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Background Excretory-secretory (ES) products are crucial in maintaining helminths in the host. Consequently, the proteins of ES are potential vaccine molecules and potential therapeutic agents for autoimmune diseases. Heligmosomoides polygyrus bakeri, a gastrointestinal parasite of mice, is a model of hookworm infection in humans. ES produced by both sexes of H. polygyrus bakeri L4 stage cultured separately shows different immunomodulatory properties than ES obtained when both sexes are cultured together. Accordingly, the objective of this study was to identify and compare the excretory-secretory molecules from single-sex and mixed cultures. Methods The composition of ES of male and female L4 stage nematodes in the presence (cultured together) or absence (cultured alone) of the opposite sex was examined. Proteins were identified using mass spectrometry. The functions of identified proteins were explored with Blast2GO. Results A total of 258 proteins derived from mixed larval culture in the presence of sex pheromones were identified, 160 proteins from pure female cultures and 172 from pure male cultures. Exposure of nematodes to the sex pheromones results in abundant production of proteins with immunomodulatory properties such as Val proteins, acetylcholinesterases, TGF-β mimic 9 and HpARI. Proteins found only in ES from mixed larval cultures were TGF-β mimics 6 and 7 as well as galectin. Conclusions The presence of the opposite sex strongly influences the composition of ES products, probably by chemical (pheromone) communication between individuals. However, examination of the composition of ES from various conditions gives an opportunity for searching for new potentially therapeutic compounds and anthelminthics as well as components of vaccines. Manipulation of the nematode environment might be important for the studies on the immunomodulatory potential of nematodes. Graphical Abstract

Galectins are a family of proteins that bind β-galactosides and play key roles in a variety of cellular processes including host defence. They have been well studied in hosts but less so in gastrointestinal nematodes. Both host and parasite galectins are present in the gastrointestinal tract following infection. Parasite galectins can both bind antibody, especially highly glycosylated IgE and be bound by antibody. Parasite galectins may act as molecular sponges that soak up antibody. Host galectins promote mast cell degranulation while parasite galectins inhibit degranulation. Host and parasite galectins can also bind mucins and influence mucus viscosity. As the protective response against gastrointestinal nematode infection is partly dependent on IgE mediated mast cell degranulation and mucus, the interactions between host and parasite galectins play key roles in determining the outcome of infection.

The gastrointestinal nematode Heligmosomoides polygyrus bakeri shows enhanced survival in mice with colitis. As the antibody response plays an important role in antiparasitic immunity, antibodies against male and female L4 H. polygyrus were examined in mice with and without colitis. Levels of specific antibodies in the mucosa and serum were determined by enzyme-linked immunosorbent assay and immunogenic proteins of male and female parasites were identified using 2D electrophoresis and mass spectrometry. The function of identified proteins was explored with Blast2Go. Nematodes in mice with colitis induced higher levels of specific immunoglobulin G (IgG1) and IgA, a lower level of IgE in the small intestine and a higher level of IgE in serum against female L4. Infected mice with colitis recognized 12 proteins in male L4 and 10 in female L4. Most of the recognized proteins from male L4 were intermediate filament proteins, whereas the proteins from female L4 were primarily actins and galectins. Nematodes from mice with colitis were immunogenically different from nematodes from control mice. This phenomenon gives new insights into helminth therapy as well as host–parasite interactions.

Altered regulatory T cell (Treg) function could contribute to MS. The expression of activating and inhibitory receptors influences the activity of Tregs. Our aim was to investigate T cell phenotypes in relapsing–remitting MS (RRMS) patients at an early phase of the disease. We examined the influence of demographic parameters on the distribution of CD4+ and CD8+ T cell subclasses by generalized linear modeling. We also studied the expression of the following markers—CTLA-4, GITR, PD-1, FoxP3, Helios, CD28, CD62L, CD103—on T cell subsets from peripheral blood with a 14-color flow cytometry panel. We used an antibody array to define the profiles of 34 Th1/Th2/Th17 cytokines in the serum. Expression of PD-1 and GITR on CD4+ and CD8+ Tregs was decreased in RRMS patients. The proinflammatory factors IFN-γ, IL-17, IL-17F, TGFβ-1, TGFβ-3, IL-1SRII, IL-12 p40, sgp130, IL-6sR were significantly increased in RRMS patients. Therefore, a deficiency of PD-1 and GITR immune checkpoints on CD4+ and CD8+ Tregs is a feature of RRMS and might underlie impaired T cell control.

Nematode infection is a major threat to the health of humans, domestic animals and wildlife. Nematodes vary in their effect on the host and in the mechanisms underlying immunity but the general features are becoming clear. There is considerable variation among individuals in resistance to infection and much of this variation is due to genetic variation in the immune response. The major histocompatibility complex has a strong influence on resistance to infection but other genes are collectively more important. Resistant individuals produce more IgA, eosinophils, IgE and mast cells than susceptible individuals and this is a consequence of stronger type 2 (Th2) immune responses. A variety of factors promote Th2 responses including genetic background, diet, molecules produced by the parasite and the location of the infection. A variety of cells and molecules including proteins, glycolipids and RNA act in concert to promote responses and to regulate the response. Nematodes themselves also modulate the host response and over 20 parasite-derived immunomodulatory molecules have been identified. Different species of nematodes modulate the immune response in different ways and probably use multiple molecules. The reasons for this are unclear and the interactions among immunomodulators have still to be investigated.

Autoimmunological diseases are an increasing problem nowadays in societies. Due to complex etiology, effective therapy against immune disorders is still needed. A promising alternative for the current methods of treatment can be helminthic therapy. Series of tests on animal models as well as clinical studies indicates that parasitic infection can inhibit inflammation in inflammatory bowel diseases and multiple sclerosis. Effectiveness of therapy with helminths, mainly gut nematodes depends on the activity of many compounds released during infection. Despite hopeful results, mechanisms activated by nematodes aren’t explained yet, besides, therapeutically use of live parasites is controversial. Most of studies are focused on searching parasitic factors. The use of this compound in autoimmunological diseases could be an alternative for current medicaments. The aim of current study is summarizing and discussing helminth therapy of autoimmunological disorder on multiple sclerosis and inflammatory bowel diseases examples as well as using parasitic compounds as a potential pharmaceutical component.

The experimental autoimmune encephalomyelitis (EAE) animal model of Multiple Sclerosis (MS) is characterized by episodic neurologic dysfunction arising as a consequence of perivascular mononuclear cell infiltration and demyelination in the CNS. Leukocyte integrins, which are responsible for migration through the endothelial, play key roles in the pathogenesis of autoimmune diseases and chronic inflammation. Intestinal infection of mice with Heligmosomoides polygyrus appears to target CD11b (integrin αM), which is highly expressed on myeloid cells and is critical for their migration and function. H. polygyrus infection induces suppression of ongoing experimental EAE and extensive infiltration of CD11b+ cells to the CNS. Therefore, the aim of the present study was to characterize the phenotype and activity of CD11b+ cells accompanying the tissue phase infection of L4 H. polygyrus in EAE mice. It was found that the cells displayed a CD11b+ state with a distinct phenotype characterised by the expression of co-stimulatory CD80/CD86, CD40, MHCII, F4/80 and the mannose receptor CD206. This activation state illustrates the heterogeneity of CD11b+ cells in EAE mice following nematode invasion; these may have important consequences for understanding the effects of CD11b integrin, which is involved in the downregulation of neuroinflammatory disorders.

Mast cell degranulation is the major mechanism influencing establishment and survival of the abomasal nematode Teladorsagia circumcincta and probably many other gastrointestinal nematodes. Host galectins-3 and -9 have been shown to bind IgE and positively and negatively influence mast cell degranulation. As incoming nematodes produce large amounts of galectin, we hypothesised that nematode galectin competes with host galectin and inhibits mast cell degranulation. ELISA was used to show that nematode galectin reduced total IgE activity. Galectin also reduced the binding of sheep IgE to the surface of a mast cell line and decreased the release of LCT-4 and Beta hexosaminidase but not MMP-9. These results indicate that nematode galectin influences mast cell degranulation and identify a potential immunomodulatory mechanism used by nematodes to enhance their establishment and survival.

Galectins are a family of proteins that bind β-galactosides and play key roles in a variety of cellular processes including host defense and entry of parasites into the host cells. They have been well studied in hosts but less so in parasites. As both host and parasite galectins are highly upregulated proteins following infection, galectins are an area of increasing interest and their role in immune modulation has only recently become clear. Correlation of CNS parasitic diseases with mental disorders as a result of direct or indirect interaction has been observed. Therefore, galectins produced by the parasite should be taken into consideration as potential therapeutic agents., Highlights • Galectins are important players in CNS parasitic infections. • Host galectins take a part in immunomodulation and facilitate parasitic survival during parasitic CNS infection. • Galectins produced by the parasite should be taken into consideration as potential therapeutic agents of mental diseases.

Autoimmune diseases are increasingly recognized as disease entities in which dysregulated cytokines contribute to tissue-specific inflammation. In organ-specific and multiorgan autoimmune diseases, the cytokine profiles show some similarities. Despite these similarities, the cytokines have different roles in the pathogenesis of different diseases. Altered levels or action of cytokines can result from changes in cell signaling. This article describes alterations in the JAK-STAT, TGF-β and NF-κB signaling pathways, which are involved in the pathogenesis of multiple sclerosis and systemic lupus erythematosus. There is a special focus on T cells in preclinical models and in patients afflicted with these chronic inflammatory diseases.

An effective host immune system prevents the growth of most cancer cells. However, as intestinal nematodes are able to induce both immunotolerance and immunosuppression in the host, it is possible that their presence could allow co-occurring cancer cells to proliferate and metastasize. Our findings indicate that previous, subsequent or concurrent intestinal nematode infection affects the formation of lung metastatic nodules in mice experimentally infected with Heligmosomoides polygyrus. In addition, pre-infection with nematodes renders mice resistant to metastasis development in lungs, with the inoculated EL4 cancer cells being located mainly in mesenteric lymph nodes. The present paper discusses the nematode-induced mechanisms which may influence the metastatic process.

The gastrointestinal nematode Heligmosomoides polygyrus bakeri shows enhanced survival in mice with colitis. As the antibody response plays an important role in antiparasitic immunity, antibodies against male and female L4 H. polygyrus were examined in mice with and without colitis. Levels of specific antibodies in the mucosa and serum were determined by enzyme-linked immunosorbent assay and immunogenic proteins of male and female parasites were identified using 2D electrophoresis and mass spectrometry. The function of identified proteins was explored with Blast2Go. Nematodes in mice with colitis induced higher levels of specific immunoglobulin G (IgG(1)) and IgA, a lower level of IgE in the small intestine and a higher level of IgE in serum against female L4. Infected mice with colitis recognized 12 proteins in male L4 and 10 in female L4. Most of the recognized proteins from male L4 were intermediate filament proteins, whereas the proteins from female L4 were primarily actins and galectins. Nematodes from mice with colitis were immunogenically different from nematodes from control mice. This phenomenon gives new insights into helminth therapy as well as host–parasite interactions.

Myeloid-derived suppressor cells (MDSCs) are heterogeneous population of monocyte and granulocyte progenitors that are highly suppressive against T cells. In BALB/c mice infected with a nematode Heligmosomoides polygyrus bakeri, we studied the dynamics of MDSCs, identified as CD11b+Gr-1+, induction in different tissues along with the development of parasite infection. We observed that MDSC-like cells are induced both by larvae and adult stages of H polygyrus bakeri. Gr-1+ cells of suppressive phenotype are recruited in the bone marrow, peripheral blood and peritoneal cavity during histotropic phase of infection and are present at that time in the intestine wall, where worms reside. Later, during intestinal phase, suppressive Gr-1+ cells increased in mesenteric lymph nodes and the spleen. l-arginine metabolism was important for the protective immunity, and parasite-induced Gr-1+ cells showed elevated arginase-1 and iNOS expression. Inhibition of arginase-1 and l-arginine administration caused reduced level of infection that coincided with weaker suppressive phenotype of Gr-1+ cells. We identified that l-arginine pathway activation and induction of MDSC-like cells characterize immunosuppressive state during H polygyrus bakeri infection in mice. Our findings confirm the role of MDSCs in parasitic infections and point l-arginine pathway as a potential target for immunomodulation during nematode infections.

One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the “second brain” and be responsible for neurodegenerative disorders like Alzheimer’s disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.

Summary Development of modern medicine and better living conditions in the 20th century helped in reducing a number of cases of infectious diseases. During the same time, expansion of autoimmunological disorders was noticed. Among other are Inflammatory Bowel Diseases (IBD) including ulcerative colitis and Crohn’s disease which are chronic and relapsing inflammation of the gastrointestinal tract. Absence of effective treatment in standard therapies effects the search for alternative opportunities. As per hygienic hypothesis increasing number of cases of autoimmune diseases is as a result of reduced exposure to pathogens, especially parasites. Thus, one of the promising remedial acts against IBD and other allergic and autoimmune disorders is “helminth therapy”. Cure with helminths seems to be the most effective therapy of IBD currently proposed. Helminth therapy focuses on advantageous results that have been obtained from the clinical trials, but its mechanisms are still unclear. Explanation of this phenomenon would help to develop new drugs against IBD based on helminth immunomodulatory molecules.

Helminths use various immunomodulatory and anti-inflammatory strategies to evade immune attack by the host. During pathological conditions, these strategies alter the course of disease by reducing immune-mediated pathology. The study examines the therapeutic effect of the nematode L4 stage based on an in vivo model of multiple sclerosis, monophasic encephalomyelitis (EAE), induced by sensitization with MOG35–55 peptide in C57BL/6 female mice infected with the intestinal nematode Heligmosomoides polygyrus. The EAE remission was correlated with altered leukocyte number identified in the central nervous system (CNS), and temporary permeability of the blood–brain barrier at the histotrophic phase of infection. At 6 days post-infection, when the L4 stage had almost completely attenuated the clinical severity and pathological signs of EAE, CD25+ cell numbers expanded significantly, with parallel growth of CD8+ and CD4+, both CD25+Foxp3+ and CD25+Foxp3− subsets and alternatively activated macrophages. The phenotypic changes in distinct subsets of cerebrospinal fluid cells were correlated with an inhibited proliferative response of encephalitogenic T cells and elevated levels of nerve growth factor and TGF-β. These results enhance our understanding of mechanisms involved in the inhibition of immune responses in the CNS during nematode infection.

Summary In the northern areas of Pakistan, the use of Artemisia based therapeutics is a common practice. Plants of genus Artemisia are known to possess anthelmintic and therapeutic effect. Infections caused by gastrointestinal nematodes are major threat to livestock industry across the world resulting in loss of production and indirect economic losses due to high cost of anthelmintic drugs. Present study was carried out to evaluate in vitro and in vivo effect of Artemisia sieversiana and Artemisia parviflora on Haemonchus contortus, a parasitic nematode of small ruminants. Methanolic plant extract was tested against three different developmental stages using an egg hatch assay, infective larvae and adult worm motility assay. Different concentrations were used for the bioassays and post exposure mortality was recorded after 8 hr for adult worms and infective larvae, while egg inhibition percentage was observed after 27 hr. A highly significant ability to inhibit the egg hatching (100 %) was recorded for both plant extracts while, the highest activity for adult worm assay and larvicidal assay was 90 % for A. sieversiana. The highest activity for adult motility and larvicidal assay for A. parviflora was 89 % and 86.6 % respectively. For in vivo trials maximum parentage reduction was 77.0 % for A. sieversiana and 73.6 % for A. parviflora. It is concluded that selected plant extracts were effective in reducing worm burden in animals.

Avena sativa L., 1753 (Poaceae) is used as feed for livestock and as a crop rotation agent. The purpose of the study was to examine the molecular mechanisms behind the antihelminth activity of the oat saponins avenacoside B (AveB) and 26-desglucoavenacoside B (26DGAveB) by evaluating their effect on Heligmosomoides bakeri, a parasitic nematode of mice. The avenacosides AveB and 26DGAveB were separated and purified from A. sativa green leaves, and their mycotoxic activity was confirmed against the fungus Trichoderma harzianum. The anti-nematode activity of the avenacosides was measured by egg hatching assay. In the surviving L3 larvae exposed to avenacosides, the expression of CED-9, a protein of the apoptosis pathway, was identified by Western blotting. The protein profile of L3 larvae was monitored by High Performance Liquid Chromatography (HPLC). The action of saponins on glycoprotein pump (Pgp) activity in L3 larvae was compared to that of the pump blocker Verapamil (VPL). A mouse model was used to measure the infectivity of L3 larvae exposed to AveB and 26DGAveB, and the outcome of the immune response. Both compounds induced morphological changes in larvae and blocked Pgp activity; however, only 26DGAveB provoked expression of CED-9. The infected mice displayed changes in the molecular pattern of larval proteins and enhanced IL-4 production, indicating that avenacosides reduced the infectivity of H. bakeri larvae. In avenacosides, the residue without glucose at the C26 position demonstrated greater anti-nematode activity. Our findings indicate that A. sativa compounds are natural products with anti-parasitic activity.

Acanthamoeba is a free-living protist pathogen, which is present in every place on Earth. 50 to 100 percent of the adult population has serum antibodies, specific for Acanthamoeba antigens. Acanthamoeba is an etiological agent of keratitis and encephalitis diagnosed in human. Acanthamoeba keratitis occurs in healthy persons and may lead to visual impairment and blindness, because corneal infection with this parasite fails to induce cell-mediated immune response due to the absence of resident antigen-presenting cells in the cornea. Systemic immunization with Acanthamoeba antigens induces Th1 cell-mediated immunity and serum IgG antibody, but do not prevent the development of keratitis. Immunization via mucosal surfaces stimulates IgA antibodies in tears and protects against the development of keratitis. Amoebae feed mainly on bacteria, fungi, and algae. By transferring intracellular bacteria, amoeba contributes to the spread of diseases dangerous to humans. Some microorganisms have evolved to become resistant to protist, since they are not internalized or able to survive, grow, and exit free-living protists after internalization. In many cases, the bacteria inside living amoebae survive longer, and multiply better, showing higher virulence. There is a hypothesis, which assumes that Acanthamoeba and symbiontic bacteria survive and multiply better in moist soil, rich in nitrogen compounds, particularly in the vicinity of the root systems of Alnus glutinosa, infected with nitrogen-fixing bacteria Frankia alni. Impact of soil environment created by nitrogen-fixing bacterium Frankia alni on specific relations between protists Acanthamoeba and highly pathogenic bacteria strains in Alnus glutinosa habitats in Poland continue to be established.

Nematode infection is one of the principal diseases suffered by sheep and the class II region of the MHC has been repeatedly associated with differences in susceptibility and resistance to infection. The aim of this study was to examine the association of MHC class II haplotypes in a flock of Texel sheep with faecal egg counts and antibody responsiveness. Two haplotypes carried the DRB1*11:01 allele which has previously been associated with reduced egg counts in Scottish Blackface and Suffolk sheep. One of the two haplotypes was associated with reduced egg counts in the Texel breed, and both haplotypes were associated with reduced IgA activity against an extract from fourth-stage larvae. The reduced IgA activity is probably a consequence of reduced numbers of fourth-stage larvae in sheep carrying the resistance allele. The association of specific MHC alleles with reduced egg counts, reduced worm numbers and decreased IgA activity provides a mechanism for the density-dependent regulation of parasite growth and fecundity.

Lambs with the Major Histocompatibility Complex DRB1*1101 allele have been shown to produce fewer nematode eggs following natural and deliberate infection. These sheep also possess fewer adult Teladorsagia circumcincta than sheep with alternative alleles at the DRB1 locus. However, it is unclear if this allele is responsible for the reduced egg counts or merely acts as a marker for a linked gene. This study defined the MHC haplotypes in a population of naturally infected Scottish Blackface sheep by PCR amplification and sequencing, and examined the associations between MHC haplotypes and faecal egg counts by generalised linear mixed modelling. The DRB1*1101 allele occurred predominately on one haplotype and a comparison of haplotypes indicated that the causal mutation or mutations occurred in or around this locus. Additional comparisons with another resistant haplotype indicated that mutations in or around the DQB2*GU191460 allele were also responsible for resistance to nematode infections. Further analyses identified six amino acid substitutions in the antigen binding site of DRB1*1101 that were significantly associated with reductions in the numbers of adult T. circumcincta.

The mouse intestinal parasite Heligmosomoides polygyrus demonstrates adaptation to the inflammatory milieu as a result of colitis induced by dextran sulphate sodium (DSS). Nematodes from mice with colitis had different effects on dendritic cells than nematodes from mice without colitis. Immature JAWSII cells pre-exposed to L4 stage H. polygyrus from DSS-treated mice were adoptively transferred to mice with induced colitis. After two days, a higher disease activity index, macroscopic damage score and colon histology score were observed. MLN T cells isolated nine days after transfer demonstrated proinflammatory IFN-γ and IL-17 production. Transfer of JAWSII stimulated with male or female L4 larvae from a control invasion resulted in a slight improvement of colitis; in addition, dendritic cells exposed to H. polygyrus female L4 larvae, provoked migration of CD8+CD25+ T cells from MLN to the colon. Nematodes from an inflammatory environment changed cytokine production by dendritic cells. Inflammatory milieu changing nematode immunomodulatory activity affects dendritic cell functions, which offers new insight into the helminth-host relationship.

Helminths and their products are strong candidates for the treatment of autoimmunological disorders and allergies. Being a key population of antigen-presenting cells, dendritic cells play a crucial role in the therapeutic potential of worms. The study compares the effects of live pre-male and pre-female L4 stage Heligmosomoides polygyrus administration on the maturation and activation of the JAWS II line of immature dendritic cells. On stimulation with L4 stage H. polygyrus, JAWS II cells acquire semi-mature status and induce Th2 and regulatory responses in vitro. The strongest immunosuppressive effect on JAWS II cells was observed following stimulation with both sexes of nematodes together; this was manifested as immature dendritic cell morphology, proliferation inhibition, cell cycle change, decreased translocation of NF-κB into the nucleus, and lower expression of surface cellular costimulatory molecules CD80, CD86 and MHC I. However, greater production of proinflammatory (IL-12p70, TNF-α, IL-6) and Th2 response-promoting cytokines (IL-4) was observed by JAWS II following exposure to both sexes compared to male or female larvae alone. Sex had no influence on the viability, apoptosis process or endocytosis abilities of the JAWS II cell line. The findings indicate that the presence of only a single sex of the parasite influences a developed response, resulting in reduced proinflammatory and an antiparasitic reaction.

Current study was designed to evaluate in vivo and in vitro anthelmintic activity of Artemisia vestita Wall ex DC. and Artemisia maritima L. against Haemonchus contortus in comparison with ivermectin to investigate the effect of plant extracts on survival of infective L3 and adults under in vitro condition. Plant extracts were given to H. contortus infected sheep orally and it was infected with L3 stage of H. contortus at dose of 5000 larvae/sheep. Total of 25-30 larvae were incubated with plant extracts in PBS alone and ivermectin at different concentration used as positive control. It was recorded that there is a significant decrease in fecal egg count (FEC) after post-treatment period for both plants. The highest fecal egg count reduction for A. vestita was 87.2% at 100mg/kg while for A. maritima it was 84.5% on day 28 post-treatment. Investigated extracts indicated significant activity against larvae and adult worms.

The purpose of this study was to evaluate the potential of chitosan units released during natural degradation of the polymer to activate the immune system against T. spiralis infection. High molecular weight chitosan was injected intraperitoneally into C57BL/6 mice. Flow cytometry and cytokine concentration, measured by ELISA, were used to characterize peritoneal cell populations during T. spiralis infection. The strong chemo-attractive properties of chitosan caused considerable infiltration into the peritoneal cavity of CD11b+ cells, with reduced expression of MHC class II, CD80, CD86, Dectin-1 or CD23 receptors in comparison to T. spiralis-infected mice. After prolonged chitosan biodegradation, cell populations expressing IL-4R, MR and Dectin-1 receptors were found to coexist with elevated IL-6, IL-10, TGF-β and IgA production. IgA cross-reacted with T. spiralis antigen and chitosan. It was found that chitosan treatment attracted immune cells with low activity, which resulted in the number of nematodes increasing. The glucosamine and N-acetyl-D-glucosamine residues were recognized by wheat germ agglutinin (WGA) lectin and therefore any biodegradable chitosan units may actively downregulate the immune response to the parasite. The findings are relevant for both people and animals treated with chitosan preparations.

It is estimated that more than half of the nowadays known species are pathogenic parasites. Among macroparasites gastrointestinal nematodes are one of most common and having significant impact on life and health. Those organisms reveal strong, specific immune response in host, involving primary mechanisms associated with regulatory and Th2 cells. Referring to immunomodulatory abilities of helminths, parasite infections started to be considered as a possible therapy for many autoimmune diseases. Clinical trials on 2nd and 3rd stage are conducted in spite that treatment has not been recognized as safe for common use. Despite that the safety of treatment with parasites is still controversial and widely discussed. Our knowledge about mechanisms used by helminth to moderate immune response is still inadequate to predict possible effect of long lasting parasite infection on individual patients.

Understanding the structure of the major histocompatibility complex, especially the number and frequency of alleles, loci and haplotypes, is crucial for efficient investigation of the way in which the MHC influences susceptibility to disease. Nematode infection is one of the most important diseases suffered by sheep, and the class II region has been repeatedly associated with differences in susceptibility and resistance to infection. Texel sheep are widely used in many different countries and are relatively resistant to infection. This study determined the number and frequency of MHC class II genes in a small flock of Texel sheep. There were 18 alleles at DRB1, 9 alleles at DQA1, 13 alleles at DQB1, 8 alleles at DQA2 and 16 alleles at DQB2. Several haplotypes had no detectable gene products at DQA1, DQB1 or DQB2, and these were defined as null alleles. Despite the large numbers of alleles, there were only 21 distinct haplotypes in the population. The relatively small number of observed haplotypes will simplify finding disease associations because common haplotypes provide more statistical power but complicate the discrimination of causative mutations from linked marker loci. Electronic supplementary material The online version of this article (doi:10.1007/s00251-016-0962-6) contains supplementary material, which is available to authorized users.

Saponins of marigold ( Calendula officinalis), in particular derivatives of 3-O-monoglucuronide of oleanolic acid, are able to reduce infectivity of Heligmosomoides polygyrus in mice. The purpose of this study was to understand the immune activation provoked by third-stage larvae exposed to marigold glucuronides. We also examined the pattern of glycosylation of larval antigens which appeared to be crucial for induction of cytokine production in BALB/c mice; higher concentrations of IL-6, IFN-γ, IL-10 and TNF-α were observed in serum or intestine one week post infection. Three weeks later, in the chronic phase of infection, cells in culture were able to produce IL-6, IFN-γ, TNF-α and IL-17. Restimulation of cells with H. polygyrus antigen resulted in reduced production of IL-6, and TNF-α. The pattern of cytokine production co-existed with reduced expression of terminal glucose, α-linked mannose, N-acetyl-galactosamine, β-galactose, N-acetyl-glucosamine and α-fucose in several protein bands. Galactose, as a new terminal carbohydrate residue appeared in 20–24 kDa protein bands. The number of immunogenic epitopes in parasitic antigens was reduced; only three protein bands of 56, 26 and 12 kDa were recognized by IgG1. These studies provide a model system to find the glycosylated molecules expressed on nematodes that improve establishment and survival and characterize cytokine production in mice infected with larvae exposed to saponin. Identification of these molecules is the first step in the recognition of key antigenic epitopes able to induce protective or tolerogenic immune responses.

Many laboratory studies and epidemiological observations confirm that nematodes prevent some immune-mediated diseases. The development of immunologically well-defined laboratory models of intestinal nematode infection has allowed significant advances to be made in understanding the immunological basis of effector mechanisms operating during infection under controlled laboratory conditions. The Heligmosomoides polygyrus- mouse system is used for studies of parasite immunomodulation. H. polygyrus causes a chronic, asymptomatic intestinal infection and effectively maintains both local and systemic tolerance to reduce allergic and autoimmune inflammation. However, exposure of mice to H. polygyrus antigen reduced spontaneous and glucocorticoid-induced apoptosis of CD4- positive T cells in mesenteric lymph node (MLN). In this study we evaluate the proliferation, cytokine secretion, cell cycle progression and expression of apoptosis related genes in MLN CD4 T cells of uninfected and H. polygyrus infected mice ex vivo and in vitro after restimulation with parasite excretory secretory antigen (ESAg), somatic antigen (SAg) and fraction 9 (F9Ag) of somatic antigen. For the first time we explain the influence of H. polygyrus antigens on the intrinsic pathway of apoptosis. We found that the proliferation provoked by fraction 9 and inhibition of apoptosis was dependent on a low Bax/Bcl-2 ratio, dramatical upregulation of survivin, D1 cyclin, P-glycoprotein, and loss of p27Kip1 protein with inhibition of active caspase-3 but not caspase- 8.

Primary exposure of mice to gastrointestinal nematode infection with Heligmosomoides polygyrus reduces inflammation in an experimental model of multiple sclerosis. In this study, we aimed to evaluate the ability of H. polygyrus L4 larvae and adults infection to reduce the symptoms of ongoing experimental autoimmune encephalomyelitis (EAE) in female C57Bl/6 mice. EAE was induced by myelin oligodendrocyte glycoprotein MOG p35–55 and after 21 days mice were orally infected with 200 infective larvae (L3) of H. polygyrus . Reduction in EAE symptoms was observed from 2 days post infection and the symptoms were almost completely inhibited at 6 days post infection. This effect was associated with limited total protein content in the cerebrospinal fluid; CSF, and significant decreased pro-inflammatory IL-12p40 concentration and increased concentration of the regulatory cytokines IL-10, TGF-β and IL-6 in the CSF and in the serum. The reduction of EAE symptoms in the enteral phase was associated with higher IL-12p40 concentration in the CSF and very low concentrations of IL-17A and IL-2 in the serum. The fourth stage of gastrointestinal nematode can reverse systemic inflammation in animal models of multiple sclerosis by reducing IL-12 and promoting regulatory cytokines production. The mechanism induced by adult nematodes which sustained EAE inhibition can be provoked by regulatory mechanism connected with reduce IL-17A concentration.

Host immunosuppression occurs during chronic nematode infection, partly due to effector T-cell hyporesponsiveness. The role of P-glycoprotein (P-gp), a member of the ABC transporter family, has been assessed in T-cell activity. This study assesses the possible role of P-gp in T-cell activity during nematode infection. Our findings indicate that blockade of P-gp in vivo increased protection against Heligmosomoides polygyrus nematode infection and was associated with the enhanced T-cell activity. Three P-gp-inhibitors, verapamil (VRP), cyclosporine (CsA) and tariquidar (XR9576), were used to determine the influence of nematode infection on the P-gp function of T cells. The influence of the nematode on the uptake, efflux and kinetics of extrusion in T-cell subsets CD4+ and CD8+ was assessed by the accumulation of Rho123 dye. The results indicate that H. polygyrus infection contributes to the inhibition of T-cell function by elevating P-gp activity. The blockade of P-gp in the T cells of infected mice led to an impressive increase in T-cell proliferation and IL-4 cytokine release through the upregulation of NF-κB activation. These results provide the first evidence that the P-gp function of T cells is altered during nematode infection to open the way for further studies aiming to explore the role of P-gp in host-parasite interactions.

The probability of infection with fungi, as well as parasitic nematodes or arthropods may increase in overcrowded population of animals and human. The widespread overuse of drugs and immunosuppressants for veterinary or medical treatment create an opportunity for many pathogenic species. The aim of the review is to present the common molecular characteristics of such pathogens as fungi and nematodes and other chitin bearing animals, which may both activate and downregulate the immune response of the host. Although these pathogens are evolutionary distinct and distant, they may provoke similar immune mechanisms. The role of chitin in these phenomena will be reviewed, highlighting the immune reactions that may be induced in mammals by this natural polymer.

The precise mechanism of the very effective therapeutic effect of gastrointestinal nematodes on some autoimmune diseases is not clearly understood and is currently being intensively investigated. Treatment with living helminths has been initiated to reverse intestinal immune-mediated diseases in humans. However, little attention has been paid to the phenotype of nematodes in the IBD-affected gut and the consequences of nematode adaptation. In the present study, exposure of Heligmosomoides polygyrus larvae to the changed cytokine milieu of the intestine during colitis reduced inflammation in an experimental model of dextran sulphate sodium (DSS)- induced colitis, but increased nematode establishment in the moderate-responder BALB/c mouse strain. We used mass spectrometry in combination with two-dimensional Western blotting to determine changes in protein expression and changes in nematode antigens recognized by IgG1 in mice with colitis. We show that nematode larvae immunogenicity is changed by colitis as soon as 6 days post-infection; IgG1 did not recognize highly conserved proteins Lev-11 (isoform 1 of tropomyosin α1 chain), actin-4 isoform or FTT-2 isoform a (14-3-3 family) protein. These results indicate that changes in the small intestine provoked by colitis directly influence the nematode proteome. The unrecognized proteins seem to be key antigenic epitopes able to induce protective immune responses. The proteome changes were associated with weak immune recognition and increased larval adaptation and worm growth, altered localization in the intestine and increased survival of males but reduced worm fecundity. In this report, the mechanisms influencing nematode survival and the consequences of changed immunogenicity that reflect the immune response at the site colonized by the parasite in mice with colitis are described. The results are relevant to the use of live parasites to ameliorate IBD.

Summary Primary exposure of mice to the nematode Heligmosomoides polygyrus infection reduces inflammation in an experimental model of colitis. The aim of the present investigation was to evaluate whether the reduced inflammation provoked by H. polygyrus L4 larvae in BALB/c mice treated with dextran sulphate sodium is associated with changed expression of opioids in the small intestine and colon. Colitis was induced by 5% Dextran sulphate sodium (DSS) oral administration for 3 days before oral infection with 200 infective larvae (L3) H. polygyrus until the end of the experiment, 6 days post-infection. Clinical disease symptoms were monitored daily. The expressions of proopiomelanocortin POMC1, MOR1 (Oprm1) – opioid receptor and β-endorphin were determined by RT-PCR, Western blot and immunoassay, respectively, in the colon and small intestine of mice. RT-PCR analysis of colon tissues showed up-regulation of the expression of POMC and MOR1 opioid-dependent genes in mice with DSS-induced colitis. H. polygyrus L4 larvae inhibited DSS-induced colitis symptoms that were correlated with increased IL-1β, TNF-α, IL-6, myeloperoxidase (MPO) concentration, macrophages infiltration and MOR1, POMC and β-endorphin increased expression in the small intestine and inhibition of those in the colon.

1.1 Parasitism Parasitism is an antagonistic relationship between organisms of different species where the parasite benefits at the expense of the host. Helminths are long-living, multicellular parasites. There are two major phylla of helminths; Nematodes and Platyhelminthes. The nematodes contain the intestinal worms known as soil-transmitted helminths including hookworms, whipworms and the filarial worms that cause lymphatic filariasis and onchocerciasis. The Platyhelminthes, known as flatworms, include the flukes and the tapeworms. Both nematodes, flukes and tapeworms widely infect humans and animals (Hotez & Kamath, 2009). Most of the parasitic species causing weakness and disease survive in and explore the host as natural environment. Helminths can be found in a great variety of tissue niches, and although they cause very high morbidity, direct mortality of the host species remains low (Brooker, 2010). Human hookworm infection is a common soiltransmitted helminth infection that is caused by the nematode parasites Necator americanus and Ancylostoma duodenale. Hookworm infections are asymptomatic however substantially contributes to the incidence of anemia and malnutrition in developing nations (de Silva et. al 2003, WHO 2010). Filarial diseases are rarely fatal and morbidity of human filariasis results mainly from the host reaction to microfilariae or developing adult worms in different areas of the body. Most of the filarial infected individuals have a subclinical condition associated with patent infection, and acute manifestations which are rarely life threatening. However, chronic manifestations, such as lymphedema (elephantiasis) and hydrocele, are debilitating (Keiser et al., 2002). Schistosomes, the blood flukes reside in the mesenteric and vesical venules. They have a life span of many years and daily produce large numbers of eggs, which must traverse the gut or bladder tissues on their way to the lumens of the excretory organs. Many of the eggs remain in the host tissues, inducing immunologically mediated granulomatous inflammation and fibrosis (Warren, 1982). The relationship between the presence of schistosome infection and clinical morbidity revealed schistosomiasis-related disease and associated death (Van der Werf et al., 2003). Worldwide, many cestode infestations occur with very low prevalence of infections and are asymptomatic. Nevertheless some of the more serious infestations result in symptoms from mass effects on vital organs, inflammatory responses, nutritional deficiencies, and the potential of fatal anaphylaxis (Del Brutto, 2005; Morar & Feldman, 2003; Ozturk et al., 2007).