal mice from Th2 to Th1; this leads to suppression of goblet cell proliferation in the small intestine epithelium, of mucin production and of production of resistin-like molecule-β (RELMβ), thereby prolonging the infection. Thus, in the absence of basophils, host animals fail to develop a Th2-type immune response and cannot substantially expel worms (73, 74). In contrast, although Ba103-mediated basophil removal suppresses Th2 cell development, IgE production and eosinophil proliferation during filarial L. sigmodontis infection, there is no effect on the population of infected filaria (75). Thus, interesting results have been obtained, supporting previous hypotheses that basophils influence Th2 differentiation (73, 76–78). However, since FcεRIα and CD200R3 are also expressed on mast cells, this method may not provide sufficient specificity. To resolve this problem, genetically modified basophil-deficient mice were developed (e.g. Mcpt8-DTR, Mcpt8Cre, BasTreck) (79). Even when basophils were removed in Mcpt8-DTR mice by administration of diphtheria toxin, infection with N. brasiliensis induced conventional differentiation of T cells into Th2 cells, as well as normal antibody production and eosinophil induction; importantly, the worm burden was also unaffected. This indicates that basophils are not involved in the host immune response to primary infection by N. brasiliensis (80). Basophils are, however, important in the immune response to re-infection by N. brasiliensis. When N. brasiliensis re-infects wild-type mice, the larvae are captured intra-dermally and blocked from migration to the lungs. Additionally, basophils and monocytes accumulate around larvae captured within the skin. In contrast, during infection of basophil-deficient mice, larvae can migrate to the lungs as in primary infections. Notably, parasite-specific IgE binds to FcεRI on basophils. When parasite antigens interact with basophil-bound IgE, the basophils produce IL-4 and IL-13. This stimulates monocyte differentiation into M2 macrophages, production of the arginine-degrading enzyme arginase 1 and the capture of larvae in skin (Fig. 4). Thus, during re-infection, the antibody-dependent immune response blocks infection of N. brasiliensis (68). However, basophils do not completely block invasion of N. brasiliensis in the skin, as some larvae can pass through the lungs and migrate to the intestinal tract. In this case, basophils also protect against parasitic infection of the small intestine. Binding of parasite antigen to FcεRI-bound parasite-specific IgE causes basophils within the small intestine to produce IL-4. The IL-4 then increases proliferation and activation of Th2 cells, resulting in elimination of the worms (Fig. 4). Basophils also induce Th2 enhancement in the intestinal tract during H. polygyrus infection (81). Fig. 4. View largeDownload slide Contributions of basophils during re-infection by nematodes. On re-infection by N. brasiliensis larvae in the skin, basophils are rapidly recruited to the infected site. In the presence of IgE, basophils produce IL-4 and IL-13. IL-4 stimulates macrophages to differentiate into M2 macrophages and induces arginase 1 (Arg1) production, which inhibits larval migration to the lung. Some larvae that escape from the basophil-mediated skin trap can migrate to the intestine, where basophils also recognize worm antigens by IgE–FcεRI and produce IL-4. IL-4 stimulates Th2 cell accumulation and the production of Th2 cytokines that activate effector cells for expulsion of the parasite. Fig. 4. View largeDownload slide Contributions of basophils during re-infection by nematodes. On re-infection by N. brasiliensis larvae in the skin, basophils are rapidly recruited to the infected site. In the presence of IgE, basophils produce IL-4 and IL-13. IL-4 stimulates macrophages to differentiate into M2 macrophages and induces arginase 1 (Arg1) production, which inhibits larval migration to the lung. Some larvae that escape from the basophil-mediated skin trap can migrate to the intestine, where basophils also recognize worm antigens by IgE–FcεRI and produce IL-4. IL-4 stimulates Th2 cell accumulation and the production of Th2 cytokines that activate effector cells for expulsion of the parasite. Mast cells are important for resistance against S. venezuelensis infection; this was determined by studies of c-Kit mutant mice that lack mast cells (82). Involvement of basophils has been suggested, since infection with worms is more prolonged in c-Kit mutant IL-3-deficient mice where mast cells and basophils cannot increase (36). Recently the role of basophils was analysed in a basophil-deficient mouse model (Mcpt8-DTR), where an increased number of eggs were observed in faeces and an increased number of adult worms were observed in the small intestine; however, prolonged infection, as seen in mast cell-deficient mice, was not noticeable. Furthermore, S. venezuelensis infects skin, as does N. brasiliensis, but basophils do not protect against re-infection by S. venezuelensis (83). Activation of non-immune cells by Th2 cytokines Th2 cytokines, including IL-13 (produced by local Th2 cells and ILC2s), act on non-immune cells and are involved in the expulsion of helminths (Fig. 5) (26, 84). In the gastrointestinal tract, IL-13 directly acts on intestinal epithelial cells to induce goblet cell hyperplasia and mucin production, which prevent helminth adhesion to the intestinal surface and wash them away (85). Fig. 5. View largeDownload slide IL-13 is a central mediator in the intestine for expulsion of nematodes. IL-13 from Th2 cells or ILC2s stimulates epithelial cells in the intestine. Activated epithelial cells proliferate and differentiate into Paneth cells, goblet cells and tuft cells. Paneth cells produce anti-microbial peptides, such as RELMβ; goblet cells secrete massive amounts of mucin into the intestinal lumen; tuft cells produce IL-25, which activates ILC2s. Enhanced proliferation of epithelial cells hastens the migration of epithelial cells towards the tips of villi, where senescent or dead epithelial cells are shed. Additionally, IL-13 acts on smooth muscle cells to increase peristalsis. These cooperative effects remove nematodes from the intestinal mucosa. Fig. 5. View largeDownload slide IL-13 is a central mediator in the intestine for expulsion of nematodes. IL-13 from Th2 cells or ILC2s stimulates epithelial cells in the intestine. Activated epithelial cells proliferate and differentiate into Paneth cells, goblet cells and tuft cells. Paneth cells produce anti-microbial peptides, such as RELMβ; goblet cells secrete massive amounts of mucin into the intestinal lumen; tuft cells produce IL-25, which activates ILC2s. Enhanced proliferation of epithelial cells hastens the migration of epithelial cells towards the tips of villi, where senescent or dead epithelial cells are shed. Additionally, IL-13 acts on smooth muscle cells to increase peristalsis. These cooperative effects remove nematodes from the intestinal mucosa. Activated epithelial cells (Paneth cells) also secrete anti-microbial peptides, including RELMβ (86). The RELMβ is important for eliminating parasites (e.g. N. brasiliensis and H. polygyrus) that live in the lumen; however, it is ineffective against nematodes such as T. spiralis entering the epithelium. IL-13 and IL-9 expel helminths from the intestinal tract by activating intestinal smooth muscle cells to enhance peristalsis (87, 88). In addition, enhancement of epithelial cell turnover is an important host response against helminth infection. Epithelial cells actively divide near the base of the villi, differentiate into absorptive epithelium and goblet cells and migrate towards the tip of the villi, where senescent epithelial cells drop off from the tip (89). During T. muris infection, this epithelial cell replacement is enhanced by the action of IL-13 and amphiregulin, thereby eliminating adherent worms and reducing the epithelial area where they can grow (90, 91). Furthermore, tuft cells in the intestinal epithelium constitutively produce IL-25 to maintain ILC2s in the lamina propria. IL-4 and IL-13 induce tuft cell hyperplasia and enhance the production of IL-25, contributing to the expulsion of N. brasiliensis (92, 93). Immune regulation by helminth infection Importantly, many parasitic infections become chronic because of various immune evasion strategies developed by parasites that have coexisted with humanity for millennia. An important parasite strategy is to control the host immune system. Various ES products released by helminths, including prostaglandins, induce T-cell development into a parasite-favourable type by regulating activity of antigen-presenting cells through suppressed IL-12 production (94, 95). In host animals, many parasitic infections increase numbers of Treg cells, which are central to immune regulation (96). Since Treg cells suppress extreme Th2 and Th1/Th17 responses, this can attenuate immune activity against helminths. Though immune regulation is a common feature of chronic parasitic infection, it is also advantageous for the host. During Schistosoma infection, if Th1/Th17-type inflammation is continuous and outcomes include hepatic disorders, splenomegaly and portal hypertension, which may result in death; however, by changing to Th2-type inflammation, severe symptoms can be avoided. Importantly, if the Th2 immune response is excessive, it can also become pathologic, but excessive Th2 inflammation can be suppressed by IL-10 and TGF-β, major products of Treg cells (97). Conversely, low-specificity immunosuppression may be beneficial for the host in certain situations. A ‘hygiene hypothesis’ suggests that the living environment may be too clean in developed countries; thus, the near-complete elimination of pathogen infection may cause immune dysfunction, including allergies and autoimmune diseases (98–101). Although a decrease in parasitic diseases is not the only change associated with improved hygiene, there is evidence that immune cells in parasite-infected hosts are less responsive (102, 103) and that re-activity recovers when the parasites are exterminated (104). In addition, Treg cells from helminth-infected hosts have been shown to suppress airway inflammation in a mouse asthma model (105). Attempts have been made to utilize these anti-inflammatory effects to treat symptoms of autoimmune diseases and inflammatory bowel diseases (106). The current method is to infect patients with a small number of nematodes; thus far, it seems to be safe, but has not yet proven effective. Importantly, parasite infection is not entirely beneficial to the host. Often, it may reduce resistance against other infectious diseases or even exacerbate inflammatory diseases (107). In contrast, with further study of the mechanism of immune regulation by helminths, medical therapy may be possible using a parasite ES component, rather than the parasite itself (106). Thus, the risk of pathogenicity might be avoided, and the patient’s physiological resistance to infection would also be maintained. Conclusions A host attempts to eliminate invading parasites through an epithelial barrier, innate immunity and acquired immunity; however, parasites can avoid and regulate immune responses, thereby creating an optimal environment for their own maturation and breeding while at the same time allowing the host to survive by avoiding excessive damage. The host is able to adjust its immune responses to expel the parasite without excessive self-damage, and to avoid excessive suppression that would impair its ability to protect against other pathogens. These conflicting immunological processes occur in many parasitic infections and are sufficiently controlled that one response does not become excessive, much like the response to commensal bacteria. Some parasites persist for several years; for many centuries, it has been suggested that infection by parasites is normal for humans. Viral infection is still a widespread phenomenon and bacteria can be important symbionts with the human body. Thus, it is possible that parasites are the only pathogens that are rapidly decreasing in developed countries, thereby disturbing the balance between immune reactions and pathogen invasion; the rise of inflammatory diseases, including allergies and autoimmune diseases, is quite conspicuous. Perhaps clarification of the mechanism of immune regulation by parasite infection will contribute greatly to the treatment for inflammatory diseases. Moreover, elucidation of the immune regulatory mechanism may lead to the development of therapeutic methods to effectively eliminate life-threatening or nuisance parasites. Funding This work was supported in part by a grant from the Japan Society for the promotion of Science KAKENHI-C grant number 17K08813 (to K.Y.). Conflicts of Interest statement the authors declare no conflicts of interest. Acknowledgements We thank Tadamitsu Kishimoto (Osaka University) for the kind donations to the Department of Immunology, Hyogo College of Medicine. References 1 Shen, B. 2015. A new golden age of natural products drug discovery. Cell  163: 1297. Google Scholar CrossRef Search ADS PubMed  2 Van Voorhis, W. C., Hooft van Huijsduijnen, R. and Wells, T. N. 2015. Profile of William C. Campbell, Satoshi Ōmura, and Youyou Tu, 2015 Nobel Laureates in physiology or medicine. Proc. Natl Acad. Sci. USA  112: 15773. Google Scholar CrossRef Search ADS   3 Burg, R. W., Miller, B. M., Baker, E. E.et al.   1979. Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob. Agents Chemother . 15: 361. Google Scholar CrossRef Search ADS PubMed  4 Blair, L. S. and Campbell, W. C. 1978. Efficacy of avermectins against Ancylostoma caninum in dogs. J. Helminthol . 52: 305. Google Scholar CrossRef Search ADS PubMed  5 Klayman, D. L. 1985. Qinghaosu (artemisinin): an antimalarial drug from China. Science  228: 1049. Google Scholar CrossRef Search ADS PubMed  6 WHO/Technical Report of the TDR Disease Reference Group on Helminth Infections 2012. Research priorities for helminth infections. WHO. Tech. Rep. Ser . 972: 1 7 Waite, R. C., Velleman, Y., Woods, G., Chitty, A. and Freeman, M. C. 2016. Integration of water, sanitation and hygiene for the control of neglected tropical diseases: a review of progress and the way forward. Int. Health . 8( Suppl. 1): i22. Google Scholar CrossRef Search ADS PubMed  8 Garcia, L. S. (ed.). 2009. Practical Guide to Diagnostic Parasitology . 2nd edn. American Society for Microbiology Press, Washington D.C. Google Scholar CrossRef Search ADS   9 Kemp, M., Kurtzhals, J. A., Kharazmi, A. and Theander, T. G. 1993. Interferon-gamma and interleukin-4 in human Leishmania donovani infections. Immunol. Cell Biol . 71 (Pt 6): 583. Google Scholar CrossRef Search ADS PubMed  10 Urban, J. F. Jr, Madden, K. B., Svetić, A.et al.   1992. The importance of Th2 cytokines in protective immunity to nematodes. Immunol. Rev . 127: 205. Google Scholar CrossRef Search ADS PubMed  11 Voehringer, D. 2009. The role of basophils in helminth infection. Trends Parasitol . 25: 551. Google Scholar CrossRef Search ADS PubMed  12 Else, K. J. and Finkelman, F. D. 1998. Intestinal nematode parasites, cytokines and effector mechanisms. Int. J. Parasitol . 28: 1145. Google Scholar CrossRef Search ADS PubMed  13 Grencis, R. K. 2015. Immunity to helminths: resistance, regulation, and susceptibility to gastrointestinal nematodes. Annu. Rev. Immunol . 33: 201. Google Scholar CrossRef Search ADS PubMed  14 Nausch, N. and Mutapi, F. 2017. Group 2 ILCs: a way of enhancing immune protection against human helminths? Parasite Immunol . doi: 10.1111/pim.12450. 15 Filbey, K., Bouchery, T. and Le Gros, G. 2017. The role of ILC2 in hookworm infection. Parasite Immunol . doi: 10.1111/pim.12429. 16 Male, D., Brostoff, J., Roth, D. and Roitt, I. 2012. Immunology E-Book, 8th Edition: With Student Consult Online Access . Elsevier Health Sciences, Amsterdam, the Netherlands. 17 Nutman, T. B. 2015. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite Immunol . 37: 304. Google Scholar CrossRef Search ADS PubMed  18 Ruitenberg, E. J., Elgersma, A., Kruizinga, W. and Leenstra, F. 1977. Trichinella spiralis infection in congenitally athymic (nude) mice. Parasitological, serological and haematological studies with observations on intestinal pathology. Immunology  33: 581. Google Scholar PubMed  19 Prowse, S. J., Mitchell, G. F., Ey, P. L. and Jenkin, C. R. 1978. Nematospiroides dubius: susceptibility to infection and the development of resistance in hypothymic (nude) BALB/c mice. Aust. J. Exp. Biol. Med. Sci . 56: 561. Google Scholar CrossRef Search ADS PubMed  20 Mitchell, G. F., Hogarth-Scott, R. S., Edwards, R. D. and Moore, T. 1976. Studies on immune responses to parasite antigens in mice. III. Nippostrongylus brasiliensis infections in hypothymic nu/nu mice. Int. Arch. Allergy Appl. Immunol . 52: 95. Google Scholar CrossRef Search ADS PubMed  21 Else, K. J., Finkelman, F. D., Maliszewski, C. R. and Grencis, R. K. 1994. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med . 179: 347. Google Scholar CrossRef Search ADS PubMed  22 Urban, J. F. Jr, Katona, I. M., Paul, W. E. and Finkelman, F. D. 1991. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc. Natl Acad. Sci. USA  88: 5513. Google Scholar CrossRef Search ADS   23 Sasaki, O., Sugaya, H., Ishida, K. and Yoshimura, K. 1993. Ablation of eosinophils with anti-IL-5 antibody enhances the survival of intracranial worms of Angiostrongylus cantonensis in the mouse. Parasite Immunol . 15: 349. Google Scholar CrossRef Search ADS PubMed  24 Abe, T. and Nawa, Y. 1988. Worm expulsion and mucosal mast cell response induced by repetitive IL-3 administration in Strongyloides ratti-infected nude mice. Immunology  63: 181. Google Scholar PubMed  25 Faulkner, H., Humphreys, N., Renauld, J. C., Van Snick, J. and Grencis, R. 1997. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol . 27: 2536. Google Scholar CrossRef Search ADS PubMed  26 Urban, J. F. Jr, Noben-Trauth, N., Donaldson, D. D.et al.   1998. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity  8: 255. Google Scholar CrossRef Search ADS PubMed  27 Bancroft, A. J., McKenzie, A. N. and Grencis, R. K. 1998. A critical role for IL-13 in resistance to intestinal nematode infection. J. Immunol . 160: 3453. Google Scholar PubMed  28 White, R. R. and Artavanis-Tsakonas, K. 2012. How helminths use excretory secretory fractions to modulate dendritic cells. Virulence  3: 668. Google Scholar CrossRef Search ADS PubMed  29 Laan, L. C., Williams, A. R., Stavenhagen, K.et al.   2017. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J . 31: 719. Google Scholar CrossRef Search ADS PubMed  30 Bouchery, T., Kyle, R., Ronchese, F. and Le Gros, G. 2014. The differentiation of CD4(+) T-helper cell subsets in the context of helminth parasite infection. Front. Immunol . 5: 487. Google Scholar CrossRef Search ADS PubMed  31 Cardoso, V., Chesné, J., Ribeiro, H.et al.   2017. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature  549: 277. Google Scholar CrossRef Search ADS PubMed  32 Wallrapp, A., Riesenfeld, S. J., Burkett, P. R.et al.   2017. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature  549: 351. Google Scholar CrossRef Search ADS PubMed  33 Klose, C. S. N., Mahlakõiv, T., Moeller, J. B.et al.   2017. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature  549: 282. Google Scholar CrossRef Search ADS PubMed  34 Galli, S. J. and Hammel, I. 1994. Mast cell and basophil development. Curr. Opin. Hematol . 1: 33. Google Scholar PubMed  35 Maruyama, H., Yabu, Y., Yoshida, A., Nawa, Y. and Ohta, N. 2000. A role of mast cell glycosaminoglycans for the immunological expulsion of intestinal nematode, Strongyloides venezuelensis. J. Immunol . 164: 3749. Google Scholar CrossRef Search ADS PubMed  36 Lantz, C. S., Boesiger, J., Song, C. H.et al.   1998. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature  392: 90. Google Scholar CrossRef Search ADS PubMed  37 Onah, D. N. and Nawa, Y. 2004. Mucosal mast cell-derived chondroitin sulphate levels in and worm expulsion from FcRgamma-knockout mice following oral challenge with Strongyloides venezuelensis. J. Vet. Sci . 5: 221. Google Scholar PubMed  38 Sasaki, Y., Yoshimoto, T., Maruyama, H.et al.   2005. IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. J. Exp. Med . 202: 607. Google Scholar CrossRef Search ADS PubMed  39 Yasuda, K., Matsumoto, M. and Nakanishi, K. 2014. Importance of both innate immunity and acquired immunity for rapid expulsion of S. venezuelensis. Front. Immunol . 5: 118. Google Scholar CrossRef Search ADS PubMed  40 Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell  102: 553. Google Scholar CrossRef Search ADS PubMed  41 Matsumoto, M., Sasaki, Y., Yasuda, K.et al.   2013. IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection. Infect. Immun . 81: 2518. Google Scholar CrossRef Search ADS PubMed  42 Boyce, J. A. 2003. Mast cells: beyond IgE. J. Allergy Clin. Immunol . 111: 24. Google Scholar CrossRef Search ADS PubMed  43 Reynolds, L. A., Filbey, K. J. and Maizels, R. M. 2012. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin. Immunopathol . 34: 829. Google Scholar CrossRef Search ADS PubMed  44 Hepworth, M. R., Daniłowicz-Luebert, E., Rausch, S.et al.   2012. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc. Natl Acad. Sci. USA  109: 6644. Google Scholar CrossRef Search ADS   45 Shimokawa, C., Kanaya, T., Hachisuka, M.et al.   2017. Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity  46: 863. Google Scholar CrossRef Search ADS PubMed  46 Swift, H. F., Boots, R. H. and Miller, C. P. 1922. A cutaneous nematode infection in monkeys. J. Exp. Med . 35: 599. Google Scholar CrossRef Search ADS PubMed  47 Löffler, W. 1935. Flüchtige Lungeninfiltrate mit Eosinophilie. Klinische Wochenschrift . 14: 297 Google Scholar CrossRef Search ADS   48 Kondo, Y., Yoshimoto, T., Yasuda, K.et al.   2008. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol . 20: 791. Google Scholar CrossRef Search ADS PubMed  49 Yasuda, K., Muto, T., Kawagoe, T.et al.   2012. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl Acad. Sci. USA  109: 3451. Google Scholar CrossRef Search ADS   50 Tindall, N. R. and Wilson, P. A. 1990. An extended proof of migration routes of immature parasites inside hosts: pathways of Nippostrongylus brasiliensis and Strongyloides ratti in the rat are mutually exclusive. Parasitology  100(Pt 2): 281. Google Scholar CrossRef Search ADS PubMed  51 Takamure, A. 1995. Migration route of Strongyloides venezuelensis in rodents. Int. J. Parasitol . 25: 907. Google Scholar CrossRef Search ADS PubMed  52 Ramalho-Pinto, F. J., McLaren, D. J. and Smithers, S. R. 1978. Complement-mediated killing of schistosomula of Schistosoma mansoni by rat eosinophils in vitro. J. Exp. Med . 147: 147. Google Scholar CrossRef Search ADS PubMed  53 Gounni, A. S., Lamkhioued, B., Ochiai, K.et al.   1994. High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature  367: 183. Google Scholar CrossRef Search ADS PubMed  54 Abbas, A. K., Lichtman, A. H. and Pillai, S. 2014. Cellular and Molecular Immunology E-Book . 8th edn. Elsevier Health Sciences, Amsterdam, the Netherlands. 55 Knott, M. L., Matthaei, K. I., Giacomin, P. R., Wang, H., Foster, P. S. and Dent, L. A. 2007. Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis. Int. J. Parasitol . 37: 1367. Google Scholar CrossRef Search ADS PubMed  56 Hewitson, J. P., Filbey, K. J., Esser-von Bieren, J.et al.   2015. Concerted activity of IgG1 antibodies and IL-4/IL-25-dependent effector cells trap helminth larvae in the tissues following vaccination with defined secreted antigens, providing sterile immunity to challenge infection. PLoS Pathog . 11: e1004676. Google Scholar CrossRef Search ADS PubMed  57 Cadman, E. T., Thysse, K. A., Bearder, S.et al.   2014. Eosinophils are important for protection, immunoregulation and pathology during infection with nematode microfilariae. PLoS Pathog . 10: e1003988. Google Scholar CrossRef Search ADS PubMed  58 Swartz, J. M., Dyer, K. D., Cheever, A. W.et al.   2006. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood  108: 2420. Google Scholar CrossRef Search ADS PubMed  59 O’Connell, A. E., Hess, J. A., Santiago, G. A.et al.   2011. Major basic protein from eosinophils and myeloperoxidase from neutrophils are required for protective immunity to Strongyloides stercoralis in mice. Infect. Immun . 79: 2770. Google Scholar CrossRef Search ADS PubMed  60 Svensson, M., Bell, L., Little, M. C., DeSchoolmeester, M., Locksley, R. M. and Else, K. J. 2011. Accumulation of eosinophils in intestine-draining mesenteric lymph nodes occurs after Trichuris muris infection. Parasite Immunol . 33: 1. Google Scholar CrossRef Search ADS PubMed  61 Huang, L. and Appleton, J. A. 2016. Eosinophils in helminth infection: defenders and dupes. Trends Parasitol . 32: 798. Google Scholar CrossRef Search ADS PubMed  62 Mitreva, M. and Jasmer, D. P. 2006. Biology and genome of Trichinella spiralis. WormBook: the online review of C. elegans biology . Nov 23:1. 63 Huang, L., Gebreselassie, N. G., Gagliardo, L. F.et al.   2014. Eosinophil-derived IL-10 supports chronic nematode infection. J. Immunol . 193: 4178. Google Scholar CrossRef Search ADS PubMed  64 Babayan, S. A., Read, A. F., Lawrence, R. A., Bain, O. and Allen, J. E. 2010. Filarial parasites develop faster and reproduce earlier in response to host immune effectors that determine filarial life expectancy. PLoS Biol . 8: e1000525. Google Scholar CrossRef Search ADS PubMed  65 Hagan, P., Blumenthal, U. J., Dunn, D., Simpson, A. J. and Wilkins, H. A. 1991. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature  349: 243. Google Scholar CrossRef Search ADS PubMed  66 Woolhouse, M. E., Taylor, P., Matanhire, D. and Chandiwana, S. K. 1991. Acquired immunity and epidemiology of Schistosoma haematobium. Nature  351: 757. Google Scholar CrossRef Search ADS PubMed  67 Buys, J., Wever, R., van Stigt, R. and Ruitenberg, E. J. 1981. The killing of newborn larvae of Trichinella spiralis by eosinophil peroxidase in vitro. Eur. J. Immunol . 11: 843. Google Scholar CrossRef Search ADS PubMed  68 Obata-Ninomiya, K., Ishiwata, K., Tsutsui, H.et al.   2013. The skin is an important bulwark of acquired immunity against intestinal helminths. J. Exp. Med . 210: 2583. Google Scholar CrossRef Search ADS PubMed  69 Muñoz-Caro, T., Rubio R., M. C., Silva, L. M.et al.   2015. Leucocyte-derived extracellular trap formation significantly contributes to Haemonchus contortus larval entrapment. Parasit. Vectors  8: 607. Google Scholar CrossRef Search ADS PubMed  70 Min, B., Prout, M., Hu-Li, J.et al.   2004. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med . 200: 507. Google Scholar CrossRef Search ADS PubMed  71 Denzel, A., Maus, U. A., Rodriguez Gomez, M.et al.   2008. Basophils enhance immunological memory responses. Nat. Immunol . 9: 733. Google Scholar CrossRef Search ADS PubMed  72 Tsujimura, Y., Obata, K., Mukai, K.et al.   2008. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity  28: 581. Google Scholar CrossRef Search ADS PubMed  73 Perrigoue, J. G., Saenz, S. A., Siracusa, M. C.et al.   2009. MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat. Immunol . 10: 697. Google Scholar CrossRef Search ADS PubMed  74 Giacomin, P. R., Siracusa, M. C., Walsh, K. P.et al.   2012. Thymic stromal lymphopoietin-dependent basophils promote Th2 cytokine responses following intestinal helminth infection. J. Immunol . 189: 4371. Google Scholar CrossRef Search ADS PubMed  75 Torrero, M. N., Hübner, M. P., Larson, D., Karasuyama, H. and Mitre, E. 2010. Basophils amplify type 2 immune responses, but do not serve a protective role, during chronic infection of mice with the filarial nematode Litomosoides sigmodontis. J. Immunol . 185: 7426. Google Scholar CrossRef Search ADS PubMed  76 Yoshimoto, T., Yasuda, K., Tanaka, H.et al.   2009. Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat. Immunol . 10: 706. Google Scholar CrossRef Search ADS PubMed  77 Sokol, C. L., Chu, N. Q., Yu, S., Nish, S. A., Laufer, T. M. and Medzhitov, R. 2009. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol . 10: 713. Google Scholar CrossRef Search ADS PubMed  78 Nakanishi, K. 2010. Basophils as APC in Th2 response in allergic inflammation and parasite infection. Curr. Opin. Immunol . 22: 814. Google Scholar CrossRef Search ADS PubMed  79 Eberle, J. U. and Voehringer, D. 2016. Role of basophils in protective immunity to parasitic infections. Semin. Immunopathol . 38: 605. Google Scholar CrossRef Search ADS PubMed  80 Ohnmacht, C., Schwartz, C., Panzer, M., Schiedewitz, I., Naumann, R. and Voehringer, D. 2010. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity  33: 364. Google Scholar CrossRef Search ADS PubMed  81 Schwartz, C., Turqueti-Neves, A., Hartmann, S., Yu, P., Nimmerjahn, F. and Voehringer, D. 2014. Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion. Proc. Natl Acad. Sci. USA  111: E5169. Google Scholar CrossRef Search ADS   82 Khan, A. I., Horii, Y., Tiuria, R., Sato, Y. and Nawa, Y. 1993. Mucosal mast cells and the expulsive mechanisms of mice against Strongyloides venezuelensis. Int. J. Parasitol . 23: 551. Google Scholar CrossRef Search ADS PubMed  83 Mukai, K., Karasuyama, H., Kabashima, K.et al.   2017. Differences in the importance of mast cells, basophils, IgE, and IgG versus that of CD4+ T cells and ILC2 cells in primary and secondary immunity to Strongyloides venezuelensis. Infect. Immun . 85: e00053 Google Scholar CrossRef Search ADS PubMed  84 Finkelman, F. D., Shea-Donohue, T., Morris, S. C.et al.   2004. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev . 201: 139. Google Scholar CrossRef Search ADS PubMed  85 Hasnain, S. Z., Evans, C. M., Roy, M.et al.   2011. Muc5ac: a critical component mediating the rejection of enteric nematodes. J. Exp. Med . 208: 893. Google Scholar CrossRef Search ADS PubMed  86 Herbert, D. R., Yang, J. Q., Hogan, S. P.et al.   2009. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J. Exp. Med . 206: 2947. Google Scholar CrossRef Search ADS PubMed  87 Akiho, H., Blennerhassett, P., Deng, Y. and Collins, S. M. 2002. Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol . 282: G226. Google Scholar CrossRef Search ADS PubMed  88 Khan, W. I., Richard, M., Akiho, H.et al.   2003. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect. Immun . 71: 2430. Google Scholar CrossRef Search ADS PubMed  89 Potten, C. S. 1998. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos. Trans. R. Soc. Lond. B. Biol. Sci . 353: 821. Google Scholar CrossRef Search ADS PubMed  90 Cliffe, L. J., Humphreys, N. E., Lane, T. E., Potten, C. S., Booth, C. and Grencis, R. K. 2005. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science  308: 1463. Google Scholar CrossRef Search ADS PubMed  91 Zaiss, D. M., Yang, L., Shah, P. R., Kobie, J. J., Urban, J. F. and Mosmann, T. R. 2006. Amphiregulin, a Th2 cytokine enhancing resistance to nematodes. Science  314: 1746. Google Scholar CrossRef Search ADS PubMed  92 von Moltke, J., Ji, M., Liang, H. E. and Locksley, R. M. 2016. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature  529: 221. Google Scholar CrossRef Search ADS PubMed  93 Gerbe, F., Sidot, E., Smyth, D. J.et al.   2016. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature  529: 226. Google Scholar CrossRef Search ADS PubMed  94 Massacand, J. C., Stettler, R. C., Meier, R.et al.   2009. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc. Natl Acad. Sci. USA  106: 13968. Google Scholar CrossRef Search ADS   95 Maizels, R. M., Pearce, E. J., Artis, D., Yazdanbakhsh, M. and Wynn, T. A. 2009. Regulation of pathogenesis and immunity in helminth infections. J. Exp. Med . 206: 2059. Google Scholar CrossRef Search ADS PubMed  96 Metenou, S., Dembele, B., Konate, S.et al.   2010. At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells. J. Immunol . 184: 5375. Google Scholar CrossRef Search ADS PubMed  97 Finlay, C. M., Walsh, K. P. and Mills, K. H. 2014. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol. Rev . 259: 206. Google Scholar CrossRef Search ADS PubMed  98 Strachan, D. P. 1989. Hay fever, hygiene, and household size. BMJ  299: 1259. Google Scholar CrossRef Search ADS PubMed  99 Bach, J. F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med . 347: 911. Google Scholar CrossRef Search ADS PubMed  100 Ege, M. J., Mayer, M., Normand, A. C.et al.  ; GABRIELA Transregio 22 Study Group. 2011. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med . 364: 701. Google Scholar CrossRef Search ADS PubMed  101 Bach, J. F. 2017. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat. Rev. Immunol . doi: 10.1038/nri.2017. 102 Piessens, W. F., McGreevy, P. B., Piessens, P. W.et al.   1980. Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens. J. Clin. Invest . 65: 172. Google Scholar CrossRef Search ADS PubMed  103 McCurley, T. L., Abe, T., Carter, C. E. and Colley, D. G. 1986. Studies of tolerance in schistosomiasis. Cell. Immunol . 99: 411. Google Scholar CrossRef Search ADS PubMed  104 Sartono, E., Kruize, Y. C., Kurniawan, A.et al.   1995. Elevated cellular immune responses and interferon-gamma release after long-term diethylcarbamazine treatment of patients with human lymphatic filariasis. J. Infect. Dis . 171: 1683. Google Scholar CrossRef Search ADS PubMed  105 Wilson, M. S., Taylor, M. D., Balic, A., Finney, C. A., Lamb, J. R. and Maizels, R. M. 2005. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J. Exp. Med . 202: 1199. Google Scholar CrossRef Search ADS PubMed  106 Vukman, K. V., Lalor, R., Aldridge, A. and O’Neill, S. M. 2016. Mast cells: new therapeutic target in helminth immune modulation. Parasite Immunol . 38: 45. Google Scholar CrossRef Search ADS PubMed  107 McKay, D. M. 2015. Not all parasites are protective. Parasite Immunol . 37: 324. Google Scholar CrossRef Search ADS PubMed  © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

Host responses to intestinal nematodes

Loading next page...
 
/lp/ou_press/host-responses-to-intestinal-nematodes-5CI70ukj0V
Publisher
Oxford University Press
Copyright
© The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
ISSN
0953-8178
eISSN
1460-2377
D.O.I.
10.1093/intimm/dxy002
Publisher site
See Article on Publisher Site

Abstract

Abstract Helminth infection remains common in developing countries, where residents who suffer from the consequences of such infections can develop serious physical and mental disorders and often persist in the face of serious economic problems. Intestinal nematode infection induces the development of Th2-type immune responses including the B-cell IgE response; additionally, this infection induces an increase in the numbers and activation of various types of effector cells, such as mast cells, eosinophils and basophils, as well as the induction of goblet cell hyperplasia, anti-microbial peptide production and smooth-muscle contraction, all of which contribute to expel nematodes. Innate immunity is important in efforts to eliminate helminth infection; cytokines, including IL-25, IL-33 and thymic stromal lymphopoietin, which are products of epithelial cells and mast cells, induce Th2 cells and group 2 innate lymphoid cells to proliferate and produce Th2 cytokines. Nematodes also facilitate chronic infection by suppression of immune reactions through an increased number of Treg cells. Immunosuppression by parasite infection may ultimately be beneficial for the host animals; indeed, a negative correlation has been found between parasite infection and the prevalence of inflammatory disease in humans. helminths, IgE, IL-13, mast cells, Th2 Introduction The 2015 Nobel Prize in Physiology or Medicine was awarded to Satoshi Omura, William Campbell and Youyou Tu (1, 2). Omura and Campbell developed the revolutionary therapeutic drug, ivermectin (3, 4), to cure both onchocerciasis (river blindness) and lymphatic filariasis; Tu developed a new malaria treatment, artemisinin (5). Awarding the Nobel Prize for development of anti-parasitic drugs indicates that parasitic infections remain highly important targets for medical research. Indeed, according to a World Health Organization (WHO) survey, >1 billion people worldwide are currently infected with intestinal parasites (6). When infected with parasites, many individuals develop a chronic infection, which often manifests as severe anaemia and malnutrition and is dependent on the type and number of parasites (7). The infection of children with parasites may induce developmental disorders and delay cognitive development; for some children, these infections may become lethal. Parasites include the unicellular eukaryotes, protozoa (e.g. malaria, toxoplasma, amoeba) and the multicellular helminths, which are classified as trematodes, cestodes and nematodes (nematodes include trichinella, hookworm, ascarid, filaria) (8). There is a wide variety of methods and sites of parasitic infections; similarly, there is a wide variety of host immune responses that are dependent upon the nature of the infecting parasite. However, there are some general trends within parasitic infections: Th1-type immune responses develop in response to protozoan infections (9), whereas Th2-type immune responses develop in response to helminthic infections (10). Th2 immune cells aid the immune response through production of Th2 cytokines. These Th2 cytokines induce the production of antibodies, particularly IgE, and promote an increase in the number of eosinophils and basophils in blood and tissues (11). Furthermore, in mucosal tissues, such as the gastrointestinal tract, Th2 cytokines induce goblet cell hyperplasia and mucin production, as well as the accumulation of mast cells (12, 13). In addition to the immune response induced by Th2 cells, the broader mechanism of anti-helminthic innate immunity is under active investigation. Notably, group 2 innate lymphoid cells (ILC2s), activated by cytokines from epithelial cells, have received much attention as a powerful source of Th2 cytokines (14, 15). Moreover, various immune responses have developed to attack infecting parasites, but many helminths acquire the ability to escape these immune responses (16); thus, the infection becomes chronic (17). This recent knowledge of innate type and acquired type immune responses against helminths was largely obtained by intensive studies on intestinal nematode infections. Thus, in this article, we focus on immune responses to common intestinal nematodes of experimental animals. Intestinal nematodes strongly induce a Th2-type immune response The importance of T cells in the anti-parasitic response was originally demonstrated in classical experiments where nude mice infected with various helminths showed their inability to expel infected parasites normally (18–20). In normal hosts infected with helminths, naive T cells differentiate into Th2 cells. During infection by Trichuris muris (T. muris), mice with a dominant Th2-type immune response are resistant to the infection, whereas mice with a dominant Th1-type immune response are susceptible to the infection (21). This indicates that Th2 cell differentiation is important for protection against helminths (Fig. 1). Fig. 1. View largeDownload slide Th2-dominant immune responses protect host animals from nematode infection. When nematode larvae infect host animals, the worms stimulate or damage epithelial cells, which then produce epithelial cell-derived cytokines. Parasites release ES products, including PGE2, which suppresses the induction of IL-12 from dendritic cells (DCs). ES products also stimulate the release of NMU from neurons. Epithelial cell-derived cytokines and NMU cooperatively activate ILC2s to produce Th2 cytokines. Antigen-captured DCs induce development of Th2 cells, which can then produce Th2 cytokines. Th2 cytokines activate multiple effector cells including mast cells, basophils (Baso), eosinophils (Eo), goblet cells, M2 macrophages (M2Mϕ) and B cells; some of these effector cells contribute to expulsion of the helminths dependently on the type of helminths, for instance goblet cells induce expulsion of N. brasiliensis and mast cells are important in expulsion of S. venezuelensis. Fig. 1. View largeDownload slide Th2-dominant immune responses protect host animals from nematode infection. When nematode larvae infect host animals, the worms stimulate or damage epithelial cells, which then produce epithelial cell-derived cytokines. Parasites release ES products, including PGE2, which suppresses the induction of IL-12 from dendritic cells (DCs). ES products also stimulate the release of NMU from neurons. Epithelial cell-derived cytokines and NMU cooperatively activate ILC2s to produce Th2 cytokines. Antigen-captured DCs induce development of Th2 cells, which can then produce Th2 cytokines. Th2 cytokines activate multiple effector cells including mast cells, basophils (Baso), eosinophils (Eo), goblet cells, M2 macrophages (M2Mϕ) and B cells; some of these effector cells contribute to expulsion of the helminths dependently on the type of helminths, for instance goblet cells induce expulsion of N. brasiliensis and mast cells are important in expulsion of S. venezuelensis. Th2 cells are induced by parasitic infection and produce Th2 cytokines, including IL-3, IL-4, IL-5, IL-9 and IL-13, which activate effector mechanisms that are necessary to eliminate parasitic intestinal helminths (22–26). Mice that lack IL-4 and IL-13 production develop chronic infections, even when the mice are genetically resistant to infection (27). Conversely, administration of an antibody that neutralizes IFN-γ and thus enhances the Th2-type immune response, to mice with a susceptible genetic background causes consistent expulsion of the worms (21). Although it is unclear why naive T cells differentiate into Th2 cells in hosts infected by helminths, there are several possible reasons. First, helminths exhibit very few TLR ligands that induce dendritic cells to produce IL-12, which is important for differentiation of Th1 cells. Second, parasites might produce excretory/secretory (ES) molecules that suppress IL-12 production while enhancing production of cytokines that inducing Th2 cells [e.g. thymic stromal lymphopoietin (TSLP), IL-25 and IL-33] from non-hematopoietic epithelial cells (28–30). Under these circumstances, Th2 cells and Th2 cytokines work to induce the activation of many cell types with anti-helminthic functions, including mast cells, eosinophils, basophils and epithelial cells (discussed below). Furthermore, IL-4 induces B cells to produce antibodies, including IgE. These effector cells and molecules act synergistically to expel infected helminths. We note that ILC2s are an important source of Th2 cytokines, inducing substantial production of IL-5, IL-9 and IL-13 in response to the IL-33 released from nematode-damaged epithelial cells. Recently, Cardoso et al. (31) reported that a neuropeptide, neuromedin U (NMU), is produced by mucosal neurons stimulated either by IL-33 or by Nippostrongylus brasiliensis (N. brasiliensis) ES products. NMU strongly stimulates activation of ILC2s, inducing Th2 cytokine production (32), and contributes to protection against N. brasiliensis infection (33) (Fig. 1). Functions of mast cells IL-3 and IL-9, products of activated Th2 cells, synergistically induce the accumulation of mucosal mast cells (MMCs) in the mucosa of the small intestine (34). These IL-3- and IL-9-stimulated MMCs release chondroitin sulfate, preventing nematode adhesion to, and penetration of, the mucous membrane (Fig. 2A) (35). Strongyloides spp. are expelled by this mechanism (36–38). Strongyloides venezuelensis (S. venezuelensis) is a convenient infection model of human Strongyloides; its adult worms invade the intestinal mucosa and excrete large amounts of eggs into the intestinal lumen (39). However, when a Th2-type immune response is induced, these adult worms are expelled from the intestinal tract after ~12 days of infection, largely by action of MMCs (38). However, even when MMCs are present, clearance of the infection is delayed in Fc receptor γchain (FcRγ)-deficient mice (37). This indicates that antibodies are necessary for parasite expulsion by MMCs; however, the critical antibody isotype remains unknown. Fig. 2. View largeDownload slide Role of mast cells in the expulsion of nematode infection. (A) Th2 cells produce IL-3 and IL-9, which induce proliferation and differentiation of MMCs. MMCs express both FcεRI and FcγRIII, which can bind nematode ES antigen (ES-Ag) using IgE and IgG1, respectively, resulting in activation of the MMCs to release granule contents and expel S. venezuelensis. (B) MMCs produce IL-33 upon activation of P2X7R by ATP from damaged epithelial cells; this IL-33 activates ILC2s to produce IL-13 resulting in induction of goblet cell hyperplasia to protect against H. polygyrus infection. Fig. 2. View largeDownload slide Role of mast cells in the expulsion of nematode infection. (A) Th2 cells produce IL-3 and IL-9, which induce proliferation and differentiation of MMCs. MMCs express both FcεRI and FcγRIII, which can bind nematode ES antigen (ES-Ag) using IgE and IgG1, respectively, resulting in activation of the MMCs to release granule contents and expel S. venezuelensis. (B) MMCs produce IL-33 upon activation of P2X7R by ATP from damaged epithelial cells; this IL-33 activates ILC2s to produce IL-13 resulting in induction of goblet cell hyperplasia to protect against H. polygyrus infection. Recently, we investigated this aspect, using mice deficient in activation-induced cytidine deaminase (AID), who have no capacity to switch immunoglobulin classes during infection (40). Thus, they can produce IgM, but not IgG, IgA or IgE, when infected with S. venezuelensis. Further, they required a longer period (>9 additional days) for parasite expulsion, compared with wild-type mice. Th2 cells and MMCs exhibit normal development in both wild-type and AID-deficient mice (41). Additionally, during infection with N. brasiliensis, AID-deficient mice are able to expel N. brasiliensis, suggesting that their goblet cell development remains intact. Therefore, we purified IgG1 and/or IgE from the sera of normal mice that had been infected twice with S. venezuelensis; we administered these purified antisera to AID-deficient mice. Both isotypes promoted expulsion of parasites in a dose-dependent manner (41). Furthermore, a combination of IgG1 and IgE collaboratively augments the capacity of AID-deficient mice to expel S. venezuelensis (41). IgE constitutes a trace (~1/200) compared with the concentration of IgG in blood, but demonstrates a strong effect; in normal mice, both IgG and IgE work together to eliminate S. venezuelensis. Thus, the FcRγ-mediated activation of MMCs by cooperative efforts of IgG1 and IgE is important for elimination of S. venezuelensis. We previously reported that C57BL/6 mice, after treatment with IL-18 and IL-2, are able to promptly expel surgically implanted adult S. venezuelensis worms (38). These mice developed mucosal mastocytosis and exhibited high levels of serum mMCP1, a marker of MMC activation. These results revealed that proper activation of MMCs is important for expulsion of S. venezuelensis. Notably, the protective function of mast cells is observed in the late stages of infection, where Th2 cells stimulate various cell types through the activity of Th2 cytokines (42). In contrast, during defence against the rodent nematode Heligmosomoides polygyrus (H. polygyrus), mast cells are required for the early Th2 immune response (43, 44). KitW/KitW-v mice lacking mast cells cannot sufficiently induce Th2 immune responses against H. polygyrus. These studies also demonstrated the importance of IL-25, IL-33 and TSLP from mast cells. Shimokawa et al. also reported the importance of IL-33 production from mast cells, and further noted that Spi-B-deficient mice possess an increased number of mast cells and are thereby resistant to H. polygyrus (45). These mast cells utilize ATP stimulation to produce IL-33, which activates ILC2s to produce IL-13 and goblet cell hyperplasia (Fig. 2B). Parasite infection and eosinophils The accumulation of eosinophils in nematode-infected sites was shown in classical experiments (46). Later, investigators discovered the relationship between parasitic infection and pulmonary eosinophilia (Löffler’s syndrome) (47). Although the mechanism of this eosinophil accumulation was unknown for many years, we described this mechanism using an S. venezuelensis infection model. First, we demonstrated that nasal administration of IL-33 could induce pulmonary eosinophilia, even in Rag2-deficient mice (48). Next, we examined whether S. venezuelensis could induce pulmonary eosinophilia in wild-type and Rag2-deficient mice (49). Some parasitic intestinal nematode larvae, including S. venezuelensis and N. brasiliensis, do not travel directly to the intestinal tract upon percutaneous or oral infection; instead, they arrive at the lung via the bloodstream, then penetrate the alveolar cavity and ascend to the throat, where they are swallowed with sputum. Finally, they reach the small intestine and begin maturation (50, 51). Thus, injury of the lung tissue is induced by parasitic larvae, stimulating release of IL-33 from type II alveolar epithelial cells (ATIIs). This IL-33 induces ILC2s to accumulate, proliferate and produce IL-5 and IL-13, which combine to induce pulmonary eosinophilic inflammation (Löffler’s syndrome) (Fig. 3) (49). Fig. 3. View largeDownload slide Mechanism of Löffler’s syndrome. Strongyloides venezuelensis larvae infect host animals through the skin, then migrate to the lung via the bloodstream (shown at the bottom of the figure). When the larvae reach the lung, they penetrate blood vessels and alveolar walls by disrupting the endothelial and epithelial cell layers. The dead cells release damage-associated molecular patterns such as IL-33, which stimulates ILC2s to proliferate and produce Th2 cytokines. IL-5 and IL-13 cooperatively induce eosinophilia in the lung. AM, alveolar macrophage; ATI, type I alveolar epithelial cell; ATII, type II alveolar epithelial cell. Fig. 3. View largeDownload slide Mechanism of Löffler’s syndrome. Strongyloides venezuelensis larvae infect host animals through the skin, then migrate to the lung via the bloodstream (shown at the bottom of the figure). When the larvae reach the lung, they penetrate blood vessels and alveolar walls by disrupting the endothelial and epithelial cell layers. The dead cells release damage-associated molecular patterns such as IL-33, which stimulates ILC2s to proliferate and produce Th2 cytokines. IL-5 and IL-13 cooperatively induce eosinophilia in the lung. AM, alveolar macrophage; ATI, type I alveolar epithelial cell; ATII, type II alveolar epithelial cell. In vitro experiments demonstrated that eosinophils have the ability to kill schistosomula in combination with antibodies and complement (52, 53). Importantly, IgE and eosinophil cytotoxicity (antibody-dependent cellular cytotoxicity) has been widely reported as a mechanism for helminth exclusion (54). However, the in vivo role for IgE and eosinophils is not yet clear because expression of high-affinity FcεRIα is not often found in murine eosinophils, the most common experiment animal model. During N. brasiliensis infection of eosinophil-deficient mice and normal wild-type mice, comparable numbers of adult worms harboured in the intestinal tract are detected in both types of mice; however, increased number of eggs are detected only in faeces of the eosinophil-deficient mice (55). During H. polygyrus infection, eosinophil-deficient mice harbour more worms than wild-type mice do (56). In microfilarial infection achieved by intravenous administration of Brugia malayi, the population of microfilaria decreases shortly after infection in wild-type mice, whereas the population remains stable after infection in eosinophil-deficient mice (57). Thus, eosinophils contribute in a limited manner to host defence, as shown by the lack of effect in infectious models of Schistosoma mansoni (58), Strongyloides stercoralis larvae (59) and T. muris (60), though eosinophils are able to kill the larvae of all these species in vitro. Conversely, it has been reported that eosinophils may promote infection (61). New larvae of Trichinella spiralis (T. spiralis) formed in the intestinal tract migrate to muscles, where they invade muscle fibres and become capsular larvae (62). Here, Treg cells are induced by eosinophil-produced IL-10; larvae can thus survive because IL-10 suppresses production of nitric oxide (NO). However, eosinophil-deficient mice exhibit insufficient Treg cell differentiation, enhanced IFN-γ expression, enhanced NO production and a reduced cystic larvae population (63). Furthermore, larvae of Litomosoides sigmodontis (L. sigmodontis), a rodent filaria, grow more rapidly in the presence of eosinophils, suggesting that eosinophils support the growth of larvae (64). Once a host is infected by a parasite, it can gain immunity against the parasite, and thus become resistant to re-infection by the same parasite (65, 66). When wild-type mice are re-infected with N. brasiliensis, parasite larvae are captured in the skin and fewer larvae are able to reach the lung, whereas eosinophil-deficient mice allow many larvae to reach the lung (55). Eosinophils may support parasitism of T. spiralis during primary infection; however, eosinophils work during re-infection to inhibit migration of new larvae and proliferation of intramuscular larvae (61). Parasite-specific antibodies support eosinophil-mediated infection resistance. Antibodies support in vitro activities of eosinophils against T. spiralis larvae: binding, degranulation and killing (67). Antibodies have also been shown to synergize with basophils and M2 macrophages to inhibit movement of N. brasiliensis and H. polygyrus (68); eosinophils may function similarly to control parasites. Eosinophils can release DNA to capture antigens (similar to neutrophils); this has been demonstrated in vitro during capture of Haemonchus contortus larvae (69). Protective immunity of basophils to parasitic infection Min et al. (70) reported an ~50-fold increase in number of IL-4-producing basophils in the liver and lungs of mice infected with N. brasiliensis, as well as a focused role of basophils in the host response. In order to clarify the in vivo function of basophils, the basophils were removed using antibodies for FcεRIα chain (MAR-1) (71) or for CD200R3 (Ba103) (72); this was used in some parasite infection models. Oral administration of whipworm eggs (T. muris) in a resistant murine model leads to goblet cell hyperplasia in the intestinal epithelium at 21 days post-infection; it also causes development of Th2 cells in mesenteric lymph nodes, thus expelling the worms (21). In this model, basophils also increase in a TSLP-dependent manner. However, depletion of basophils through MAR-1 antibody administration shifts the dominant cell balance in normal mice from Th2 to Th1; this leads to suppression of goblet cell proliferation in the small intestine epithelium, of mucin production and of production of resistin-like molecule-β (RELMβ), thereby prolonging the infection. Thus, in the absence of basophils, host animals fail to develop a Th2-type immune response and cannot substantially expel worms (73, 74). In contrast, although Ba103-mediated basophil removal suppresses Th2 cell development, IgE production and eosinophil proliferation during filarial L. sigmodontis infection, there is no effect on the population of infected filaria (75). Thus, interesting results have been obtained, supporting previous hypotheses that basophils influence Th2 differentiation (73, 76–78). However, since FcεRIα and CD200R3 are also expressed on mast cells, this method may not provide sufficient specificity. To resolve this problem, genetically modified basophil-deficient mice were developed (e.g. Mcpt8-DTR, Mcpt8Cre, BasTreck) (79). Even when basophils were removed in Mcpt8-DTR mice by administration of diphtheria toxin, infection with N. brasiliensis induced conventional differentiation of T cells into Th2 cells, as well as normal antibody production and eosinophil induction; importantly, the worm burden was also unaffected. This indicates that basophils are not involved in the host immune response to primary infection by N. brasiliensis (80). Basophils are, however, important in the immune response to re-infection by N. brasiliensis. When N. brasiliensis re-infects wild-type mice, the larvae are captured intra-dermally and blocked from migration to the lungs. Additionally, basophils and monocytes accumulate around larvae captured within the skin. In contrast, during infection of basophil-deficient mice, larvae can migrate to the lungs as in primary infections. Notably, parasite-specific IgE binds to FcεRI on basophils. When parasite antigens interact with basophil-bound IgE, the basophils produce IL-4 and IL-13. This stimulates monocyte differentiation into M2 macrophages, production of the arginine-degrading enzyme arginase 1 and the capture of larvae in skin (Fig. 4). Thus, during re-infection, the antibody-dependent immune response blocks infection of N. brasiliensis (68). However, basophils do not completely block invasion of N. brasiliensis in the skin, as some larvae can pass through the lungs and migrate to the intestinal tract. In this case, basophils also protect against parasitic infection of the small intestine. Binding of parasite antigen to FcεRI-bound parasite-specific IgE causes basophils within the small intestine to produce IL-4. The IL-4 then increases proliferation and activation of Th2 cells, resulting in elimination of the worms (Fig. 4). Basophils also induce Th2 enhancement in the intestinal tract during H. polygyrus infection (81). Fig. 4. View largeDownload slide Contributions of basophils during re-infection by nematodes. On re-infection by N. brasiliensis larvae in the skin, basophils are rapidly recruited to the infected site. In the presence of IgE, basophils produce IL-4 and IL-13. IL-4 stimulates macrophages to differentiate into M2 macrophages and induces arginase 1 (Arg1) production, which inhibits larval migration to the lung. Some larvae that escape from the basophil-mediated skin trap can migrate to the intestine, where basophils also recognize worm antigens by IgE–FcεRI and produce IL-4. IL-4 stimulates Th2 cell accumulation and the production of Th2 cytokines that activate effector cells for expulsion of the parasite. Fig. 4. View largeDownload slide Contributions of basophils during re-infection by nematodes. On re-infection by N. brasiliensis larvae in the skin, basophils are rapidly recruited to the infected site. In the presence of IgE, basophils produce IL-4 and IL-13. IL-4 stimulates macrophages to differentiate into M2 macrophages and induces arginase 1 (Arg1) production, which inhibits larval migration to the lung. Some larvae that escape from the basophil-mediated skin trap can migrate to the intestine, where basophils also recognize worm antigens by IgE–FcεRI and produce IL-4. IL-4 stimulates Th2 cell accumulation and the production of Th2 cytokines that activate effector cells for expulsion of the parasite. Mast cells are important for resistance against S. venezuelensis infection; this was determined by studies of c-Kit mutant mice that lack mast cells (82). Involvement of basophils has been suggested, since infection with worms is more prolonged in c-Kit mutant IL-3-deficient mice where mast cells and basophils cannot increase (36). Recently the role of basophils was analysed in a basophil-deficient mouse model (Mcpt8-DTR), where an increased number of eggs were observed in faeces and an increased number of adult worms were observed in the small intestine; however, prolonged infection, as seen in mast cell-deficient mice, was not noticeable. Furthermore, S. venezuelensis infects skin, as does N. brasiliensis, but basophils do not protect against re-infection by S. venezuelensis (83). Activation of non-immune cells by Th2 cytokines Th2 cytokines, including IL-13 (produced by local Th2 cells and ILC2s), act on non-immune cells and are involved in the expulsion of helminths (Fig. 5) (26, 84). In the gastrointestinal tract, IL-13 directly acts on intestinal epithelial cells to induce goblet cell hyperplasia and mucin production, which prevent helminth adhesion to the intestinal surface and wash them away (85). Fig. 5. View largeDownload slide IL-13 is a central mediator in the intestine for expulsion of nematodes. IL-13 from Th2 cells or ILC2s stimulates epithelial cells in the intestine. Activated epithelial cells proliferate and differentiate into Paneth cells, goblet cells and tuft cells. Paneth cells produce anti-microbial peptides, such as RELMβ; goblet cells secrete massive amounts of mucin into the intestinal lumen; tuft cells produce IL-25, which activates ILC2s. Enhanced proliferation of epithelial cells hastens the migration of epithelial cells towards the tips of villi, where senescent or dead epithelial cells are shed. Additionally, IL-13 acts on smooth muscle cells to increase peristalsis. These cooperative effects remove nematodes from the intestinal mucosa. Fig. 5. View largeDownload slide IL-13 is a central mediator in the intestine for expulsion of nematodes. IL-13 from Th2 cells or ILC2s stimulates epithelial cells in the intestine. Activated epithelial cells proliferate and differentiate into Paneth cells, goblet cells and tuft cells. Paneth cells produce anti-microbial peptides, such as RELMβ; goblet cells secrete massive amounts of mucin into the intestinal lumen; tuft cells produce IL-25, which activates ILC2s. Enhanced proliferation of epithelial cells hastens the migration of epithelial cells towards the tips of villi, where senescent or dead epithelial cells are shed. Additionally, IL-13 acts on smooth muscle cells to increase peristalsis. These cooperative effects remove nematodes from the intestinal mucosa. Activated epithelial cells (Paneth cells) also secrete anti-microbial peptides, including RELMβ (86). The RELMβ is important for eliminating parasites (e.g. N. brasiliensis and H. polygyrus) that live in the lumen; however, it is ineffective against nematodes such as T. spiralis entering the epithelium. IL-13 and IL-9 expel helminths from the intestinal tract by activating intestinal smooth muscle cells to enhance peristalsis (87, 88). In addition, enhancement of epithelial cell turnover is an important host response against helminth infection. Epithelial cells actively divide near the base of the villi, differentiate into absorptive epithelium and goblet cells and migrate towards the tip of the villi, where senescent epithelial cells drop off from the tip (89). During T. muris infection, this epithelial cell replacement is enhanced by the action of IL-13 and amphiregulin, thereby eliminating adherent worms and reducing the epithelial area where they can grow (90, 91). Furthermore, tuft cells in the intestinal epithelium constitutively produce IL-25 to maintain ILC2s in the lamina propria. IL-4 and IL-13 induce tuft cell hyperplasia and enhance the production of IL-25, contributing to the expulsion of N. brasiliensis (92, 93). Immune regulation by helminth infection Importantly, many parasitic infections become chronic because of various immune evasion strategies developed by parasites that have coexisted with humanity for millennia. An important parasite strategy is to control the host immune system. Various ES products released by helminths, including prostaglandins, induce T-cell development into a parasite-favourable type by regulating activity of antigen-presenting cells through suppressed IL-12 production (94, 95). In host animals, many parasitic infections increase numbers of Treg cells, which are central to immune regulation (96). Since Treg cells suppress extreme Th2 and Th1/Th17 responses, this can attenuate immune activity against helminths. Though immune regulation is a common feature of chronic parasitic infection, it is also advantageous for the host. During Schistosoma infection, if Th1/Th17-type inflammation is continuous and outcomes include hepatic disorders, splenomegaly and portal hypertension, which may result in death; however, by changing to Th2-type inflammation, severe symptoms can be avoided. Importantly, if the Th2 immune response is excessive, it can also become pathologic, but excessive Th2 inflammation can be suppressed by IL-10 and TGF-β, major products of Treg cells (97). Conversely, low-specificity immunosuppression may be beneficial for the host in certain situations. A ‘hygiene hypothesis’ suggests that the living environment may be too clean in developed countries; thus, the near-complete elimination of pathogen infection may cause immune dysfunction, including allergies and autoimmune diseases (98–101). Although a decrease in parasitic diseases is not the only change associated with improved hygiene, there is evidence that immune cells in parasite-infected hosts are less responsive (102, 103) and that re-activity recovers when the parasites are exterminated (104). In addition, Treg cells from helminth-infected hosts have been shown to suppress airway inflammation in a mouse asthma model (105). Attempts have been made to utilize these anti-inflammatory effects to treat symptoms of autoimmune diseases and inflammatory bowel diseases (106). The current method is to infect patients with a small number of nematodes; thus far, it seems to be safe, but has not yet proven effective. Importantly, parasite infection is not entirely beneficial to the host. Often, it may reduce resistance against other infectious diseases or even exacerbate inflammatory diseases (107). In contrast, with further study of the mechanism of immune regulation by helminths, medical therapy may be possible using a parasite ES component, rather than the parasite itself (106). Thus, the risk of pathogenicity might be avoided, and the patient’s physiological resistance to infection would also be maintained. Conclusions A host attempts to eliminate invading parasites through an epithelial barrier, innate immunity and acquired immunity; however, parasites can avoid and regulate immune responses, thereby creating an optimal environment for their own maturation and breeding while at the same time allowing the host to survive by avoiding excessive damage. The host is able to adjust its immune responses to expel the parasite without excessive self-damage, and to avoid excessive suppression that would impair its ability to protect against other pathogens. These conflicting immunological processes occur in many parasitic infections and are sufficiently controlled that one response does not become excessive, much like the response to commensal bacteria. Some parasites persist for several years; for many centuries, it has been suggested that infection by parasites is normal for humans. Viral infection is still a widespread phenomenon and bacteria can be important symbionts with the human body. Thus, it is possible that parasites are the only pathogens that are rapidly decreasing in developed countries, thereby disturbing the balance between immune reactions and pathogen invasion; the rise of inflammatory diseases, including allergies and autoimmune diseases, is quite conspicuous. Perhaps clarification of the mechanism of immune regulation by parasite infection will contribute greatly to the treatment for inflammatory diseases. Moreover, elucidation of the immune regulatory mechanism may lead to the development of therapeutic methods to effectively eliminate life-threatening or nuisance parasites. Funding This work was supported in part by a grant from the Japan Society for the promotion of Science KAKENHI-C grant number 17K08813 (to K.Y.). Conflicts of Interest statement the authors declare no conflicts of interest. Acknowledgements We thank Tadamitsu Kishimoto (Osaka University) for the kind donations to the Department of Immunology, Hyogo College of Medicine. References 1 Shen, B. 2015. A new golden age of natural products drug discovery. Cell  163: 1297. Google Scholar CrossRef Search ADS PubMed  2 Van Voorhis, W. C., Hooft van Huijsduijnen, R. and Wells, T. N. 2015. Profile of William C. Campbell, Satoshi Ōmura, and Youyou Tu, 2015 Nobel Laureates in physiology or medicine. Proc. Natl Acad. Sci. USA  112: 15773. Google Scholar CrossRef Search ADS   3 Burg, R. W., Miller, B. M., Baker, E. E.et al.   1979. Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob. Agents Chemother . 15: 361. Google Scholar CrossRef Search ADS PubMed  4 Blair, L. S. and Campbell, W. C. 1978. Efficacy of avermectins against Ancylostoma caninum in dogs. J. Helminthol . 52: 305. Google Scholar CrossRef Search ADS PubMed  5 Klayman, D. L. 1985. Qinghaosu (artemisinin): an antimalarial drug from China. Science  228: 1049. Google Scholar CrossRef Search ADS PubMed  6 WHO/Technical Report of the TDR Disease Reference Group on Helminth Infections 2012. Research priorities for helminth infections. WHO. Tech. Rep. Ser . 972: 1 7 Waite, R. C., Velleman, Y., Woods, G., Chitty, A. and Freeman, M. C. 2016. Integration of water, sanitation and hygiene for the control of neglected tropical diseases: a review of progress and the way forward. Int. Health . 8( Suppl. 1): i22. Google Scholar CrossRef Search ADS PubMed  8 Garcia, L. S. (ed.). 2009. Practical Guide to Diagnostic Parasitology . 2nd edn. American Society for Microbiology Press, Washington D.C. Google Scholar CrossRef Search ADS   9 Kemp, M., Kurtzhals, J. A., Kharazmi, A. and Theander, T. G. 1993. Interferon-gamma and interleukin-4 in human Leishmania donovani infections. Immunol. Cell Biol . 71 (Pt 6): 583. Google Scholar CrossRef Search ADS PubMed  10 Urban, J. F. Jr, Madden, K. B., Svetić, A.et al.   1992. The importance of Th2 cytokines in protective immunity to nematodes. Immunol. Rev . 127: 205. Google Scholar CrossRef Search ADS PubMed  11 Voehringer, D. 2009. The role of basophils in helminth infection. Trends Parasitol . 25: 551. Google Scholar CrossRef Search ADS PubMed  12 Else, K. J. and Finkelman, F. D. 1998. Intestinal nematode parasites, cytokines and effector mechanisms. Int. J. Parasitol . 28: 1145. Google Scholar CrossRef Search ADS PubMed  13 Grencis, R. K. 2015. Immunity to helminths: resistance, regulation, and susceptibility to gastrointestinal nematodes. Annu. Rev. Immunol . 33: 201. Google Scholar CrossRef Search ADS PubMed  14 Nausch, N. and Mutapi, F. 2017. Group 2 ILCs: a way of enhancing immune protection against human helminths? Parasite Immunol . doi: 10.1111/pim.12450. 15 Filbey, K., Bouchery, T. and Le Gros, G. 2017. The role of ILC2 in hookworm infection. Parasite Immunol . doi: 10.1111/pim.12429. 16 Male, D., Brostoff, J., Roth, D. and Roitt, I. 2012. Immunology E-Book, 8th Edition: With Student Consult Online Access . Elsevier Health Sciences, Amsterdam, the Netherlands. 17 Nutman, T. B. 2015. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite Immunol . 37: 304. Google Scholar CrossRef Search ADS PubMed  18 Ruitenberg, E. J., Elgersma, A., Kruizinga, W. and Leenstra, F. 1977. Trichinella spiralis infection in congenitally athymic (nude) mice. Parasitological, serological and haematological studies with observations on intestinal pathology. Immunology  33: 581. Google Scholar PubMed  19 Prowse, S. J., Mitchell, G. F., Ey, P. L. and Jenkin, C. R. 1978. Nematospiroides dubius: susceptibility to infection and the development of resistance in hypothymic (nude) BALB/c mice. Aust. J. Exp. Biol. Med. Sci . 56: 561. Google Scholar CrossRef Search ADS PubMed  20 Mitchell, G. F., Hogarth-Scott, R. S., Edwards, R. D. and Moore, T. 1976. Studies on immune responses to parasite antigens in mice. III. Nippostrongylus brasiliensis infections in hypothymic nu/nu mice. Int. Arch. Allergy Appl. Immunol . 52: 95. Google Scholar CrossRef Search ADS PubMed  21 Else, K. J., Finkelman, F. D., Maliszewski, C. R. and Grencis, R. K. 1994. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med . 179: 347. Google Scholar CrossRef Search ADS PubMed  22 Urban, J. F. Jr, Katona, I. M., Paul, W. E. and Finkelman, F. D. 1991. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc. Natl Acad. Sci. USA  88: 5513. Google Scholar CrossRef Search ADS   23 Sasaki, O., Sugaya, H., Ishida, K. and Yoshimura, K. 1993. Ablation of eosinophils with anti-IL-5 antibody enhances the survival of intracranial worms of Angiostrongylus cantonensis in the mouse. Parasite Immunol . 15: 349. Google Scholar CrossRef Search ADS PubMed  24 Abe, T. and Nawa, Y. 1988. Worm expulsion and mucosal mast cell response induced by repetitive IL-3 administration in Strongyloides ratti-infected nude mice. Immunology  63: 181. Google Scholar PubMed  25 Faulkner, H., Humphreys, N., Renauld, J. C., Van Snick, J. and Grencis, R. 1997. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol . 27: 2536. Google Scholar CrossRef Search ADS PubMed  26 Urban, J. F. Jr, Noben-Trauth, N., Donaldson, D. D.et al.   1998. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity  8: 255. Google Scholar CrossRef Search ADS PubMed  27 Bancroft, A. J., McKenzie, A. N. and Grencis, R. K. 1998. A critical role for IL-13 in resistance to intestinal nematode infection. J. Immunol . 160: 3453. Google Scholar PubMed  28 White, R. R. and Artavanis-Tsakonas, K. 2012. How helminths use excretory secretory fractions to modulate dendritic cells. Virulence  3: 668. Google Scholar CrossRef Search ADS PubMed  29 Laan, L. C., Williams, A. R., Stavenhagen, K.et al.   2017. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J . 31: 719. Google Scholar CrossRef Search ADS PubMed  30 Bouchery, T., Kyle, R., Ronchese, F. and Le Gros, G. 2014. The differentiation of CD4(+) T-helper cell subsets in the context of helminth parasite infection. Front. Immunol . 5: 487. Google Scholar CrossRef Search ADS PubMed  31 Cardoso, V., Chesné, J., Ribeiro, H.et al.   2017. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature  549: 277. Google Scholar CrossRef Search ADS PubMed  32 Wallrapp, A., Riesenfeld, S. J., Burkett, P. R.et al.   2017. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature  549: 351. Google Scholar CrossRef Search ADS PubMed  33 Klose, C. S. N., Mahlakõiv, T., Moeller, J. B.et al.   2017. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature  549: 282. Google Scholar CrossRef Search ADS PubMed  34 Galli, S. J. and Hammel, I. 1994. Mast cell and basophil development. Curr. Opin. Hematol . 1: 33. Google Scholar PubMed  35 Maruyama, H., Yabu, Y., Yoshida, A., Nawa, Y. and Ohta, N. 2000. A role of mast cell glycosaminoglycans for the immunological expulsion of intestinal nematode, Strongyloides venezuelensis. J. Immunol . 164: 3749. Google Scholar CrossRef Search ADS PubMed  36 Lantz, C. S., Boesiger, J., Song, C. H.et al.   1998. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature  392: 90. Google Scholar CrossRef Search ADS PubMed  37 Onah, D. N. and Nawa, Y. 2004. Mucosal mast cell-derived chondroitin sulphate levels in and worm expulsion from FcRgamma-knockout mice following oral challenge with Strongyloides venezuelensis. J. Vet. Sci . 5: 221. Google Scholar PubMed  38 Sasaki, Y., Yoshimoto, T., Maruyama, H.et al.   2005. IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. J. Exp. Med . 202: 607. Google Scholar CrossRef Search ADS PubMed  39 Yasuda, K., Matsumoto, M. and Nakanishi, K. 2014. Importance of both innate immunity and acquired immunity for rapid expulsion of S. venezuelensis. Front. Immunol . 5: 118. Google Scholar CrossRef Search ADS PubMed  40 Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell  102: 553. Google Scholar CrossRef Search ADS PubMed  41 Matsumoto, M., Sasaki, Y., Yasuda, K.et al.   2013. IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection. Infect. Immun . 81: 2518. Google Scholar CrossRef Search ADS PubMed  42 Boyce, J. A. 2003. Mast cells: beyond IgE. J. Allergy Clin. Immunol . 111: 24. Google Scholar CrossRef Search ADS PubMed  43 Reynolds, L. A., Filbey, K. J. and Maizels, R. M. 2012. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin. Immunopathol . 34: 829. Google Scholar CrossRef Search ADS PubMed  44 Hepworth, M. R., Daniłowicz-Luebert, E., Rausch, S.et al.   2012. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc. Natl Acad. Sci. USA  109: 6644. Google Scholar CrossRef Search ADS   45 Shimokawa, C., Kanaya, T., Hachisuka, M.et al.   2017. Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity  46: 863. Google Scholar CrossRef Search ADS PubMed  46 Swift, H. F., Boots, R. H. and Miller, C. P. 1922. A cutaneous nematode infection in monkeys. J. Exp. Med . 35: 599. Google Scholar CrossRef Search ADS PubMed  47 Löffler, W. 1935. Flüchtige Lungeninfiltrate mit Eosinophilie. Klinische Wochenschrift . 14: 297 Google Scholar CrossRef Search ADS   48 Kondo, Y., Yoshimoto, T., Yasuda, K.et al.   2008. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol . 20: 791. Google Scholar CrossRef Search ADS PubMed  49 Yasuda, K., Muto, T., Kawagoe, T.et al.   2012. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl Acad. Sci. USA  109: 3451. Google Scholar CrossRef Search ADS   50 Tindall, N. R. and Wilson, P. A. 1990. An extended proof of migration routes of immature parasites inside hosts: pathways of Nippostrongylus brasiliensis and Strongyloides ratti in the rat are mutually exclusive. Parasitology  100(Pt 2): 281. Google Scholar CrossRef Search ADS PubMed  51 Takamure, A. 1995. Migration route of Strongyloides venezuelensis in rodents. Int. J. Parasitol . 25: 907. Google Scholar CrossRef Search ADS PubMed  52 Ramalho-Pinto, F. J., McLaren, D. J. and Smithers, S. R. 1978. Complement-mediated killing of schistosomula of Schistosoma mansoni by rat eosinophils in vitro. J. Exp. Med . 147: 147. Google Scholar CrossRef Search ADS PubMed  53 Gounni, A. S., Lamkhioued, B., Ochiai, K.et al.   1994. High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature  367: 183. Google Scholar CrossRef Search ADS PubMed  54 Abbas, A. K., Lichtman, A. H. and Pillai, S. 2014. Cellular and Molecular Immunology E-Book . 8th edn. Elsevier Health Sciences, Amsterdam, the Netherlands. 55 Knott, M. L., Matthaei, K. I., Giacomin, P. R., Wang, H., Foster, P. S. and Dent, L. A. 2007. Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis. Int. J. Parasitol . 37: 1367. Google Scholar CrossRef Search ADS PubMed  56 Hewitson, J. P., Filbey, K. J., Esser-von Bieren, J.et al.   2015. Concerted activity of IgG1 antibodies and IL-4/IL-25-dependent effector cells trap helminth larvae in the tissues following vaccination with defined secreted antigens, providing sterile immunity to challenge infection. PLoS Pathog . 11: e1004676. Google Scholar CrossRef Search ADS PubMed  57 Cadman, E. T., Thysse, K. A., Bearder, S.et al.   2014. Eosinophils are important for protection, immunoregulation and pathology during infection with nematode microfilariae. PLoS Pathog . 10: e1003988. Google Scholar CrossRef Search ADS PubMed  58 Swartz, J. M., Dyer, K. D., Cheever, A. W.et al.   2006. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood  108: 2420. Google Scholar CrossRef Search ADS PubMed  59 O’Connell, A. E., Hess, J. A., Santiago, G. A.et al.   2011. Major basic protein from eosinophils and myeloperoxidase from neutrophils are required for protective immunity to Strongyloides stercoralis in mice. Infect. Immun . 79: 2770. Google Scholar CrossRef Search ADS PubMed  60 Svensson, M., Bell, L., Little, M. C., DeSchoolmeester, M., Locksley, R. M. and Else, K. J. 2011. Accumulation of eosinophils in intestine-draining mesenteric lymph nodes occurs after Trichuris muris infection. Parasite Immunol . 33: 1. Google Scholar CrossRef Search ADS PubMed  61 Huang, L. and Appleton, J. A. 2016. Eosinophils in helminth infection: defenders and dupes. Trends Parasitol . 32: 798. Google Scholar CrossRef Search ADS PubMed  62 Mitreva, M. and Jasmer, D. P. 2006. Biology and genome of Trichinella spiralis. WormBook: the online review of C. elegans biology . Nov 23:1. 63 Huang, L., Gebreselassie, N. G., Gagliardo, L. F.et al.   2014. Eosinophil-derived IL-10 supports chronic nematode infection. J. Immunol . 193: 4178. Google Scholar CrossRef Search ADS PubMed  64 Babayan, S. A., Read, A. F., Lawrence, R. A., Bain, O. and Allen, J. E. 2010. Filarial parasites develop faster and reproduce earlier in response to host immune effectors that determine filarial life expectancy. PLoS Biol . 8: e1000525. Google Scholar CrossRef Search ADS PubMed  65 Hagan, P., Blumenthal, U. J., Dunn, D., Simpson, A. J. and Wilkins, H. A. 1991. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature  349: 243. Google Scholar CrossRef Search ADS PubMed  66 Woolhouse, M. E., Taylor, P., Matanhire, D. and Chandiwana, S. K. 1991. Acquired immunity and epidemiology of Schistosoma haematobium. Nature  351: 757. Google Scholar CrossRef Search ADS PubMed  67 Buys, J., Wever, R., van Stigt, R. and Ruitenberg, E. J. 1981. The killing of newborn larvae of Trichinella spiralis by eosinophil peroxidase in vitro. Eur. J. Immunol . 11: 843. Google Scholar CrossRef Search ADS PubMed  68 Obata-Ninomiya, K., Ishiwata, K., Tsutsui, H.et al.   2013. The skin is an important bulwark of acquired immunity against intestinal helminths. J. Exp. Med . 210: 2583. Google Scholar CrossRef Search ADS PubMed  69 Muñoz-Caro, T., Rubio R., M. C., Silva, L. M.et al.   2015. Leucocyte-derived extracellular trap formation significantly contributes to Haemonchus contortus larval entrapment. Parasit. Vectors  8: 607. Google Scholar CrossRef Search ADS PubMed  70 Min, B., Prout, M., Hu-Li, J.et al.   2004. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med . 200: 507. Google Scholar CrossRef Search ADS PubMed  71 Denzel, A., Maus, U. A., Rodriguez Gomez, M.et al.   2008. Basophils enhance immunological memory responses. Nat. Immunol . 9: 733. Google Scholar CrossRef Search ADS PubMed  72 Tsujimura, Y., Obata, K., Mukai, K.et al.   2008. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity  28: 581. Google Scholar CrossRef Search ADS PubMed  73 Perrigoue, J. G., Saenz, S. A., Siracusa, M. C.et al.   2009. MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat. Immunol . 10: 697. Google Scholar CrossRef Search ADS PubMed  74 Giacomin, P. R., Siracusa, M. C., Walsh, K. P.et al.   2012. Thymic stromal lymphopoietin-dependent basophils promote Th2 cytokine responses following intestinal helminth infection. J. Immunol . 189: 4371. Google Scholar CrossRef Search ADS PubMed  75 Torrero, M. N., Hübner, M. P., Larson, D., Karasuyama, H. and Mitre, E. 2010. Basophils amplify type 2 immune responses, but do not serve a protective role, during chronic infection of mice with the filarial nematode Litomosoides sigmodontis. J. Immunol . 185: 7426. Google Scholar CrossRef Search ADS PubMed  76 Yoshimoto, T., Yasuda, K., Tanaka, H.et al.   2009. Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat. Immunol . 10: 706. Google Scholar CrossRef Search ADS PubMed  77 Sokol, C. L., Chu, N. Q., Yu, S., Nish, S. A., Laufer, T. M. and Medzhitov, R. 2009. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol . 10: 713. Google Scholar CrossRef Search ADS PubMed  78 Nakanishi, K. 2010. Basophils as APC in Th2 response in allergic inflammation and parasite infection. Curr. Opin. Immunol . 22: 814. Google Scholar CrossRef Search ADS PubMed  79 Eberle, J. U. and Voehringer, D. 2016. Role of basophils in protective immunity to parasitic infections. Semin. Immunopathol . 38: 605. Google Scholar CrossRef Search ADS PubMed  80 Ohnmacht, C., Schwartz, C., Panzer, M., Schiedewitz, I., Naumann, R. and Voehringer, D. 2010. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity  33: 364. Google Scholar CrossRef Search ADS PubMed  81 Schwartz, C., Turqueti-Neves, A., Hartmann, S., Yu, P., Nimmerjahn, F. and Voehringer, D. 2014. Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion. Proc. Natl Acad. Sci. USA  111: E5169. Google Scholar CrossRef Search ADS   82 Khan, A. I., Horii, Y., Tiuria, R., Sato, Y. and Nawa, Y. 1993. Mucosal mast cells and the expulsive mechanisms of mice against Strongyloides venezuelensis. Int. J. Parasitol . 23: 551. Google Scholar CrossRef Search ADS PubMed  83 Mukai, K., Karasuyama, H., Kabashima, K.et al.   2017. Differences in the importance of mast cells, basophils, IgE, and IgG versus that of CD4+ T cells and ILC2 cells in primary and secondary immunity to Strongyloides venezuelensis. Infect. Immun . 85: e00053 Google Scholar CrossRef Search ADS PubMed  84 Finkelman, F. D., Shea-Donohue, T., Morris, S. C.et al.   2004. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev . 201: 139. Google Scholar CrossRef Search ADS PubMed  85 Hasnain, S. Z., Evans, C. M., Roy, M.et al.   2011. Muc5ac: a critical component mediating the rejection of enteric nematodes. J. Exp. Med . 208: 893. Google Scholar CrossRef Search ADS PubMed  86 Herbert, D. R., Yang, J. Q., Hogan, S. P.et al.   2009. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J. Exp. Med . 206: 2947. Google Scholar CrossRef Search ADS PubMed  87 Akiho, H., Blennerhassett, P., Deng, Y. and Collins, S. M. 2002. Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol . 282: G226. Google Scholar CrossRef Search ADS PubMed  88 Khan, W. I., Richard, M., Akiho, H.et al.   2003. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect. Immun . 71: 2430. Google Scholar CrossRef Search ADS PubMed  89 Potten, C. S. 1998. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos. Trans. R. Soc. Lond. B. Biol. Sci . 353: 821. Google Scholar CrossRef Search ADS PubMed  90 Cliffe, L. J., Humphreys, N. E., Lane, T. E., Potten, C. S., Booth, C. and Grencis, R. K. 2005. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science  308: 1463. Google Scholar CrossRef Search ADS PubMed  91 Zaiss, D. M., Yang, L., Shah, P. R., Kobie, J. J., Urban, J. F. and Mosmann, T. R. 2006. Amphiregulin, a Th2 cytokine enhancing resistance to nematodes. Science  314: 1746. Google Scholar CrossRef Search ADS PubMed  92 von Moltke, J., Ji, M., Liang, H. E. and Locksley, R. M. 2016. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature  529: 221. Google Scholar CrossRef Search ADS PubMed  93 Gerbe, F., Sidot, E., Smyth, D. J.et al.   2016. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature  529: 226. Google Scholar CrossRef Search ADS PubMed  94 Massacand, J. C., Stettler, R. C., Meier, R.et al.   2009. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc. Natl Acad. Sci. USA  106: 13968. Google Scholar CrossRef Search ADS   95 Maizels, R. M., Pearce, E. J., Artis, D., Yazdanbakhsh, M. and Wynn, T. A. 2009. Regulation of pathogenesis and immunity in helminth infections. J. Exp. Med . 206: 2059. Google Scholar CrossRef Search ADS PubMed  96 Metenou, S., Dembele, B., Konate, S.et al.   2010. At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells. J. Immunol . 184: 5375. Google Scholar CrossRef Search ADS PubMed  97 Finlay, C. M., Walsh, K. P. and Mills, K. H. 2014. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol. Rev . 259: 206. Google Scholar CrossRef Search ADS PubMed  98 Strachan, D. P. 1989. Hay fever, hygiene, and household size. BMJ  299: 1259. Google Scholar CrossRef Search ADS PubMed  99 Bach, J. F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med . 347: 911. Google Scholar CrossRef Search ADS PubMed  100 Ege, M. J., Mayer, M., Normand, A. C.et al.  ; GABRIELA Transregio 22 Study Group. 2011. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med . 364: 701. Google Scholar CrossRef Search ADS PubMed  101 Bach, J. F. 2017. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat. Rev. Immunol . doi: 10.1038/nri.2017. 102 Piessens, W. F., McGreevy, P. B., Piessens, P. W.et al.   1980. Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens. J. Clin. Invest . 65: 172. Google Scholar CrossRef Search ADS PubMed  103 McCurley, T. L., Abe, T., Carter, C. E. and Colley, D. G. 1986. Studies of tolerance in schistosomiasis. Cell. Immunol . 99: 411. Google Scholar CrossRef Search ADS PubMed  104 Sartono, E., Kruize, Y. C., Kurniawan, A.et al.   1995. Elevated cellular immune responses and interferon-gamma release after long-term diethylcarbamazine treatment of patients with human lymphatic filariasis. J. Infect. Dis . 171: 1683. Google Scholar CrossRef Search ADS PubMed  105 Wilson, M. S., Taylor, M. D., Balic, A., Finney, C. A., Lamb, J. R. and Maizels, R. M. 2005. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J. Exp. Med . 202: 1199. Google Scholar CrossRef Search ADS PubMed  106 Vukman, K. V., Lalor, R., Aldridge, A. and O’Neill, S. M. 2016. Mast cells: new therapeutic target in helminth immune modulation. Parasite Immunol . 38: 45. Google Scholar CrossRef Search ADS PubMed  107 McKay, D. M. 2015. Not all parasites are protective. Parasite Immunol . 37: 324. Google Scholar CrossRef Search ADS PubMed  © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Journal

International ImmunologyOxford University Press

Published: Mar 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

Monthly Plan

  • Read unlimited articles
  • Personalized recommendations
  • No expiration
  • Print 20 pages per month
  • 20% off on PDF purchases
  • Organize your research
  • Get updates on your journals and topic searches

$49/month

Start Free Trial

14-day Free Trial

Best Deal — 39% off

Annual Plan

  • All the features of the Professional Plan, but for 39% off!
  • Billed annually
  • No expiration
  • For the normal price of 10 articles elsewhere, you get one full year of unlimited access to articles.

$588

$360/year

billed annually
Start Free Trial

14-day Free Trial