Worm Expulsion Research Articles

The basophil: Resolved questions and new avenues of investigation

The contribution that the subset of leukocytes known as basophils makes to immunity is controversial. A clear picture of the function of basophils has been slow to emerge, mainly due to functional studies on basophils in vivo being hampered by limitations in reagent availability and specificity. These issues were discussed by Schwartz and Voehringer in the June 2011 issue of BioEssays 1. The authors speculated that many outstanding issues surrounding basophil function would soon be resolved following recent development of specific means to delete and track basophils in vivo. Indeed, in subsequent months more definitive determination of basophil function has emerged using these tools. Thus, we here provide a brief update on the function of basophils in immunity. Whether basophils serve as antigen-presenting cells (APCs) that prime TH2 cell responses, the T cell subset controlling allergic and anti-parasitic immunity, was controversial 1. Sullivan and colleagues demonstrated that basophils do not play an essential role in the priming of TH2 cells following Schistosoma mansoni egg infection or in the papain-induced model of allergy 2. Moreover, their data revealed that basophils do not form stable conjugates with antigen-specific T cells, a prerequisite for an effective APC. The same study addressed another controversy pertaining to the function of basophils as effector cells in host defense against parasites. It was demonstrated that basophils provide a non-redundant source of IL-4 in infected tissues, which, in collaboration with T cell-derived IL-4, mediated worm expulsion following Nippostrongylus brasiliensis infection 2. Thus, a picture is now emerging whereby anti-parasitic immunity is not reliant on basophils as APCs, but requires cooperative responses between basophils and CD4+ T cells as effector cells. One explanation for discrepancies regarding reported functions of basophils may also be explained by recent findings demonstrating significant heterogeneity in basophils. Whilst IL-3 has long been considered the critical factor mediating basophil differentiation, recent studies have identified a novel function for the cytokine thymic stromal lymphopoetin (TSLP), which drives production of basophils distinct from those reliant on IL-3 3, 4. These studies further demonstrated that peripheral basophillia in murine models of atopic dermatitis and Trichinella spiralis infection are TSLP-dependent and can occur in the presence or absence of IL-3, raising the question of whether specific subtypes of basophils mediate distinct responses. Basophils have also been implicated as important effector cells driving pathogenesis of IgE-mediated chronic allergic inflammation (IgE-CAI) of the skin. However, recent work using new genetic tools to delete basophils surprisingly identified an anti-inflammatory role of basophils in this setting. Egawa et al. 5 demonstrated that basophils promoted differentiation of inflammatory monocytes into anti-inflammatory M2 macrophages rather than typical inflammatory M1 macrophages. Basophil-induced M2 macrophage differentiation subsequently dampened allergic inflammation during IgE-CAI. Thus, an intriguing possibility now emerges that basophils function as important regulators of macrophage differentiation in a range of inflammatory settings, which could have important implications for treatment in various inflammatory pathologies. Thus, as the important questions regarding the function of basophils in mice begin to be definitively addressed with novel genetic tools, new questions arise. Are there subsets of basophils yet to be identified that are capable of acting as APCs? Does boosting basophil responses provide a means to control macrophage-driven inflammation? Finally, and crucially, do these findings with regard to basophils in murine experimental models accurately reflect the functional significance of basophils in humans?

Primed effector macrophages mediate rapid worm expulsion after N. brasiliensis infection (P4247)

Abstract The innate immune cell populations that mediate macroparasite expulsion remain largely undefined. We examined the role of innate cells in the immune response to the nematode parasite, Nippostrongylus brasiliensis, hypothesizing that they may mediate the markedly accelerated CD4-independent worm expulsion occurring after secondary inoculation. By three days after secondary inoculation, immunofluorescence microscopy demonstrated a localized infiltrate of macrophages and eosinophils surrounding the L3 in the lung, and lung L3 showed reduced ATP, indicating impaired metabolism. Transfer of macrophages from N. brasiliensis primed WT mice to naïve recipients resulted in accelerated expulsion after primary inoculation, similar to WT mice given a secondary inoculation; this protective effect was blocked when primed macrophages were transferred from IL-4Rα-/- donor mice. Culture of L3 with sorted macrophages from primed WT, but not IL-4Rα-/-, mice resulted in macrophage adhesion to L3, decreased L3 metabolism and increased L3 mortality. Neutrophil (Ly6G+) depletion during priming blocked protective immunity after secondary inoculation and depletion of neutrophils in primed mice blocked protective effects of transferred macrophages in recipient mice and inhibited their in vitro binding to L3. These data indicate that neutrophils in the context of a type 2 cytokine environment prime effector macrophages that can directly bind parasites and mediate worm damage and expulsion.

IgG and IgE Collaboratively Accelerate Expulsion of Strongyloides venezuelensis in a Primary Infection

The host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model. Here we show that induction of immunoglobulin G (IgG) and IgE is a prerequisite for rapid expulsion of S. venezuelensis during a primary infection. Activation-induced cytidine deaminase-deficient (AID(-/-)) mice, which lack the ability to switch IgM to other isotypes, normally developed T-helper 2 (Th2) cells and intestinal mastocytosis after infection with S. venezuelensis. Although AID(-/-) mice expelled Nippostrongylus brasiliensis normally, they required a much longer period to expel S. venezuelensis than wild-type (WT) mice. Adoptive transfers of immune sera from S. venezuelensis-infected but not N. brasiliensis-infected mice restored the ability of AID(-/-) mice to promptly expel S. venezuelensis. Immune serum-derived IgG and IgE induced worm expulsion via Fc γ receptor III (FcγRIII) and Fc ε receptor I (FcεRI), respectively, and a mixture of IgG and IgE showed collaborative effects. Whereas FcγRIII(-/-) mice or FcεRIα(-/-) mice normally could expel S. venezuelensis, FcγRIII(-/-) mice, when their IgE was neutralized by anti-IgE, or FcεRIα(-/-) mice, when their IgG binding to FcγRIII was blocked by anti-FcγRIII, showed a markedly reduced ability to expel S. venezuelensis. These data reveal that IgG and IgE play redundant roles but act in concert to accelerate S. venezuelensis expulsion. Mast cell-deficient mice, even those equipped with immune serum-derived IgG or IgE, failed to expel S. venezuelensis promptly, suggesting that mast cells are cellular targets of IgG and IgE.

Requirement for Core 2 O-Glycans for Optimal Resistance to Helminth Infection

The migration of lymphocytes to the small intestine is controlled by expression of the integrin α4β7 and the chemokine receptor CCR9. However, the molecules that specifically regulate migration to the large intestine remain unclear. Immunity to infection with the large intestinal helminth parasite Trichuris muris is dependent upon CD4+ T cells that migrate to the large intestine. We examine the role of specific chemokine receptors, adhesion molecules and glycosyltransferases in the development of protective immunity to Trichuris. Mice deficient in expression of the chemokine receptors CCR2 or CCR6 were resistant to infection with Trichuris. Similarly, loss of CD34, CD43, CD44 or PSGL-1 had no effect on resistance to infection. In contrast, simultaneous deletion of the Core2 β1,6-N-acetylglucosaminyltransferase (C2GnT) enzymes C2GnT1 and C2Gnt2 resulted in delayed expulsion of worms. These results suggest that C2GnT-dependent modifications may play a role in migration of protective immune cells to the large intestine.

Lactobacillus rhamnosus Ingestion Promotes Innate Host Defense in an Enteric Parasitic Infection

Enteric parasite infections around the world are a huge economic burden and decrease the quality of life for many people. The use of beneficial bacteria has attracted attention for their potential therapeutic applications in various diseases. However, the effects of beneficial bacteria in enteric parasitic infections remain largely unexplored. We investigated the effects of ingestion of Lactobacillus rhamnosus (JB-1) in a model of enteric nematode (Trichuris muris) infection. C57BL/6 (resistant to infection), AKR (susceptible to infection), interleukin 10 (IL-10) knockout (KO), and mucin Muc2 KO mice were infected with T. muris and treated orally with probiotic JB-1 or medium. The mice were sacrificed on various days postinfection to examine goblet cells, epithelial cell proliferation, cytokines, and worm burdens. Treatment with JB-1 significantly enhanced worm expulsion in resistant C57BL/6 mice, and this was associated with increases in IL-10 levels, goblet cell numbers, and epithelial cell proliferation. Beneficial effects of JB-1 were absent in IL-10 KO and resistant mice treated with γ-irradiated bacteria. Live JB-1 treatment also expedited worm expulsion in Muc2 KO mice and, more importantly, in AKR mice (susceptible to infection). Injection of IL-10 directly into the colonic tissue of uninfected mice induced goblet cell hyperplasia. These findings demonstrate that JB-1 modulates goblet cell biology and promotes parasite expulsion via an IL-10-mediated pathway and provide novel insights into probiotic effects on innate defense in nematode infection.

Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity.

Type 2 immunity is essential for host protection against nematode infection but is detrimental in allergic inflammation or asthma. There is a major research focus on the effector molecules and specific cell types involved in the initiation of type 2 immunity. Recent work has implicated an important role of epithelial-derived cytokines, IL-25 and IL-33, acting on innate immune cells that are believed to be the initial sources of type 2 cytokines IL-4/IL-5/IL-13. The identities of the cell types that mediate the effects of IL-25/IL-33, however, remain to be fully elucidated. In the present study, we demonstrate that macrophages as IL-25/IL-33-responsive cells play an important role in inducing type 2 immunity using both in vitro and in vivo approaches. Macrophages produced type 2 cytokines IL-5 and IL-13 in response to the stimulation of IL-25/IL-33 in vitro, or were the IL-13-producing cells in mice administrated with exogenous IL-33 or infected with Heligmosomoides bakeri. In addition, IL-33 induced alternative activation of macrophages primarily through autocrine IL-13 activating the IL-4Rα-STAT6 pathway. Moreover, depletion of macrophages attenuated the IL-25/IL-33-induced type 2 immunity in mice, while adoptive transfer of IL-33-activated macrophages into mice with a chronic Heligmosomoides bakeri infection induced worm expulsion accompanied by a potent type 2 protective immune response. Thus, macrophages represent a unique population of the innate immune cells pivotal to type 2 immunity and a potential therapeutic target in controlling type 2 immunity-mediated inflammatory pathologies.

Participation of MyD88 and Interleukin-33 as Innate Drivers of Th2 Immunity to Trichinella spiralis

Trichinella spiralis is a highly destructive parasitic nematode that invades and destroys intestinal epithelial cells, injures many different tissues during its migratory phase, and occupies and transforms myotubes during the final phase of its life cycle. We set out to investigate the role in immunity of innate receptors for potential pathogen- or danger-associated molecular patterns (PAMPs or DAMPs). Focusing on the MyD88-dependent receptors, which include Toll-like receptors (TLRs) and interleukin-1 (IL-1) family members, we found that MyD88-deficient mice expelled worms normally, while TLR2/4-deficient mice showed accelerated worm expulsion, suggesting that MyD88 was active in signaling pathways for more than one receptor during intestinal immunity. A direct role for PAMPs in TLR activation was not supported in a transactivation assay involving a panel of murine and human TLRs. Mice deficient in the IL-1 family receptor for the DAMP, IL-33 (called ST2), displayed reduced intestinal Th2 responses and impaired mast cell activation. IL-33 was constitutively expressed in intestinal epithelial cells, where it became concentrated in nuclei within 2 days of infection. Nuclear localization was an innate response to infection that occurred in intestinal regions where worms were actively migrating. Th2 responses were also compromised in the lymph nodes draining the skeletal muscles of ST2-deficient mice, and this correlated with increased larval burdens in muscle. Our results support a mechanism in which the immune system recognizes and responds to tissue injury in a way that promotes Th2 responses.

The effects of astaxanthin in improving age associated declines of Th2 immune responses

Event Abstract Back to Event The effects of astaxanthin in improving age associated declines of Th2 immune responses Motoko Morimoto1*, Shohei Abe1, Noritsugu Azuma1, Sayaka Kamei1 and Kanami Dewa1 1 Miyagi University, School of Food, Agricultural and Environmental Sciences, Japan [Objective] Astaxanthin is one of the natural antioxidant carotenoid mainly derived from crab,salmon and trout. This study aims to determine whether dietary astaxanthincould modulate mucosal immunity in the gut in aged mice. [Method] Aged (18 months old) Balb/c female mice were orally administered with 6mg/kg body weight of astaxanthin or saline for 4 weeks. After 3 weeks, micewere infected with Nippostrongylus brasiliensis(Nb), which is gastroinfectional nematode in rodents. Tissues were taken from the small intestine, and total RNA was extracted and analyzed by real time PCR for IL-4, IL-13, IL-10, IFNγ and NOS2. For lipid peroxidation measurements in the liver, the thiobarbituric acid (TBA) assay was also performed. [Results] The lipoperoxide level in the 18M mice were significantly higher compared with that in the 3 months old mice. However, it significantly decreased after astaxanthin administration. Aged mice failed worm expulsion with declining Th2 immune responses, while Th2 cytokine gene expression was recovered and worm expulsion progressed in astaxanthin-fed aged mice. INFγ didn’t show any change. NOS2 was down-regulated and IL-10 increased after infection in astaxanthin fed-mice. FACS analysis revealed that CD4+CD25+Foxp3- T cells increased in aged mice, but these cells disappeared after astaxanthin administration. [Conclusions] These data showed that astaxanthin exhibited the effect of inhibition of oxidative stress and improved Th2 immune responses which declined during aging. Keywords: Aging, th2, Parasites, astaxanthin, Oxidative Stress Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Host-pathogen interactions Citation: Morimoto M, Abe S, Azuma N, Kamei S and Dewa K (2013). The effects of astaxanthin in improving age associated declines of Th2 immune responses. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00106 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Motoko Morimoto, Miyagi University, School of Food, Agricultural and Environmental Sciences, Sendai, Miyagi, 982-0215, Japan, morimoto@myu.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Motoko Morimoto Shohei Abe Noritsugu Azuma Sayaka Kamei Kanami Dewa Google Motoko Morimoto Shohei Abe Noritsugu Azuma Sayaka Kamei Kanami Dewa Google Scholar Motoko Morimoto Shohei Abe Noritsugu Azuma Sayaka Kamei Kanami Dewa PubMed Motoko Morimoto Shohei Abe Noritsugu Azuma Sayaka Kamei Kanami Dewa Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Nippostrongylus-Induced Intestinal Hypercontractility Requires IL-4 Receptor Alpha-Responsiveness by T Cells in Mice

Gut-dwelling helminthes induce potent IL-4 and IL-13 dominated type 2 T helper cell (TH2) immune responses, with IL-13 production being essential for Nippostrongylus brasiliensis expulsion. This TH2 response results in intestinal inflammation associated with local infiltration by T cells and macrophages. The resulting increased IL-4/IL-13 intestinal milieu drives goblet cell hyperplasia, alternative macrophage activation and smooth muscle cell hypercontraction. In this study we investigated how IL-4-promoted T cells contributed to the parasite induced effects in the intestine. This was achieved using pan T cell-specific IL-4 receptor alpha-deficient mice (iLckcreIL-4Rα−/lox) and IL-4Rα-responsive control mice. Global IL-4Rα−/− mice showed, as expected, impaired type 2 immunity to N. brasiliensis. Infected T cell-specific IL-4Rα-deficient mice showed comparable worm expulsion, goblet cell hyperplasia and IgE responses to control mice. However, impaired IL-4-promoted TH2 cells in T cell-specific IL-4Rα deficient mice led to strikingly reduced IL-4 production by mesenteric lymph node CD4+ T cells and reduced intestinal IL-4 and IL-13 levels, compared to control mice. This reduced IL-4/IL-13 response was associated with an impaired IL-4/IL-13-mediated smooth muscle cell hypercontractility, similar to that seen in global IL-4Rα−/− mice. These results demonstrate that IL-4-promoted T cell responses are not required for the resolution of a primary N. brasiliensis infection. However, they do contribute significantly to an important physiological manifestation of helminth infection; namely intestinal smooth muscle cell-driven hypercontractility.

Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon

Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated.

Serine Protease(s) Secreted by the Nematode Trichuris muris Degrade the Mucus Barrier

The polymeric mucin component of the intestinal mucus barrier changes during nematode infection to provide not only physical protection but also to directly affect pathogenic nematodes and aid expulsion. Despite this, the direct interaction of the nematodes with the mucins and the mucus barrier has not previously been addressed. We used the well-established Trichuris muris nematode model to investigate the effect on mucins of the complex mixture of immunogenic proteins secreted by the nematode called excretory/secretory products (ESPs). Different regimes of T. muris infection were used to simulate chronic (low dose) or acute (high dose) infection. Mucus/mucins isolated from mice and from the human intestinal cell line, LS174T, were treated with ESPs. We demonstrate that serine protease(s) secreted by the nematode have the ability to change the properties of the mucus barrier, making it more porous by degrading the mucin component of the mucus gel. Specifically, the serine protease(s) acted on the N-terminal polymerising domain of the major intestinal mucin Muc2, resulting in depolymerisation of Muc2 polymers. Importantly, the respiratory/gastric mucin Muc5ac, which is induced in the intestine and is critical for worm expulsion, was protected from the depolymerising effect exerted by ESPs. Furthermore, serine protease inhibitors (Serpins) which may protect the mucins, in particular Muc2, from depolymerisation, were highly expressed in mice resistant to chronic infection. Thus, we demonstrate that nematodes secrete serine protease(s) to degrade mucins within the mucus barrier, which may modify the niche of the parasite to prevent clearance from the host or facilitate efficient mating and egg laying from the posterior end of the parasite that is in intimate contact with the mucus barrier. However, during a TH2-mediated worm expulsion response, serpins, Muc5ac and increased levels of Muc2 protect the barrier from degradation by the nematode secreted protease(s).

Epithelial cells ACT up in worm expulsion

Epithelial cells mediate immunity to helminths by promoting type 2 innate effector cell responses.

High Frequency of Leaf Swallowing and its Relationship to Intestinal Parasite Expulsion in “Village” Chimpanzees at Bulindi, Uganda

Self-medication by great apes to control intestinal parasite infections has been documented at sites across Africa. Chimpanzees (Pan troglodytes) swallow the leaves of certain plant species whole, without chewing. Previous studies demonstrated a relationship between chimpanzee leaf swallowing and expulsion of nematode worms (Oesophagostomum sp.) and tapeworms (Bertiella sp.) in dung. We investigated the relationship between leaf swallowing and parasite expulsion in chimpanzees inhabiting a fragmented forest-farm mosaic at Bulindi, Uganda. During 13 months whole undigested leaves occurred in chimpanzee dung at a considerably higher frequency (10.4% of dungs) than at other sites (0.4-4.0%). Leaf swallowing occurred year-round and showed no pronounced seasonality. Chimpanzees egested adults of multiple species of Oesophagostomum (including O. stephanostomum) and proglottids of two tapeworms-Bertiella sp. and probably Raillietina sp. The latter may not be a true infection, but the byproduct of predation on domestic fowl. Compared to previous studies, the co-occurrence of whole leaves and parasites in chimpanzee dung was low. Whereas the presence of leaves in dung increased the probability of adult nematode expulsion, no association between leaf swallowing and the shedding of tapeworm proglottids was apparent. Anthropogenic habitat changes have been linked to alterations in host-parasite interactions. At Bulindi, deforestation for agriculture has increased contact between apes and people. Elevated levels of leaf swallowing could indicate these chimpanzees are especially vulnerable to parasite infections, possibly due to environmental changes and/or increased stress levels arising from a high frequency of contact with humans. Frequent self-medication by chimpanzees in a high-risk environment could be a generalized adaptation to multiple parasite infections that respond differently to the behavior. Future parasitological surveys of apes and humans at Bulindi are needed for chimpanzee health monitoring and management, and to investigate the potential for disease transmission among apes, people, and domestic animals.

PWE-245 Anti-TNFα antibody therapy and parenteral corticosteroids demonstrate distinct effects in the treatment of experimental Trichuris muris-induced chronic colitis

IntroductionAnti-tumour necrosis factor (TNF) α antibody treatment and corticosteroid therapy represent central strategies in the management of Crohn's disease. Yet, over 30% of patients fail to respond. Understanding the mechanism...

PWE-246 Infliximab treatment significantly reduces inflammatory macrophage numbers while preserving regulatory macrophages in a mouse model of chronic Crohn's colitis

IntroductionInappropriate inflammatory responses to intestinal flora, augmented by host susceptibility genetics, contribute to the pathogenesis of Crohn's disease (CD). Transmural intestinal inflammation results from innate and adaptive immune cell infiltration,...

Epithelial Cell-Specific Act1 Adaptor Mediates Interleukin-25-Dependent Helminth Expulsion through Expansion of Lin−c-Kit+ Innate Cell Population

Interleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell type-specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin(-)c-Kit(+) innate cell population in the mesenteric lymph node, lung, and liver. Th2 cell-inducing cytokine (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin(-)c-Kit(+) cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin(-)c-Kit(+) innate cell population through the positive-feedback loop of IL-25, initiating the type 2 immunity against helminth infection.

A2B adenosine receptors are essential for effective worm expulsion and enhanced Th2 type immune response to the intestinal parasite Heligmosomoides polygyrus (43.12)

Abstract A2B adenosine receptor (A2B) signaling can modulate lymphocyte function.A2B receptors can control proinflammatory immune responses by enhancing IL-10 and down regulating IFN-γproduction.A2B receptors can activate mast cells to secrete IL-4,a Th2 cytokine that can trigger alternatively activated (M2) macrophages and expulsion of the intestinal nematode parasite, H. polygyrus (Hp).To examine whether A2B receptors contribute to the in vivo protective Th2-type immune response to helminthes, A2B-/- mice were infected with Hp.Worm burden and egg production were increased while serum IgE and IgG1 were reduced in A2B-/- mice compared to WT mice at day 14 after Hp inoculation. Worms recovered from A2B-/- mice at day 11 after secondary H. polygyrus inoculation exhibited higher protein and ATP levels,suggesting impaired host protective responses. Th2 cytokine expression and M2 macrophages markers were also inhibited in small intestines and in mesenteric lymph nodes (MLN) in A2B-/- mice at day11 after secondary Hp infection. Absence of A2B receptor signaling reduced IL-4 but not IFN-γ secreting MLN CD4+T cells after Hp inoculation. Eosinophil and M2 macrophage accumulation in the small intestine and increases in mucous producing intestinal epithelial cells were markedly inhibited in A2B-/- mice, after Hp secondary inoculation. These studies suggest that A2B receptors play an essential role in the development of the host protective Th2 type immune response during helminth infection.

Mast cells activate MDSC to promote inflammation (177.2)

Abstract Mast cells play an important role in promoting inflammation, controlling parasitic infection, and potentiating allergic disease. Conversely, myeloid-derived suppressor cells (MDSC) are found in tumor-bearing individuals and in models of septic shock, where they are known to have regulatory effect. We aimed to determine a possible role for interactions between MDSC and mast cells and the effect of these interactions in a mouse model of parasitic infection. Surprisingly, co-culture of these cells resulted in a drastic increase in pro-inflammatory mediator release, which was attributed entirely to MDSC. Depletion of MDSC from mice infected with Nippostrongylus brasiliensis resulted in delayed worm expulsion and a drastically increased intestinal worm burden. Conversely, this inflammatory role of MDSC seems detrimental when inflammation is chronic, as MDSC depletion in an airway hyperresponsiveness model decreased the pathology of this disease. Interestingly, we have found that mast cell conditioned-media activates both the STAT3 and ERK pathways in MDSC, which could represent a novel means of pro-inflammatory cytokine induction in MDSC. We therefore conclude that mast cells can reprogram MDSC to a pro-inflammatory phenotype, suggesting that the evolutionary purpose of these suppressive cells may be to potentiate inflammatory Th2 responses necessary for parasite expulsion.

Transcription factor RORα is critical for nuocyte development

Nuocytes are essential in innate type-2 immunity and contribute to the exacerbation of asthma responses. Here we show that nuocytes arise in the bone marrow and differentiate from common lymphoid progenitors, which makes them distinct new members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 and Notch signalling for development in vitro. Double negative 1 (DN1) and DN2 pro-T-cell progenitors maintained nuocyte potential in vitro, although the thymus was not essential for nuocyte development. Notably, the transcription factor Rorα was critical for nuocyte development and their role in parasitic worm expulsion.

Rapid and specific alterations of goblet cell mucin in rat airway and small intestine associated with resistance against Nippostrongylus brasiliensis reinfection

The intestinal parasitic nematode Nippostrongylus brasiliensis is expelled rapidly from the rat in reinfection challenge compared with that of the primary infection owing to the host defense mechanisms raised against the pre-intestinal- and intestinal-stage larvae. We examined the relationship between the mucin alterations in airway and jejunal mucosae and the worm expulsion after third-stage larva reinfection. When rats had been inoculated with fourth-stage larvae and immunized with only the intestinal-stage worms for more than 8days, the challenge larvae were expelled during the intestinal stage along with a rapid increase of the specific sialomucin in jejunal mucosa, without any effect on the bronchial mucus. When rats had been infected with third-stage larvae and immunized with only the pre-intestinal stage larvae by killing with antihelminthic, the challenge larvae were rejected during the pre-intestinal stage along with marked goblet cell hyperplasia and Muc5AC mucin hyperproduction on the bronchial mucosa, but not as a result of jejunal mucin alteration. Taking these finding together, immunization with pre-intestinal- and intestinal-stage worms independently increases the airway and intestinal goblet cell mucins, respectively, and in both cases, the mucin alterations may contribute to rapid worm expulsion upon reinfection.