Parasite Expulsion Research Articles

E proteins are important for restraining the ILC2 differentiation potential in the thymus

Abstract Innate lymphoid cells (ILCs) have gained recognition as important regulators in various immune responses. Current paradigm states that all ILCs originate from common lymphoid progenitors (CLP) in the bone marrow through an array of downstream ILC progenitors. Id2, a member of the Id family that inhibits E protein transcription factors, is expressed in these ILC progenitors and is indispensable for ILC differentiation. Interestingly, we found that down-regulating E protein function in the thymus by Id1 overexpression or deletion of two E protein genes resulted in massive expansion of ILC2s in the thymus as well as other organs where ILC2 normally reside. The phenotypic thymic ILC2s expressed ILC2 signature genes and down-regulated T lineage-specific genes. Moreover, Id1 transgenic mice exhibited spontaneous infiltration of eosinophils and heightened type 2 immune responses to the allergen, papain, in the lung. Furthermore, these mice had increased ability in the expulsion of helminth parasites, N. Brasiliensis. These results raise an interesting question as to whether the thymus is a natural site for ILC2 production and the phenotypes of the mutant mice simply highlight such capacity. Indeed, we found that wild type DN1 and DN3 thymocytes can differentiate into IL-5 and IL-13-producing ILC2 cells in vitro. Ablation of E proteins in DN3 cells accelerated the differentiation while gain of E protein function inhibited the process. Together, our data reveal a new ILC2 differentiation program occurring in the thymus and a critical role of E proteins in restraining such a differentiation potential while ensuring proper T cell production.

Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

SummaryRecent studies have demonstrated that many parasites release extracellular vesicles (EVs), yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα) and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.

Associated factors of malnutrition among African children under five years old, Bom Jesus, Angola

ABSTRACT Objective: To identify the determinants of wasting and stunting in children under five years old in the commune of Bom Jesus, Angola Methods: A population-based cross-sectional study was conducted with 742 children in 2010, and nutritional deficits were defined by World Health Organization criteria. Prevalence ratios and associated factors of wasting and stunting were estimated using Poisson regression with robust variance, using a conceptual hierarchical model Results: For both deficits, there were significant differences in the prevalence ratios according to the children's neighborhood and age. Boys and those children living in households whose water supply came from the river or lake, as well those with recent expulsion of parasites and infections were more likely to present stunting. Children of fathers with higher number of children or that which the fathers were not living at home and whose mothers were 25-34 years old were less likely to have wasting Conclusion: It was identified independent variables from different levels of determination of malnutrition, standing out the basic sanitation conditions and family structure as important predictors of the nutritional deficits. The knowledge of the associated factors of malnutrition may contribute for subside public policies in planning interventions to improve the childhood nutrition status in Bom Jesus and communes with similar characteristics in Angola.

Leaf swallowing and parasite expulsion in Khao Yai white-handed gibbons (Hylobates lar), the first report in an Asian ape species.

Leaf swallowing behavior, known as a form of self-medication for the control of nematode and tapeworm infection, occurs widely in all the African great apes (Pan troglodytes schweinfurthii, P. t. troglodytes, P. t. verus, P. t. vellerosus, Pan paniscus, Gorilla gorilla graueri), except mountain gorillas. It is also reported to occur in a similar context across a wide array of other animal taxa including, domestic dogs, wolves, brown bears, and civets. Despite long-term research on Asian great and small apes, this is the first report of leaf swallowing in an Asian species, the white-handed gibbon (Hylobates lar) in Khao Yai National Park, central Thailand. We present the first evidence of leaf swallowing (Gironniera nervosa Planch CANNABACEA) behavior (N = 5 cases) and parasite (Streptopharagus pigmentatus) expulsion (N = 4 cases), recorded during 4,300 hr of direct animal observations during two distinct research projects. We recovered 4-18 rough, hairy, and hispid surfaced leaves from each sample, undigested and folded, from the freshly evacuated feces of five different individuals (2 males, 3 females, 5 to 34+ years old) living in three different social groups, between the hours of 06:00 to 10:30. Based on close inspection of the leaves, as observed in chimpanzees, it was clear that they were taken into the mouth, one at a time, folded and detached from the stem with the teeth before swallowing them whole. All instances occurred during the rainy season, the time when nematode worms were also found in the feces, although they were not found together with leaves in the same feces. These striking similarities in the details of leaf swallowing between white-handed gibbons and African great apes, and other animal species, suggest a similar self-medicative function.

Histochemical study of the effects on abomasal mucins of Haemonchus contortus or Teladorsagia circumcincta infection in lambs

Previously, chemical analysis of gastric fundic mucin showed that infection of sheep with Haemonchus contortus or Teladorsagia circumcincta changed the proportions of monosaccharides and decreased terminal mucin fucosylation and sialylation. To identify the effects of these parasites on the two mucin-secreting cell lineages, fundic and antral tissues were collected for histochemistry from 69 lambs aged from 3–4 to 9–10 months-of-age which had received a single infection of either H. contortus or T. circumcincta and euthanased at Day 21 or 28 post- infection respectively. All fundic tissues were stained separately with: (1) with Periodic Acid Schiff (PAS) for all mucins; (2) Alcian Blue (AB) pH 2.5 for acidic mucins (sialylated and sulphated); (3) AB pH 1 for sulphated mucins and (4) High Iron Diamine (HID) for sulphated mucins. Antral and fundic tissues from 24 lambs were also stained for acidic and neutral mucins or with specific lectins for α-1-linked fucose and for α-2,3- and α-2,6-linked sialic acids. Only mucin sulphation appeared to differ visually in uninfected lambs over this age range: there was weak staining with HID in tissues from lambs 3–6 months-of-age, but was generally more intense in those over 7 months-of-age. Sulphomucins were not apparent in surface mucous cells (SMC) or generally in the upper pits. Sialylomucins were located predominantly in the pits and glands, with small amounts of sialylated mucins in SMC and on the luminal surface, mainly in younger animals up to 6 months-of-age and less in the older animals. Parasitism markedly reduced the predominantly neutral surface mucin5AC of the SMC and pit cells, despite pit elongation in both antrum and fundus, whereas the acidic Muc6 secreted by mucus neck cells (MNC) increased along with MNC hyperplasia. Sulphated mucins were present mainly from the mid-pits downward and heavy staining was more common in older animals. In these sheep, the markedly reduced neutral mucin in the SMC and pit cells in both antrum and fundus contrasts with reported hypersecretion of mucus in the intestine, which is believed to aid in parasite expulsion. It has been proposed that intestinal goblet cell hypersecretion occurs only in resistant animals, therefore reduced mucins in the abomasum may be indicative of susceptibility to abomasal parasites.

Down-regulation of E protein activity augments an ILC2 differentiation program in the thymus

Abstract Innate lymphoid cells (ILCs) have gained recognition as important regulators in various immune responses. How these cells are generated is just beginning to be understood. Current paradigm states that all three subsets of ILCs originate from common lymphoid progenitors (CLP) in the bone marrow through an array of downstream ILC progenitors. Id2, a member of the Id family that inhibits the function E protein transcription factors, is expressed in these ILC progenitors and is indispensable for ILC differentiation. Unexpectedly, we found that specifically down-regulating E protein function in the thymus by either Id1 expression or conditional deletion of two E protein genes resulted in massive expansion of ILC2s in the thymus as well as other organs where ILC2 normally reside. Consequently, the mutant mice exhibit augmented spontaneous infiltration of eosinophils and heightened responses to allergen, papain, in the lung. Furthermore, these mice also display increased ability in the expulsion of helminth parasites, N. Brasiliensis. These results raise an interesting question as to whether the thymus is a natural site for ILC2 production and the phenotypes of our mutant mice simply highlight such capacity. Indeed, lineage tracing experiments using lck-Cre/ROSA26-stop-tdTomato mice demonstrate that tdTomoto specifically marks a fraction of ILC2s in the thymus as well as in the lung, suggesting that thymus-derived ILC2s preferentially home to the lung. We also found that thymic progenitors were able to differentiate into ILC2 cells in vitro. Together, our data reveal a new ILC2 differentiation program present in the thymus, which enriches our knowledge about ILC2 ontogeny and has potential biological significance.

Surfactant Protein-D Is Essential for Immunity to Helminth Infection.

Pulmonary epithelial cell responses can enhance type 2 immunity and contribute to control of nematode infections. An important epithelial product is the collectin Surfactant Protein D (SP-D). We found that SP-D concentrations increased in the lung following Nippostrongylus brasiliensis infection; this increase was dependent on key components of the type 2 immune response. We carried out loss and gain of function studies of SP-D to establish if SP-D was required for optimal immunity to the parasite. N. brasiliensis infection of SP-D-/- mice resulted in profound impairment of host innate immunity and ability to resolve infection. Raising pulmonary SP-D levels prior to infection enhanced parasite expulsion and type 2 immune responses, including increased numbers of IL-13 producing type 2 innate lymphoid cells (ILC2), elevated expression of markers of alternative activation by alveolar macrophages (alvM) and increased production of the type 2 cytokines IL-4 and IL-13. Adoptive transfer of alvM from SP-D-treated parasite infected mice into naïve recipients enhanced immunity to N. brasiliensis. Protection was associated with selective binding by the SP-D carbohydrate recognition domain (CRD) to L4 parasites to enhance their killing by alvM. These findings are the first demonstration that the collectin SP-D is an essential component of host innate immunity to helminths.

In vivo assay of IgE activities on the expulsion of intestinal adult worms

A physiological role of immunoglobulin E (IgE) is to promote parasitic helminth expulsion. This assertion is largely based on a series of studies carried out by Capron's laboratory. They observed that IgE is an essential component of protective immunity against Schistosoma mansoni larvae both in vitro and in vivo. Then, another group reported that IgE-deficient mice show higher worm burdens than wild-type (WT) mice when mice are infected with Trichinella spiralis. Although these studies indicate anti-helminth activities of IgE targeted on larvae forms, they do not prove the fighting effects of IgE on adult worms. In contrast, a recent study demonstrates an expelling activity of IgE for adult worms through an adoptive transfer of immune serum-derived IgE into Strongyloides venezuelensis-infected mice. Here, I describe how IgE is purified from S. venezuelensis-immune sera and is transferred into infected mice to examine its effect on worm expulsion. This method will be used to advance our understanding the mechanism of S. venezuelensis expulsion and explore S. venezuelensis antigens recognized by IgE. Moreover, adoptive transfers of IgE purified from immune sera will be applicable to other helminth infection models to investigate physiological roles of IgE.

New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection.

Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite Trichuris muris. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and Nod2 double-knockout (Nod DKO) mice after T. muris infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and Nod2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or Nod2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and Nod2 agonists upregulated core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS-stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and Nod2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense.

Abstract A44: Checkpoint inhibition of adaptive immunity by IL-9 can be disrupted to achieve rapid T cell sensitization and rejection of progressive tumor challenges

Abstract Interleukin 9 (IL-9), the signature Th9 cytokine, is associated with T regulatory cell function, parasite expulsion and allergic airway inflammation. Because IL-9 can promote a tolerogenic/immunosuppressive environment, we used IL-9 knock-out (IL-9ko) mice to estimate the role of endogenous IL-9 in the biology of two aggressive breast cancers, TUBO and 4T1, and CT26 a colon carcinoma. Merely eliminating endogenous IL-9 enabled efficient sensitization of host T cells leading to early rejection of growing tumors. Duplicate tumor challenges simply grew progressively in wildtype mice. Interestingly, tumor rejection occurred without additional vaccines or immunomodulatory therapies. The IL-9ko mice acquired immunologic memory, which actively protected from residual disease and tumor rechallenges. The ability of a normally lethal tumor challenge to stimulate an enduring therapeutic response in IL-9ko mice was linked to the activation of CD8+ T cells, as IL-9ko mice failed to be cured if either CD8+ or CD4+ T cells were depleted. Importantly, T cells from tumor-rejecting IL-9ko mice retained effector competence in wildtype mice, and treatments with neutralizing anti-IL-9 significantly slowed tumor progression in wildtype mice. IL-9 inhibits the immune system's ability to prime effective immunological memory after exposure to growing tumor; it therefore functions as a checkpoint inhibitor of adaptive immunity. Optimization of IL-9 neutralization may play a unique role in immunotherapy. Citation Format: Dominique B. Hoelzinger, Ana Lucia Dominguez, Peter A. Cohen, Sandra J. Gendler. Checkpoint inhibition of adaptive immunity by IL-9 can be disrupted to achieve rapid T cell sensitization and rejection of progressive tumor challenges. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A44.

The Role of Suppressor of Cytokine Signalling 3 (SOCS3) in the Regulation of Intestinal Epithelial Cell Turnover in a Helminth Model

Gastrointestinal epithelial cells (IEC) act as a first line of defence against invading pathogens and are replenished every 4‐5 days. An increase in IEC turnover aids the expulsion of intestinal pathogens including helminth infection. SOCS3 limits IEC proliferation with its loss associated with hyperproliferation and increased tumour growth in intestinal injury and cancer models. This study investigates SOCS3 effects on IEC turnover, outcome of infection and biochemical changes in response to infection in an in vivo Trichuris muris model.Mice with IEC SOCS3 conditional knockdown and controls were infected with T. muris. Crypt depth, cell proliferation rates, worm burden and immune response were assessed. Protein expression assessed by western blotting or immunohistochemistry.Increased SOCS3 expression was observed in cecum of T. muris susceptible vs. resistant mice strains. This supported our hypothesis that increased SOCS3 may limit IEC turnover and parasite expulsion. IEC deletion of SOCS3 did not lead to resistance to infection although a trend towards increased expulsion, compared to controls, was observed. At 35 days post infection an increase in proliferation of cells in cecal crypts was observed with no change in crypt depth in knockdown animals, supporting an increase in cell turnover. No difference in crypt dynamics was apparent in early stages of T. muris infection. Loss of SOCS3 was associated with altered indoleamine 2,3‐dioxygenase (IDO) expression in goblet cells.During parasitic challenge SOCS3 modulates IEC proliferation, potentially via a mechanism mediated though altered IDO.Medical Research Council G1100211/1

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg− mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.

Abstract 3640: IL-9 is involved in the establishment of a tolerogenic milieu that prevents anti-tumor immunity

Abstract IL-9 is a Th2 cytokine associated with T regulatory cell function, parasite expulsion and allergic airway inflammation. In many tumors IL-9 contributes to the establishment of a tolerogenic / immunosuppressive environment or acts directly to drive tumor growth, whereas in melanomas it inhibits tumor growth. Little is known about the effect of IL-9 in breast cancer biology. Here we show that IL-9 is a key factor in establishing a permissive growth environment for two murine breast cancer cells lines: TUBO cells that express Her2/neu and 4T1 cells that resemble aggressive, triple-negative breast cancers. We observed that TUBO cells were rejected by 78%, and 4T1 cells by 68% of IL-9 -/- (IL-9ko) mice, and that in the remaining mice the tumors developed later and grew slower than in WT mice. Tumor rejection is CD8+ T cell dependent and is capable of producing a memory response against tumor rechallenge. Delayed depletion of CD8+ T cells in mice that had rejected 4T1 cells showed no tumor growth in 63 % of the mice, suggesting that in these mice the tumor had been completely eradicated and was not held in stasis by immune surveillance. Furthermore we found a 3.7 fold increase (p=0.007) in the number of activated CD8+ T cells derived from IL-9ko mice rejecting tumors as compared to CD8+ T cells from tumor bearing WT mice. More importantly, the transfer of activated splenocytes from IL-9ko mice led to tumor rejection in WT mice (p<0.001). Moreover, WT mice treated with neutralizing anti-IL-9 evidenced slower 4T1 tumor growth compared to untreated and isotype control antibody treated mice. These data suggest that IL-9 neutralization should be examined as an adjuvant to immunotherapeutic or chemotherapeutic approaches. Supported by the NCI : CA155295 Citation Format: Dominique B. Hoelzinger, Ana Lucia Dominguez, Peter A. Cohen, Sandra J. Gendker. IL-9 is involved in the establishment of a tolerogenic milieu that prevents anti-tumor immunity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2014-3640

MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.

Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H. polygyrus infection. Alongside increased parasite expulsion, MyD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4+ cells. In addition, MyD88−/− mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MyD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain–containing adapter–inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain H. polygyrus susceptibility in wild-type mice. To further investigate signaling pathways that are MyD88 dependent, we infected IL-1R1−/− mice with H. polygyrus. This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R–MyD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MyD88-deficient mice appears to be granuloma independent. Like IL-1R1−/− and MyD88−/− mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1−/−) also developed intestinal granulomas. Hence, IL-1R1, MyD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MyD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.

Mucosal immune responses following intestinal nematode infection.

In most natural environments, the large majority of mammals harbour parasitic helminths that often live as adults within the intestine for prolonged periods (1–2 years) 1. Although these organisms have been eradicated to a large extent within westernized human populations, those living within rural areas of developing countries continue to suffer from high infection rates. Indeed, recent estimates indicate that approximately 2·5 billion people worldwide, mainly children, currently suffer from infection with intestinal helminths (also known as geohelminths and soil-transmitted helminths) 2. Paradoxically, the eradication of helminths is thought to contribute to the increased incidence of autoimmune diseases and allergy observed in developed countries. In this review, we will summarize our current understanding of host–helminth interactions at the mucosal surface that result in parasite expulsion or permit the establishment of chronic infections with luminal dwelling adult worms. We will also provide insight into the adaptive immune mechanisms that provide immune protection against re-infection with helminth larvae, a process that is likely to be key to the future development of successful vaccination strategies. Lastly, the contribution of helminths to immune modulation and particularly to the treatment of allergy and inflammatory bowel disease will be discussed.

MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion

SummaryGroup 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.

LB-001 Suppressor Of Cytokine Signalling 3 (socs3) Impacts On Intestinal Epithelial Cell Proliferation During Intestinal Helminth Infection

IntroductionIn the murine model of whip worm infection Trichuris muris invades cecal and colonic epithelial cells and elicits either a Th1 (susceptible) or Th2 (resistant) immune response. An increase in...

Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells

It has been shown recently that MCs are required for differential regulation of the immune response by granulocytic versus monocytic MDSCs. Granulocytic MDSCs promoted parasite clearance, whereas monocytic MDSCs enhanced tumor progression; both activities were abrogated in MC-deficient mice. Herein, we demonstrate that the lack of MCs also influences MDSC trafficking. Preferential trafficking to the liver was not seen in MC-deficient mice. In addition, evidence that the MC mediator histamine was important in MDSC trafficking and activation is also shown. MDSCs express HR1-3. Blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture. In addition, histamine differentially influenced Arg1 and iNOS gene expression in MDSCs and greatly enhanced IL-4 and IL-13 message, especially in granulocytic MDSCs. Evidence that histamine influenced activity seen in vitro translated to in vivo when HR1 and HR2 antagonists blocked the effect of MDSCs on parasite expulsion and tumor metastasis. All of these data support the MDSC-mediated promotion of Th2 immunity, leading to the suggestion that allergic-prone individuals would have elevated MDSC levels. This was directly demonstrated by looking at the relative MDSC levels in allergic versus control patients. Monocytic MDSCs trended higher, whereas granulocytic MDSCs were increased significantly in allergic patients. Taken together, our studies indicate that MCs and MC-released histamine are critical for MDSC-mediated immune regulation, and this interaction should be taken into consideration for therapeutic interventions that target MDSCs.

Anti-IL-13 in Inflammatory Bowel Disease: From the Bench to the Bedside

Much work has been done to understand the molecular mechanisms underlying the inflammatory bowel diseases (IBD). IL-13 has emerged as an important cytokine effective in ulcerative colitis (UC) and fistulizing Crohn's disease (CD). IL-13 is a T helper 2-type cytokine with pleiotropic effects, involved in parasite expulsion, asthma pathophysiology, natural history of cancer and other human pathologies. Great interest has therefore been developed in inhibiting its function as a therapeutic intervention in these diseases. The multifunctional properties of IL-13, with particular emphasis on its role in both CD and UC, as well as current developing pharmacologic agents inhibiting the IL-13 signaling pathway have been reviewed. Anti-IL-13 agents seem to be promising therapeutic strategies for the future management of IBD and other human diseases.

Leaf swallowing and parasitic infection of the Chinese lesser civet Viverricula indica in northeastern Taiwan

Abstract Background Ingestion of plant parts purportedly for their non-nutritive and/or bioactive properties has been widely reported across the animal kingdom. Many of these examples are viewed as behavioral strategies to maintain health by controlling the level of parasite infections. One such behavior is leaf swallowing, the folding and swallowing of whole leaves without chewing. Void of any nutritional benefit, defecation of the whole leaves is associated with the physical expulsion of intestinal parasites. Fecal samples of the Chinese lesser civet Viverricula indica were collected along a fixed transect line monthly for 17 months in the Fushan Experimental Forest, northeastern Taiwan. We inspected samples for the occurrence of undigested leaves and parasite worms to test the possible antiparasitic function of the behavior in this species. Results Of the collected feces, 14.3% contained whole, folded, undigested leaves of grass. The co-occurrence of undigested grass and Toxocara paradoxura worms in the feces was statistically significant. Adult worms of T. paradoxura were trapped inside the fecal-grass mass or on the surface of leaves in these samples. Increases in the T. paradoxura prevalence and infection intensity were associated with a higher presence of whole leaves in the feces. Conclusions Reported for the first time in the context of self-medication for civet species, we propose that swallowing grass may facilitate expulsion of adult worms of T. paradoxura, which resembles behaviors widely reported in African great apes, bears, and geese.