Invader immunology: invasion history alters immune system function in cane toads (Rhinella marina) in tropical Australia.

Because an individual's investment into the immune system may modify its dispersal rate, immune function may evolve rapidly in an invader. We collected cane toads (Rhinella marina) from sites spanning their 75-year invasion history in Australia, bred them, and raised their progeny in standard conditions. Evolved shifts in immune function should manifest as differences in immune responses among the progeny of parents collected in different locations. Parental location did not affect the offspring's cell-mediated immune response or stress response, but blood from the offspring of invasion-front toads had more neutrophils, and was more effective at phagocytosis and killing bacteria. These latter measures of immune function are negatively correlated with rate of dispersal in free-ranging toads. Our results suggest that the invasion of tropical Australia by cane toads has resulted in rapid genetically based compensatory shifts in the aspects of immune responses that are most compromised by the rigours of long-distance dispersal.

The presence of conifer resin decreases the use of the immune system in wood ants

1. Wood ants (Formica paralugubris) incorporate large amounts of solidified conifer resin into their nest, which reduces the density of many bacteria and fungi and protects the ants against some detrimental micro-organisms. By inducing an environment unfavourable to pathogens, the presence of resin may allow workers to reduce the use of their immune system. 2. The present study tested the hypothesis that the presence of resin decreases the immune activity of wood ants. Specifically, three components of the humoral immune defences of workers kept in resin-rich and resin-free experimental nests (antibacterial, lytic, and prophenoloxidase activities) were compared. 3. The presence of resin was associated with reduced bacterial and fungal densities in nest material and with a small decrease in worker antibacterial and lytic activities. The prophenoloxidase activity was very low in all workers and was not affected by the presence of resin. 4. These results suggest that collective medication with resin reduces pathogen pressure, which in turn decreases the use of the inducible part of the immune system. More generally, the use of plant secondary compounds might be an efficient and economical way to fight pathogens.

The fate and persistence of Leishmania major in mice of different genetic backgrounds: an example of exploitation of the immune system by intracellular parasites.

Leishmania spp. are intracellular protozoan parasites that are delivered within the dermis of their vertebrate hosts. Within this peripheral tissue and the draining lymph node, they find and/or rapidly create dynamic microenvironments that determine their ultimate fate, namely their more or less successful expansion, and favour their transmission to another vertebrate host though a blood-feeding vector. Depending on their genetic characteristics as well as the genetic make-up of their hosts, once within the dermis Leishmania spp. very rapidly drive and maintain sustained T cell-dependent immune responses that arbitrate their ultimate fate within their hosts. The analysis of the parasitism exerted by Leishmania major in mice of different genetic backgrounds has allowed us to recognize some of the early and late mechanisms driven by this parasite that lead to either uncontrolled or restricted parasitism. Uncontrolled parasitism by Leishmania major characterizing mice from a few inbred strains (e.g. BALB/c) is associated with the expansion of parasite reactive Th2 CD4 lymphocytes and results from their rapid and sustained activity. In contrast, restricted parasitism characteristic of mice from the majority of inbred strains results from the development of a polarized parasite-specific Th1 CD4 response. This murine model of infection has already been and will continue to be particularly instrumental in dissecting the rules controlling the pathway of differentiation of T cells in vivo. In the long run, the understanding of these rules should contribute to the rational development of novel immunotherapeutic interventions against severe infectious diseases.

The interplay between radiation and the immune system in the field of post-radical pneumonitis and fibrosis and why it is important to understand it.

A discussion on the importance and pathogenesis of radiation-induced pneumonitis and fibrosis is provided, with a special focus on the role of the immune system. The need to understand this interaction is highlighted in view of emerging therapeutic potential.

Mobilization of hemopoietic stem cells with high-dose methotrexate plus granulocyte-colony-stimulating factor in patients with primary central nervous system lymphoma.

BACKGROUND: High-dose therapy with autologous stem cell support after standard dose induction is a promising approach for therapy of primary central nervous system lymphoma (PCNSL). High-dose methotrexate (HD-MTX) is a standard drug for induction of PCNSL; however, data about the capacity of HD-MTX plus granulocyte-colony-stimulating factor (G-CSF) to mobilize hemopoietic progenitors are lacking. STUDY DESIGN AND METHODS: This investigation describes the data from stem cell mobilization and apheresis procedures after one or two cycles of HD-MTX for induction of PCNSL within the East German Study Group for Haematology and Oncology 053 trial. Eligible patients proceeded to high-dose busulfan/thiotepa after induction therapy and mobilization. RESULTS: Data were available from nine patients with a median age of 58 years. The maximal CD34+ cell count per microL of blood after the first course of HD-MTX was 13.89 (median). Determination was repeated in six patients after the second course with a significantly higher median CD34+ cell count of 33.69 per microL. Five patients required two apheresis procedures and in four patients a single procedure was sufficient. The total yield of CD34+ cells per kg of body weight harvested by one or two leukapheresis procedures was 6.60 x 10(6) (median; range, 2.68 x 10(6)-15.80 x 10(6)). The yield of CD34+ cells exceeded the commonly accepted lower threshold of 3 x 10(6) cells per kg of body weight in eight of nine cases. Even in the ninth, hemopoietic recovery after stem cell reinfusion was rapid and safe. CONCLUSION: HD-MTX plus G-CSF is a powerful combination for stem cell mobilization in patients with PCNSL and permits safe conduction of time-condensed and dose-intense protocols with high-dose therapy followed by stem cell reinfusion after HD-MTX induction.

Secretory IgA: an actor of the interplay between the commensal flora and the intestinal immune system?

In the gastro-intestinal tract,Peyers patches have been describedas a major inductive site for mucosalsecretory IgA (SIgA) responses directedagainst pathogens. The classicalview is that SIgAserves as the firstline of defense against microorganismsby agglutining potential invadersand faciliting their clearance byperistaltic and mucociliary movements,a mechanism called immuneexclusion. Our laboratory has shownthat SIgA is not only able to be"retrotransported" into Peyers patchesvia the associated M cells, but also todeliver sizeable cargos in the form ofSIgA-based immune complexes, resultingin the onset of non-inflammatorytype of responses. Such a novelfunction raises the question of thepossible role of mucosal SIgA in theinterplay with commensal bacteriaand the contribution of the antibody inbacterial homeostasis. To address thisquestion, Lactobacillus rhamnosus(LPR) was administered into a mouseligated loop comprising a Peyerspatch, in association or not with SIgA.The fate of fluorescently labelled bacteriawas followed by laser scanningconfocal microscopy at different incubationtimes. After 2 hours of incubationin the loop, LPR bacteria arefound more abundantly in thesubepithelial dome (SED) regionwhen they are coated with SIgA thanLPR administered alone despite theyare absent from neighboring villi.Herein, it is shown that this mechanismof entry involves M cells inPeyers pathes. After their sampling byM cells, bacteria are engulfed by thedendritic cells of the subjacent SEDregion. Interestingly, LPR bacteriaare found coated by the endogenousnatural SIgA present in mice intestinalsecretions, confirming the requirementof SIgA for this type of entry.The subsequent effect on the maturationof dendritic cells after interactionwith LPR was investigated in vitroin presence or not of SIgA by measuringthe expression of CD40, CD80and CD86 surface markers with flowcytometry analyses. Results show thatDCs respond in the same way in presenceof SIgA than with LPR bacteriaalone, indicating that SIgA does notmodulate the interaction betweenDCs and bacteria in this context. Thiswork gives new evidences about theinvolvement of SIgA in the mechanismby which the intestinal immunesystem permanently checks the contentof the intestine.

Synergistic and antagonistic interaction between different branches of the immune system is related to melanin-based coloration in nestling tawny owls.

When exposed to parasites, hosts often mount energetically expensive immune responses, and this may alter resource allocation between competing life history traits including other components of the immune system. Here, we investigated whether a humoral immune challenge towards a vaccine reduces or enhances the cutaneous immune responses towards an injection of lipopolysaccharid (LPS, innate immunity) and phytohaemagglutinin (PHA, T-cell immunity) in nestling tawny owls in interaction with the degree of plumage melanin-based coloration. The humoral immune challenge enhanced the response to LPS similarly in differently coloured nestlings. In contrast, the same humoral immune challenge enhanced immune response to PHA in dark reddish melanic nestlings while reducing it in pale reddish melanic nestlings. Our results highlight that both antagonistic and synergistic interactions can take place among branches of immune system, and that the sign and magnitude of these interactions can vary with immune responses involved and the degree of melanin-based coloration.

From pathogen defence to food allergy; The multiple facets of the mucosal immune system

Résumé destiné à un large public Le système immunitaire associé aux muqueuses gastro-intestinales doit être capable de protéger notre organisme contre l'invasion de pathogènes. Parallèlement, il doit identifier en Cant que tels, des composés inoffensifs comme la nourriture ou les milliards de bactéries qui résident dans notre intestin. Le travail présenté ici aborde ces deux aspects essentiels au bon fonctionnement de notre muqueuse intestinale. Dans une première partie, la protéine nommée pièce sécrétoire a été étudiée pour ses propriétés protectrices contre le pathogène viral rotavirus. Le rôle de la pièce sécrétoire est de transporter les anticorps que nous produisons vers la surface des muqueuses. En dehors de cette fonction bien connue, il se peut que cette protéine soit également capable de protéger notre organisme contre certains virus. L'hypothèse de travail était donc que la pièce sécrétoire se lie directement au virus, l'empêchant ainsi d'infecter des cellules épithéliales de l'intestin. En utilisant différentes techniques biochimiques, cette hypothèse s'est révélée fausse car aucune interaction entre la pièce sécrétoire et le virus n'a pu être observée, et logiquement, aucune protection n'a pu prendre place. En revanche, la pièce sécrétoire se lie à d'autres structures pathogéniques et permet ainsi de neutraliser leurs effets néfastes. La pièce sécrétoire participe donc activement à la protection de nos muqueuses, en plus de son rôle de transporteur. La deuxième partie de ce travail avait pour sujet les réactions inappropriées que le système immunitaire induit parfois contre un aliment, ou, autrement dit, les allergies alimentaires. Un modèle d'allergie alimentaire à donc été développé chez la souris et a permis de mesurer plusieurs symptômes et facteurs liés à l'allergie. Puis, ce modèle a été utilisé afin de tester les effets bénéfiques d'une bactérie lactique, dite probiotique, sur le développement de l'allergie. Il a été observé que, sous certaines circonstances, l'administration de la bactérie lactique protégeait entièrement les souris contre les réactions allergiques. L'effet bénéfique dépend donc du probiotique mais également d'autres facteurs encore inconnus â ce jour. Cette étude ouvre la voie sur la compréhension des mécanismes liés aux allergies alimentaires et sur l'impact que peuvent avoir les bactéries probiotiques sur cette maladie. Résumé Le système immunitaire associé aux muqueuses intestinales doit être capable de différencier les antigènes inoffensifs tels que 1a nourriture ou les bactéries commensales des microorganismes potentiellement dangereux. Cet aspect est essentiel pour le maintien de l'homéostase intestinale et fait l'objet du travail présenté ici. Dans un premier projet, les propriétés protectrices de la protéine appelée pièce sécrétoire (SC) ont été étudiées. SC est une protéine connue pour le transport des immunoglobulines à la surface des muqueuses. Cette protéine est fortement glycosylée paz des sucres complexes, ce qui nous a mené à postuler que SC puisse interagir avec le pathogène rotavirus. Cette hypothèse était soutenue par le fait que ce virus adhère aux cellules épithéliales par des résidus glycosylés. Des analyses biochimiques et biologiques ont démontré qu'aucune interaction entre SC et le virus ne prenait place, et que par conséquent SC n'offrait aucune protection contre ce pathogène. En revanche, SC interagit avec d'autres structures pathogéniques, comme la toxine A de Clostridium difficile, et la molécule d'adhésion intimine de la bactérie entéropathogène Escherichia coli. La liaison se fait par l'intermédiaire des sucres et confère ainsi une protection contre ces pathogènes. Ainsi, SC a été identifié comme agent neutralisant au niveau de l'intestin. La deuxième partie de ce travail abordait le sujet des allergies alimentaires, et avait pour but de tester les effets bénéfiques potentiels d'une bactérie probiotique, Lactobacillus paracasei NCC2461, contre les réactions allergiques. Un modèle marin d'allergie alimentaire a été mis au point, permettant de mesurer des immunoglobulines E, des symptômes allergiques, et la dégranulation de mastocytes. Lorsque le probiotique a été administré aux souris, celles-ci ont été complètement protégées des réactions allergiques dans une première expérience. Cependant, cette protection n'a pas été reproduite et suggère que des facteurs environnementaux encore inconnus sont critiques pour que le probiotique agisse positivement. Ce travail a permis de mettre en évidence la complexité de l'approche des traitements liés aux probiotiques et ouvre la voie sur la compréhension des mécanismes liés à l'allergie. Abstract The mucosal immune system associated to the gastrointestinal mucosa must efficiently distinguish between innocuous antigens, such as food proteins and commensal bacteria and potentially infectious agents. The work presented here deals with these two essential aspects guaranteeing intestinal homeostasis. In the first part of this work, the protective properties of secretory component (SC) toward the pathogen rotavirus were investigated. SC, which allows the transport of polymeric immunoglobulins (Ig) to mucosal surfaces, is highly glycosylated with complex glycan structures. The abundance and the nature of these carbohydrates led us to speculate that SC might interact with rotavirus, which is known to bind target cells with glycan receptors. Using various biological and biochemical techniques, we demonstrated that SC did not interact with rotaviruses, nor protected epithelial cells from infection. However, SC was shown to bind to Clostridium difficile toxin A and to the enteropathogenic Echerischia coli adhesion molecule intimin in a glycan-dependent fashion. These interactions allow in vitro protection of epithelial cells using physiological concentrations of SC. These data identify SC as a microbial scavenger at mucosal surfaces, and in the context of secretory IgA, further enhance the neutralising properties of the complex. The second project was inscribed in the domain of food allergy and aimed to test the modulatory functions of a probiotic strain of Lactobacillus paracasei toward allergic reactions. A model of food-mediated allergy was developed in the mouse using mucosal sensitisation. Several parameters associated to allergy were quantified after allergen challenge, and included allergen-specific IgE, allergic signs like diarrhea and temperature drop, and degranulation of mast cells. Administration of the probiotic strain was shown to completely protect mice from allergic reactions. However, these data were not reproduced, suggesting that unknown environmental factors are required so that protection mediated by the probiotic strain occurs. This study paves the way to the understanding of the mechanisms associated to allergy, and highlights the tremendous complexity that probiotic treatments will have to face.

The effects of cocoa on the immune system

Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T-cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of Th2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota. The mechanisms involved in these influences are discussed here. Further research may elucidate the cocoa compounds involved in such an effect and also the possible medical approaches to these repercussions

MHC/Peptide-Specific Interaction of the Humoral Immune System: A New Category of Antibodies.

Abs bind to unprocessed Ags, whereas cytotoxic CD8(+) T cells recognize peptides derived from endogenously processed Ags presented in the context of class I MHC complexes. We screened, by ELISA, human sera for Abs reacting specifically with the influenza matrix protein (IMP)-derived peptide58-66 displayed by HLA-A*0201 complexes. Among 653 healthy volunteers, blood donors, and women on delivery, high-titered HLA-A*0201/IMP58-66 complex-specific IgG Abs were detected in 11 females with a history of pregnancies and in 1 male, all HLA-A*0201(-). These Abs had the same specificity as HLA-A*0201/IMP58-66-specific cytotoxic T cells and bound neither to HLA-A*0201 nor the peptide alone. No such Abs were detected in HLA-A*0201(+) volunteers. These Abs were not cross-reactive to other self-MHC class I alleles displaying IMP58-66, but bound to MHC class I complexes of an HLA nonidentical offspring. HLA-A*0201/IMP58-66 Abs were also detected in the cord blood of newborns, indicating that HLA-A*0201/IMP58-66 Abs are produced in HLA-A*0201(-) mothers and enter the fetal blood system. That Abs can bind to peptides derived from endogenous Ags presented by MHC complexes opens new perspectives on interactions between the cellular and humoral immune system.

NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability. © 2015 Wiley Periodicals, Inc.

Inorganic Nanoparticles and the Immune System: Detection, Selective Activation and Tolerance

The immune system is the responsible for body integrity and prevention of external invasion. On one side, nanoparticles are no triggers that the immune system is prepared to detect, on the other side it is known that foreign bodies, not only bacteria, viruses and parasites, but also inorganic matter, can cause various pathologies such as silicosis, asbestosis or inflammatory reactions. Therefore, nanoparticles entering the body, after interaction with proteins, will be either recognized as self-agents or detected by the immune system, encompassing immunostimulation or immunosuppression responses. The nature of these interactions seems to be dictated not specially by the composition of the material but by modifications of NP coating (composition, surface charge and structure). Herein, we explore the use of gold nanoparticles as substrates to carry multifunctional ligands to manipulate the immune system in a controlled manner, from undetection to immunostimulation. Murine bone marrow macrophages can be activated with artificial nanometric objects consisting of a gold nanoparticle functionalized with peptides. In the presence of some conjugates, macrophage proliferation was stopped and pro-inflammatory cytokines were induced. The biochemical type of response depended on the type of conjugated peptide and was correlated with the degree of ordering in the peptide coating. These findings help to illustrate the basic requirements involved in medical NP conjugate design to either activate the immune system or hide from it, in order to reach their targets before being removed by phagocytes. Additionally, it opens up the possibility to modulate the immune response in order to suppress unwanted responses resulting from autoimmunity, or allergy or to stimulate protective responses against pathogens.

Gene Regulation in The Human Immune System. Gene Expression Signatures of Th2 Cell Differentiation, Type 1 Diabetes, and Intrauterine Immune Adaptation

The human immune system is constantly interacting with the surrounding stimuli and microorganisms. However, when directed against self or harmless antigens, these vital defense mechanisms can cause great damage. In addition, the understanding the underlying mechanism of several human diseases caused by aberrant immune cell functions, for instance type 1 diabetes and allergies, remains far from being complete. In this Ph.D. study these questions were addressed using genome-wide transcriptomic analyses. Asthma and allergies are characterized by a hyperactive response of the T helper 2 (Th2) immune cells. In this study, the target genes of the STAT6 transcription factor in naïve human T cells were identified with RNAi for the first time. STAT6 was shown to act as a central activator of the genes expression upon IL-4 signaling, with both direct and indirect effects on Th2 cell transcriptome. The core transcription factor network induced by IL-4 was identified from a kinetic analysis of the transcriptome. Type 1 diabetes is an autoimmune disease influenced by both the genetic susceptibility of an individual and the disease-triggering environmental factors. To improve understanding of the autoimmune processes driving pathogenesis in the prediabetic phase in humans, a unique series of prospective whole-blood RNA samples collected from HLA-susceptible children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study was studied. Changes in different timewindows of the pathogenesis process were identified, and especially the type 1 interferon response was activated early and throughout the preclinical T1D. The hygiene hypothesis states that allergic diseases, and lately also autoimmune diseases, could be prevented by infections and other microbial contacts acquired in early childhood, or even prenatally. To study the effects of the standard of hygiene on the development of neonatal immune system, cord blood samples from children born in Finland (high standard of living), Estonia (rapid economic growth) and Russian Karelia (low standard of living) were compared. Children born in Russian Karelia deviated from Finnish and Estonian children in many aspects of the neonatal immune system, which was developmentally more mature in Karelia, resembling that of older infants. The results of this thesis offer significant new information on the regulatory networks associated with immune-mediated diseases in human. The results will facilitate understanding and further research on the role of the identified target genes and mechanisms driving the allergic inflammation and type 1 diabetes, hopefully leading to a new era of drug development.