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Sample records for adaptive immune defense

  1. Multifunctional host defense peptides: antimicrobial peptides, the small yet big players in innate and adaptive immunity.

    PubMed

    Auvynet, Constance; Rosenstein, Yvonne

    2009-11-01

    The term 'antimicrobial peptides' refers to a large number of peptides first characterized on the basis of their antibiotic and antifungal activities. In addition to their role as endogenous antibiotics, antimicrobial peptides, also called host defense peptides, participate in multiple aspects of immunity (inflammation, wound repair, and regulation of the adaptive immune system) as well as in maintaining homeostasis. The possibility of utilizing these multifunctional molecules to effectively combat the ever-growing group of antibiotic-resistant pathogens has intensified research aimed at improving their antibiotic activity and therapeutic potential, without the burden of an exacerbated inflammatory response, but conserving their immunomodulatory potential. In this minireview, we focus on the contribution of small cationic antimicrobial peptides - particularly human cathelicidins and defensins - to the immune response and disease, highlighting recent advances in our understanding of the roles of these multifunctional molecules.

  2. Adaptive immunity to fungi.

    PubMed

    Verma, Akash; Wüthrich, Marcel; Deepe, George; Klein, Bruce

    2014-11-06

    Life-threatening fungal infections have risen sharply in recent years, owing to the advances and intensity of medical care that may blunt immunity in patients. This emerging crisis has created the growing need to clarify immune defense mechanisms against fungi with the ultimate goal of therapeutic intervention. We describe recent insights in understanding the mammalian immune defenses that are deployed against pathogenic fungi. We focus on adaptive immunity to the major medically important fungi and emphasize three elements that coordinate the response: (1) dendritic cells and subsets that are mobilized against fungi in various anatomical compartments; (2) fungal molecular patterns and their corresponding receptors that signal responses and shape the differentiation of T-cell subsets and B cells; and, ultimately (3) the effector and regulatory mechanisms that eliminate these invaders while constraining collateral damage to vital tissue. These insights create a foundation for the development of new, immune-based strategies for prevention or enhanced clearance of systemic fungal diseases.

  3. Adaptive immunity to fungi.

    PubMed

    Wüthrich, Marcel; Deepe, George S; Klein, Bruce

    2012-01-01

    Only a handful of the more than 100,000 fungal species on our planet cause disease in humans, yet the number of life-threatening fungal infections in patients has recently skyrocketed as a result of advances in medical care that often suppress immunity intensely. This emerging crisis has created pressing needs to clarify immune defense mechanisms against fungi, with the ultimate goal of therapeutic applications. Herein, we describe recent insights in understanding the mammalian immune defenses deployed against pathogenic fungi. The review focuses on adaptive immune responses to the major medically important fungi and emphasizes how dendritic cells and subsets in various anatomic compartments respond to fungi, recognize their molecular patterns, and signal responses that nurture and shape the differentiation of T cell subsets and B cells. Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue.

  4. The role of mammalian antimicrobial peptides and proteins in awakening of innate host defenses and adaptive immunity.

    PubMed

    Yang, D; Chertov, O; Oppenheim, J J

    2001-06-01

    Since we live in a dirty environment, we have developed many host defenses to contend with microorganisms. The epithelial lining of our skin, gastrointestinal tract and bronchial tree produces a number of antibacterial peptides, and our phagocytic neutrophils rapidly ingest and enzymatically degrade invading organisms, as well as produce peptides and enzymes with antimicrobial activities. Some of these antimicrobial moieties also appear to alert host cells involved in both innate host defense and adaptive immune responses. The epithelial cells are a source of constitutively produced beta defensin (HBD1) and proinflammatory cytokine-inducible beta defensins (HBD2 and -3) and cathelicidin (LL37). The neutrophils-derived antimicrobial peptides are released on demand from their cytoplasmic granules. They include the enzymes cathepsin G and chymase, azurocidin, a defensins and cathelicidin. In contrast, C5a and C3b are produced by activation of the serum complement cascade. The antimicrobial moieties direct the migration and activate target cells by interacting with selected G-protein-coupled seven-transmembrane receptors (GPCRs) on cell surfaces. The beta defensins interact with the CCR6 chemokine GPCRs, whereas cathelicidins interact with the low-affinity FPRL-1 receptors. The neutrophil-derived cathepsin G acts on the high-affinity FMLP receptor (GPCR) known as FPR, while the receptors for chymase and azurocidin have not been identified as yet. The serum-derived C5a uses a GPCR known as C5aR to mediate its chemotactic and cell-activating effects. Consequently, all these ligand-receptor interactions in addition to mediating chemotaxis also activate receptor-expressing cells to produce other mediators of inflammation.

  5. Antibiotics, microbiota, and immune defense.

    PubMed

    Ubeda, Carles; Pamer, Eric G

    2012-09-01

    The gastrointestinal tract microbiota contributes to the development and differentiation of the mammalian immune system. The composition of the microbiota affects immune responses and affects susceptibility to infection by intestinal pathogens and development of allergic and inflammatory bowel diseases. Antibiotic administration, while facilitating clearance of targeted infections, also perturbs commensal microbial communities and decreases host resistance to antibiotic-resistant microbes. Here, we review recent advances that begin to define the interactions between complex intestinal microbial populations and the mammalian immune system and how this relation is perturbed by antibiotic administration. We further discuss how antibiotic-induced disruption of the microbiota and immune homeostasis can lead to disease and we review strategies to restore immune defenses during antibiotic administration.

  6. Origins of adaptive immunity.

    PubMed

    Liongue, Clifford; John, Liza B; Ward, Alister

    2011-01-01

    Adaptive immunity, involving distinctive antibody- and cell-mediated responses to specific antigens based on "memory" of previous exposure, is a hallmark of higher vertebrates. It has been argued that adaptive immunity arose rapidly, as articulated in the "big bang theory" surrounding its origins, which stresses the importance of coincident whole-genome duplications. Through a close examination of the key molecules and molecular processes underpinning adaptive immunity, this review suggests a less-extreme model, in which adaptive immunity emerged as part of longer evolutionary journey. Clearly, whole-genome duplications provided additional raw genetic materials that were vital to the emergence of adaptive immunity, but a variety of other genetic events were also required to generate some of the key molecules, whereas others were preexisting and simply co-opted into adaptive immunity.

  7. Origins of adaptive immunity.

    PubMed

    Liongue, Clifford; John, Liza B; Ward, Alister

    2011-01-01

    Adaptive immunity, involving distinctive antibody- and cell-mediated responses to specific antigens based on "memory" of previous exposure, is a hallmark of higher vertebrates. It has been argued that adaptive immunity arose rapidly, as articulated in the "big bang theory" surrounding its origins, which stresses the importance of coincident whole-genome duplications. Through a close examination of the key molecules and molecular processes underpinning adaptive immunity, this review suggests a less-extreme model, in which adaptive immunity emerged as part of longer evolutionary journey. Clearly, whole-genome duplications provided additional raw genetic materials that were vital to the emergence of adaptive immunity, but a variety of other genetic events were also required to generate some of the key molecules, whereas others were preexisting and simply co-opted into adaptive immunity. PMID:21395512

  8. Pattern Recognition Receptors in Innate Immunity, Host Defense, and Immunopathology

    ERIC Educational Resources Information Center

    Suresh, Rahul; Mosser, David M.

    2013-01-01

    Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue.…

  9. Immune defense against pneumonic plague

    PubMed Central

    Smiley, Stephen T.

    2009-01-01

    Summary Yersinia pestis is one of the world's most virulent human pathogens. Inhalation of this Gram-negative bacterium causes pneumonic plague, a rapidly progressing and usually fatal disease. Extensively antibiotic-resistant strains of Y. pestis exist and have significant potential for exploitation as agents of terrorism and biowarfare. Subunit vaccines comprised of the Y. pestis F1 and LcrV proteins are well-tolerated and immunogenic in humans but cannot be tested for efficacy, because pneumonic plague outbreaks are uncommon and intentional infection of humans is unethical. In animal models, F1/LcrV-based vaccines protect mice and cynomolgus macaques but have failed, thus far, to adequately protect African green monkeys. We lack an explanation for this inconsistent efficacy. We also lack reliable correlate assays for protective immunity. These deficiencies are hampering efforts to improve vaccine efficacy. Here, I review the immunology of pneumonic plague, focusing on evidence that humoral and cellular defense mechanisms collaborate to defend against pulmonary Y. pestis infection. PMID:18837787

  10. Pattern recognition receptors in innate immunity, host defense, and immunopathology.

    PubMed

    Suresh, Rahul; Mosser, David M

    2013-12-01

    Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue. An improved understanding of the pattern recognition receptors that mediate innate responses and their downstream effects after receptor ligation has the potential to lead to new ways to improve vaccines and prevent autoimmunity. This review focuses on the control of innate immune activation and the role that innate immune receptors play in helping to maintain tissue homeostasis.

  11. Functions of Cationic Host Defense Peptides in Immunity

    PubMed Central

    Hemshekhar, Mahadevappa; Anaparti, Vidyanand; Mookherjee, Neeloffer

    2016-01-01

    Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system. PMID:27384571

  12. Soluble Host Defense Lectins in Innate Immunity to Influenza Virus

    PubMed Central

    Ng, Wy Ching; Tate, Michelle D.; Brooks, Andrew G.; Reading, Patrick C.

    2012-01-01

    Host defenses against viral infections depend on a complex interplay of innate (nonspecific) and adaptive (specific) components. In the early stages of infection, innate mechanisms represent the main line of host defense, acting to limit the spread of virus in host tissues prior to the induction of the adaptive immune response. Serum and lung fluids contain a range of lectins capable of recognizing and destroying influenza A viruses (IAV). Herein, we review the mechanisms by which soluble endogenous lectins mediate anti-IAV activity, including their role in modulating IAV-induced inflammation and disease and their potential as prophylactic and/or therapeutic treatments during severe IAV-induced disease. PMID:22665991

  13. Adaptive immune responses to Candida albicans infection.

    PubMed

    Richardson, Jonathan P; Moyes, David L

    2015-01-01

    Fungal infections are becoming increasingly prevalent in the human population and contribute to morbidity and mortality in healthy and immunocompromised individuals respectively. Candida albicans is the most commonly encountered fungal pathogen of humans, and is frequently found on the mucosal surfaces of the body. Host defense against C. albicans is dependent upon a finely tuned implementation of innate and adaptive immune responses, enabling the host to neutralise the invading fungus. Central to this protection are the adaptive Th1 and Th17 cellular responses, which are considered paramount to successful immune defense against C. albicans infections, and enable tissue homeostasis to be maintained in the presence of colonising fungi. This review will highlight the recent advances in our understanding of adaptive immunity to Candida albicans infections.

  14. [CRISPR adaptive immunity systems of procaryotes].

    PubMed

    2012-01-01

    CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a newly identified prokaryotic immunity system against foreign genetic elements. In contrast to other cellular defense mechanisms (e.g. restriction-modification) CRISPR-mediated immunity is adaptive and can be programmed to protect cells against a particular bacteriophage or conjugative plasmid. In this review we describe general principles of CRISPR systems action and summarize known details of CRISPR systems from different microorganisms.

  15. Dietary antioxidants: immunity and host defense.

    PubMed

    Puertollano, María A; Puertollano, Elena; de Cienfuegos, Gerardo Álvarez; de Pablo, Manuel A

    2011-01-01

    Natural antioxidants may be defined as molecules that prevent cell damage against free radicals and are critical for maintaining optimum health in both animals and humans. In all living systems, cells require adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of reactive oxygen species (ROS) and to prevent damage to the immune cells. During the inflammatory processes, the activation of phagocytes and/or the action of bacterial products with specific receptors are capable of promoting the assembly of the multicomponent flavoprotein NADPH oxidase, which catalyzes the production of high amounts of the superoxide anion radical (O(2)(-)). Under these particular circumstances, neutrophils and macrophages are recognized to produce superoxide free radicals and H(2)O(2), which are essential for defence against phagocytized or invading microbes. In this state, antioxidants are absolutely necessary to regulate the reactions that release free radicals. Antioxidant nutrients commonly included in the diet such as vitamin E, vitamin C, β-carotene, selenium, copper, iron and zinc improve different immune function exhibiting an important protective role in infections caused by bacteria, viruses or parasites. As a result, dietary antioxidants have been related to modulate the host susceptibility or resistance to infectious pathogens. Overall, numerous studies have suggested that the development of tolerance, and control of inflammation are strongly correlated with specific immune mechanisms that may be altered by an inadequate supply of either macronutrients or micronutrients. Therefore, the present paper will review the effects of dietary antioxidants on immune cell function and the impact on protection against infectious microorganisms. PMID:21506934

  16. Immune response

    MedlinePlus

    Innate immunity; Humoral immunity; Cellular immunity; Immunity; Inflammatory response; Acquired (adaptive) immunity ... and usually does not react against them. INNATE IMMUNITY Innate, or nonspecific, immunity is the defense system ...

  17. Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses

    PubMed Central

    Mogensen, Trine H.

    2009-01-01

    Summary: The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications. PMID:19366914

  18. Engaging adaptive immunity with biomaterials

    PubMed Central

    Mora-Solano, Carolina; Collier, Joel H.

    2014-01-01

    Adaptive immune responses, characterized by T cells and B cells engaging and responding to specific antigens, can be raised by biomaterials containing proteins, peptides, and other biomolecules. How does one avoid, control, or exploit such responses? This review will discuss major properties and processes that influence biomaterials-directed adaptive immunity, including the physical dimensions of a material, its epitope content, and its multivalency. Selected strategies involving novel biomaterials designs will be discussed to illustrate these points of control. Specific immunological processes that biomaterials are being developed to direct will be highlighted, including minimally inflammatory scaffolds for tissue repair and immunotherapies eliciting desired B cell (antibody) responses, T cell responses, or tolerance. The continuing development of a knowledge base for specifying the strength and phenotype of biomaterials-mediated adaptive immune responses is important, not only for the engineering of better vaccines and immunotherapies, but also for managing immune responses against newer generations of increasingly biological and biomolecular materials in contexts such as tissue repair, tissue engineering, or cell delivery. PMID:24729870

  19. Immune defense in leaf-cutting ants: a cross-fostering approach.

    PubMed

    Armitage, Sophie A O; Broch, Jens F; Marín, Hermogenes Fernández; Nash, David R; Boomsma, Jacobus J

    2011-06-01

    To ameliorate the impact of disease, social insects combine individual innate immune defenses with collective social defenses. This implies that there are different levels of selection acting on investment in immunity, each with their own trade-offs. We present the results of a cross-fostering experiment designed to address the influences of genotype and social rearing environment upon individual and social immune defenses. We used a multiply mating leaf-cutting ant, enabling us to test for patriline effects within a colony, as well as cross-colony matriline effects. The worker's father influenced both individual innate immunity (constitutive antibacterial activity) and the size of the metapleural gland, which secretes antimicrobial compounds and functions in individual and social defense, indicating multiple mating could have important consequences for both defense types. However, the primarily social defense, a Pseudonocardia bacteria that helps to control pathogens in the ants' fungus garden, showed a significant colony of origin by rearing environment interaction, whereby ants that acquired the bacteria of a foster colony obtained a less abundant cover of bacteria: one explanation for this pattern would be co-adaptation between host colonies and their vertically transmitted mutualist. These results illustrate the complexity of the selection pressures that affect the expression of multilevel immune defenses.

  20. Roles of Innate and Adaptive Immunity in Respiratory Mycoplasmosis

    PubMed Central

    Cartner, Samuel C.; Lindsey, J. Russell; Gibbs-Erwin, Julie; Cassell, Gail H.; Simecka, Jerry W.

    1998-01-01

    Current evidence suggests that host defense in respiratory mycoplasmosis is dependent on both innate and humoral immunity. To further delineate the roles of innate and adaptive immunity in antimycoplasmal defenses, we intranasally infected C3H/HeSnJ-scid/scid (C3H-SCID), C3H/HeSnJ (C3H), C57BL/6J-scid/scid (C57-SCID), and C57BL/6N (C57BL) mice with Mycoplasma pulmonis and at 14 and 21 days postinfection performed quantitative cultures of lungs and spleens, quantification of lung lesions, and histopathologic assessments of all other major organs. We found that numbers of mycoplasmas in lungs were associated with genetic background (C3H susceptible, C57BL resistant) rather than functional state of adaptive immunity, indicating that innate immunity is the main contributor to antimycoplasmal defense of the lungs. Extrapulmonary dissemination of mycoplasmas with colonization of spleens and histologic lesions in multiple organs was a common occurrence in all mice. The absence of adaptive immune responses in severe combined immunodeficient (SCID) mice resulted in increased mycoplasmal colonization of spleens and lesions in extrapulmonary sites, particularly spleens, hearts, and joints, and also reduced lung lesion severity. The transfer of anti-M. pulmonis serum to infected C3H-SCID mice prevented extrapulmonary infection and disease, while the severity of lung lesions was restored by transfer of naive spleen cells to infected C3H-SCID mice. Collectively, our results strongly support the conclusions that innate immunity provides antimycoplasmal defense of the lungs and humoral immunity has the major role in defense against systemic dissemination of mycoplasmal infection, but cellular immune responses may be important in exacerbation of mycoplasmal lung disease. PMID:9673224

  1. Evolutionary responses of innate Immunity to adaptive immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Innate immunity is present in all metazoans, whereas the evolutionarily more novel adaptive immunity is limited to jawed fishes and their descendants (gnathostomes). We observe that the organisms that possess adaptive immunity lack diversity in their innate pattern recognition receptors (PRRs), rais...

  2. How Neutrophils Shape Adaptive Immune Responses

    PubMed Central

    Leliefeld, Pieter H. C.; Koenderman, Leo; Pillay, Janesh

    2015-01-01

    Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell–cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes. PMID:26441976

  3. How Neutrophils Shape Adaptive Immune Responses.

    PubMed

    Leliefeld, Pieter H C; Koenderman, Leo; Pillay, Janesh

    2015-01-01

    Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell-cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes. PMID:26441976

  4. Inflammatory bowel disease related innate immunity and adaptive immunity

    PubMed Central

    Huang, Yuan; Chen, Zhonge

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn’s disease (CD). Its pathogenesis remains not yet clear. Current researchers believe that after environmental factors act on individuals with genetic susceptibility, an abnormal intestinal immune response is launched under stimulation of intestinal flora. However, previous studies only focused on adaptive immunity in the pathogenesis of IBD. Currently, roles of innate immune response in the pathogenesis of intestinal inflammation have also drawn much attention. In this study, IBD related innate immunity and adaptive immunity were explained, especially the immune mechanisms in the pathogenesis of IBD. PMID:27398134

  5. Strategies of avoidance of host immune defenses in Asobara species.

    PubMed

    Prévost, Geneviève; Doury, Géraldine; Mabiala-Moundoungou, Alix D N; Cherqui, Anas; Eslin, Patrice

    2009-01-01

    Eggs and larvae of endophagous parasitoids face the host's immunity reaction once they penetrate the insect host's hemocele. In order to overcome the host's immune barrier, endoparasitoids have developed various strategies. Conformer parasitoids hide and/or get protected from the attack by the host's immunity cells without interfering with the host's immune system. Differently, regulator parasitoids directly attack the host's hemocytes, therefore totally inhibiting the immunity reaction of encapsulation in the parasitized host. Female wasps may also discriminate immunoreactive hosts from nonreactive, permissive ones before laying an egg. These different strategies coexist within the same genus of the braconids Asobara, endoparasitoids of Drosophila larvae. The physiological mechanisms underlying the conformer and regulator strategies in Asobara are exposed. The factors which may contribute to the diversity of the means developed by Asobara parasitoids to overcome the hosts' immunity defenses are discussed.

  6. Immunity and defense in pea aphids, Acyrthosiphon pisum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent genomic analyses of arthropod defense mechanisms suggest conservation of key elements underlying responses to pathogens, parasites, and stresses. At the center of pathogen-induced immune response are signaling pathways triggered by the recognition of fungal, bacterial, and viral signatures. T...

  7. Adaptation in the innate immune system and heterologous innate immunity.

    PubMed

    Martin, Stefan F

    2014-11-01

    The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This "design feature" of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.

  8. PPARγ Agonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us?

    PubMed

    da Rocha Junior, Laurindo Ferreira; Dantas, Andréa Tavares; Duarte, Angela Luzia Branco Pinto; de Melo Rego, Moacyr Jesus Barreto; Pitta, Ivan da Rocha; Pitta, Maira Galdino da Rocha

    2013-01-01

    Adaptive immunity has evolved as a very powerful and highly specialized tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. Cytokines and chemokines play a key role as effector mechanisms of the adaptive immunity. Some autoimmune and inflammatory diseases are caused by disturbance of the adaptive immune system. Recent advances in understanding the pathogenesis of autoimmune diseases have led to research on new molecular and therapeutic targets. PPAR γ are members of the nuclear receptor superfamily and are transcription factors involved in lipid metabolism as well as innate and adaptive immunity. PPAR γ is activated by synthetic and endogenous ligands. Previous studies have shown that PPAR agonists regulate T-cell survival, activation and T helper cell differentiation into effector subsets: Th1, Th2, Th17, and Tregs. PPAR γ has also been associated with B cells. The present review addresses these issues by placing PPAR γ agonists in the context of adaptive immune responses and the relation of the activation of these receptors with the expression of cytokines involved in adaptive immunity. PMID:23983678

  9. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation

    PubMed Central

    Muralidharan, Sujatha; Mandrekar, Pranoti

    2013-01-01

    Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders. PMID:23990626

  10. Mucosal immunity: its role in defense and allergy.

    PubMed

    Tlaskalová-Hogenová, Helena; Tucková, Ludmila; Lodinová-Zádniková, Rája; Stepánková, Renata; Cukrowska, Bozena; Funda, David P; Striz, Ilja; Kozáková, Hana; Trebichavský, Ilja; Sokol, Dan; Reháková, Zuzana; Sinkora, Jirí; Fundová, Petra; Horáková, Dana; Jelínková, Lenka; Sánchez, Daniel

    2002-06-01

    The interface between the organism and the outside world, which is the site of exchange of nutrients, export of products and waste components, must be selectively permeable and at the same time, it must constitute a barrier equipped with local defense mechanisms against environmental threats (e.g. invading pathogens). The boundaries with the environment (mucosal and skin surfaces) are therefore covered with special epithelial layers which support this barrier function. The immune system, associated with mucosal surfaces covering the largest area of the body (200-300 m(2)), evolved mechanisms discriminating between harmless antigens and commensal microorganisms and dangerous pathogens. The innate mucosal immune system, represented by epithelial and other mucosal cells and their products, is able to recognize the conserved pathogenic patterns on microbes by pattern recognition receptors such as Toll-like receptors, CD14 and others. As documented in experimental gnotobiotic models, highly protective colonization of mucosal surfaces by commensals has an important stimulatory effect on postnatal development of immune responses, metabolic processes (e.g. nutrition) and other host activities; these local and systemic immune responses are later replaced by inhibition, i.e. by induction of mucosal (oral) tolerance. Characteristic features of mucosal immunity distinguishing it from systemic immunity are: strongly developed mechanisms of innate defense, the existence of characteristic populations of unique types of lymphocytes, colonization of the mucosal and exocrine glands by cells originating from the mucosal organized tissues ('common mucosal system') and preferential induction of inhibition of the responses to nondangerous antigens (mucosal tolerance). Many chronic diseases, including allergy, may occur as a result of genetically based or environmentally induced changes in mechanisms regulating mucosal immunity and tolerance; this leads to impaired mucosal barrier

  11. Functions of antimicrobial peptides in host defense and immunity.

    PubMed

    Beisswenger, Christoph; Bals, Robert

    2005-06-01

    Antimicrobial peptides (AMPs) are effector molecules of the innate immune system. AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cytokine release, cell proliferation, angiogenesis, wound healing, chemotaxis, immune induction, and protease-antiprotease balance. Furthermore, AMPs qualify as prototypes of innovative drugs that may be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation. This review summarizes the current knowledge about the basic and applied biology of antimicrobial peptides and discusses features of AMPs in host defense and inflammation.

  12. Advances in research of fish immune-relevant genes: a comparative overview of innate and adaptive immunity in teleosts.

    PubMed

    Zhu, Lv-yun; Nie, Li; Zhu, Guan; Xiang, Li-xin; Shao, Jian-zhong

    2013-01-01

    Fish is considered to be an important model in comparative immunology studies because it is a representative population of lower vertebrates serving as an essential link to early vertebrate evolution. Fish immune-relevant genes have received considerable attention due to its role in improving understanding of both fish immunology and the evolution of immune systems. In this review, we discuss the current understanding of teleost immune-relevant genes for both innate and adaptive immunity, including pattern recognition receptors, antimicrobial peptides, complement molecules, lectins, interferons and signaling factors, inflammatory cytokines, chemokines, adaptive immunity relevant cytokines and negative regulators, major histocompatibility complexes, immunoglobulins, and costimulatory molecules. The implications of these factors on the evolutionary history of immune systems were discussed and a perspective outline of innate and adaptive immunity of teleost fish was described. This review may provide clues on the evolution of the essential defense system in vertebrates.

  13. Complex interplay of body condition, life history, and prevailing environment shapes immune defenses of garter snakes in the wild.

    PubMed

    Palacios, Maria G; Cunnick, Joan E; Bronikowski, Anne M

    2013-01-01

    The immunocompetence "pace-of-life" hypothesis proposes that fast-living organisms should invest more in innate immune defenses and less in adaptive defenses compared to slow-living ones. We found some support for this hypothesis in two life-history ecotypes of the snake Thamnophis elegans; fast-living individuals show higher levels of innate immunity compared to slow-living ones. Here, we optimized a lymphocyte proliferation assay to assess the complementary prediction that slow-living snakes should in turn show stronger adaptive defenses. We also assessed the "environmental" hypothesis that predicts that slow-living snakes should show lower levels of immune defenses (both innate and adaptive) given the harsher environment they live in. Proliferation of B- and T-lymphocytes of free-living individuals was on average higher in fast-living than slow-living snakes, opposing the pace-of-life hypothesis and supporting the environmental hypothesis. Bactericidal capacity of plasma, an index of innate immunity, did not differ between fast-living and slow-living snakes in this study, contrasting the previously documented pattern and highlighting the importance of annual environmental conditions as determinants of immune profiles of free-living animals. Our results do not negate a link between life history and immunity, as indicated by ecotype-specific relationships between lymphocyte proliferation and body condition, but suggest more subtle nuances than those currently proposed.

  14. Regulation of lung immunity and host defense by the intestinal microbiota

    PubMed Central

    Samuelson, Derrick R.; Welsh, David A.; Shellito, Judd E.

    2015-01-01

    Every year in the United States approximately 200,000 people die from pulmonary infections, such as influenza and pneumonia, or from lung disease that is exacerbated by pulmonary infection. In addition, respiratory diseases such as, asthma, affect 300 million people worldwide. Therefore, understanding the mechanistic basis for host defense against infection and regulation of immune processes involved in asthma are crucial for the development of novel therapeutic strategies. The identification, characterization, and manipulation of immune regulatory networks in the lung represents one of the biggest challenges in treatment of lung associated disease. Recent evidence suggests that the gastrointestinal (GI) microbiota plays a key role in immune adaptation and initiation in the GI tract as well as at other distal mucosal sites, such as the lung. This review explores the current research describing the role of the GI microbiota in the regulation of pulmonary immune responses. Specific focus is given to understanding how intestinal “dysbiosis” affects lung health. PMID:26500629

  15. The middle ear immune defense changes with age.

    PubMed

    Nielsen, Michelle Christine; Friis, Morten; Martin-Bertelsen, Tomas; Winther, Ole; Friis-Hansen, Lennart; Cayé-Thomasen, Per

    2016-01-01

    Otitis media is a common disease in childhood. In adults, the disease is relatively rare, but more frequently associated with complications. Possible reasons for this discrepancy are age-related differences in pathogen exposure, anatomy of the Eustachian tube and immune system. The objective of this study was to analyze the relationship between age and the mucosal immune system in the middle ear. It is hypothesized that genes involved in the middle ear immune system will change with age. A comprehensive assessment of these genetic differences using the techniques of complementary DNA has not been performed. Complementary DNA microarray technology was used to identify immune-related genes differentially expressed between the normal middle ear mucosa of young (10 days old) and adult rats (80 days old). Data were analyzed using tools of bioinformatics. A total of 260 age-related genes were identified, of which 51 genes were involved in the middle ear mucosal immune system. Genes related to the innate immune system, including alpha-defensin, calcium-binding proteins S100A9 and S100A8, were upregulated in young rats, whereas genes related to the adaptive immune system, including CD3 molecules, zeta-chain T-cell receptor-associated protein kinase and linker of activated T-cells, were upregulated in the adult. This study concludes that the normal middle ear immune system changes with age. Genes related to the innate immune system are upregulated in young rats, whereas genes related to the adaptive immune system are upregulated in adults.

  16. Secretory immunity in defense against cariogenic mutans streptococci.

    PubMed

    Russell, M W; Hajishengallis, G; Childers, N K; Michalek, S M

    1999-01-01

    Specific immune defense against cariogenic mutans streptococci is provided largely by salivary secretory IgA antibodies, which are generated by the common mucosal immune system. This system is functional in newborn infants, who develop salivary IgA antibodies as they become colonized by oral microorganisms. The mechanisms of action of salivary IgA antibodies include interference with sucrose-independent and sucrose- dependent attachment of mutans streptococci to tooth surfaces, as well as possible inhibition of metabolic activities. The goal of protecting infants against colonization by mutans streptococci might be accomplished by applying new strategies of mucosal immunization that would induce salivary IgA antibodies without the complications of parenteral immunization. Strategies of mucosal immunization against mutans streptococci currently under development include the use of surface adhesins and glucosyltransferase as key antigens, which are being incorporated into novel mucosal vaccine delivery systems and adjuvants. The oral application of preformed, genetically engineered antibodies to mutans streptococcal antigens also offers new prospects for passive immunization against dental caries. PMID:9831775

  17. Endocannabinoid signalling in innate and adaptive immunity

    PubMed Central

    Chiurchiù, Valerio; Battistini, Luca; Maccarrone, Mauro

    2015-01-01

    The immune system can be modulated and regulated not only by foreign antigens but also by other humoral factors and metabolic products, which are able to affect several quantitative and qualitative aspects of immunity. Among these, endocannabinoids are a group of bioactive lipids that might serve as secondary modulators, which when mobilized coincident with or shortly after first-line immune modulators, increase or decrease many immune functions. Most immune cells express these bioactive lipids, together with their set of receptors and of enzymes regulating their synthesis and degradation. In this review, a synopsis of the manifold immunomodulatory effects of endocannabinoids and their signalling in the different cell populations of innate and adaptive immunity is appointed, with a particular distinction between mice and human immune system compartments. PMID:25585882

  18. Ion Channels in Innate and Adaptive Immunity

    PubMed Central

    Feske, Stefan; Wulff, Heike; Skolnik, Edward Y.

    2016-01-01

    Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy. PMID:25861976

  19. Tumors STING adaptive antitumor immunity.

    PubMed

    Bronte, Vincenzo

    2014-11-20

    Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway.

  20. Alternative adaptive immunity strategies: coelacanth, cod and shark immunity.

    PubMed

    Buonocore, Francesco; Gerdol, Marco

    2016-01-01

    The advent of high throughput sequencing has permitted to investigate the genome and the transcriptome of novel non-model species with unprecedented depth. This technological advance provided a better understanding of the evolution of adaptive immune genes in gnathostomes, revealing several unexpected features in different fish species which are of particular interest. In the present paper, we review the current understanding of the adaptive immune system of the coelacanth, the elephant shark and the Atlantic cod. The study of coelacanth, the only living extant of the long thought to be extinct Sarcopterygian lineage, is fundamental to bring new insights on the evolution of the immune system in higher vertebrates. Surprisingly, coelacanths are the only known jawed vertebrates to lack IgM, whereas two IgD/W loci are present. Cartilaginous fish are of great interest due to their basal position in the vertebrate tree of life; the genome of the elephant shark revealed the lack of several important immune genes related to T cell functions, which suggest the existence of a primordial set of TH1-like cells. Finally, the Atlantic cod lacks a functional major histocompatibility II complex, but balances this evolutionary loss with the expansion of specific gene families, including MHC I, Toll-like receptors and antimicrobial peptides. Overall, these data point out that several fish species present an unconventional adaptive immune system, but the loss of important immune genes is balanced by adaptive evolutionary strategies which still guarantee the establishment of an efficient immune response against the pathogens they have to fight during their life.

  1. Immune regulatory activities of fowlicidin-1, a cathelicidin host defense peptide.

    PubMed

    Bommineni, Yugendar R; Pham, Giang H; Sunkara, Lakshmi T; Achanta, Mallika; Zhang, Guolong

    2014-05-01

    Appropriate modulation of immunity is beneficial in antimicrobial therapy and vaccine development. Host defense peptides (HDPs) constitute critically important components of innate immunity with both antimicrobial and immune regulatory activities. We previously showed that a chicken HDP, namely fowlicidin-1(6-26), has potent antibacterial activities in vitro and in vivo. Here we further revealed that fowl-1(6-26) possesses strong immunomodulatory properties. The peptide is chemotactic specifically to neutrophils, but not monocytes or lymphocytes, after injected into the mouse peritoneum. Fowl-1(6-26) also has the capacity to activate macrophages by inducing the expression of inflammatory mediators including IL-1β, CCL2, and CCL3. However, unlike bacterial lipopolysaccharide that triggers massive production of inflammatory cytokines and chemokines, fowl-1(6-26) only marginally increased their expression in mouse RAW264.7 macrophages. Additionally, fowl-1(6-26) enhanced the surface expression of MHC II and CD86 on RAW264.7 cells, suggesting that it may facilitate development of adaptive immune response. Indeed, co-immunization of mice with chicken ovalbumin (OVA) and fowl-1(6-26) augmented both OVA-specific IgG1 and IgG2a titers, relative to OVA alone. We further showed that fowl-1(6-26) is capable of preventing a methicillin-resistant Staphylococcus aureus (MRSA) infection due to its enhancement of host defense. All mice survived from an otherwise lethal infection when the peptide was administered 1-2 days prior to MRSA infection, and 50% mice were protected if receiving the peptide 4 days before infection. Taken together, with a strong capacity to stimulate innate and adaptive immunity, fowl-1(6-26) may have potential to be developed as a novel antimicrobial and a vaccine adjuvant.

  2. Editing at the crossroad of innate and adaptive immunity.

    PubMed

    Turelli, Priscilla; Trono, Didier

    2005-02-18

    Genetic information can be altered through the enzymatic modification of nucleotide sequences. This process, known as editing, was originally identified in the mitochondrial RNA of trypanosomes and later found to condition events as diverse as neurotransmission and lipid metabolism in mammals. Recent evidence reveals that editing enzymes may fulfill one of their most essential roles in the defense against infectious agents: first, as the mediators of antibody diversification, a step crucial for building adaptive immunity, and second, as potent intracellular poisons for the replication of viruses. Exciting questions are raised, which take us to the depth of the intimate relations between vertebrates and the microbial underworld.

  3. Fever, immunity, and molecular adaptations.

    PubMed

    Hasday, Jeffrey D; Thompson, Christopher; Singh, Ishwar S

    2014-01-01

    The heat shock response (HSR) is an ancient and highly conserved process that is essential for coping with environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review the phylogenetically conserved mechanisms that regulate fever and discuss the effects that febrile-range temperatures have on multiple biological processes involved in host defense and cell death and survival, including the HSR and its implications for patients with severe sepsis, trauma, and other acute systemic inflammatory states. Heat shock factor-1, a heat-induced transcriptional enhancer is not only the central regulator of the HSR but also regulates expression of pivotal cytokines and early response genes. Febrile-range temperatures exert additional immunomodulatory effects by activating mitogen-activated protein kinase cascades and accelerating apoptosis in some cell types. This results in accelerated pathogen clearance, but increased collateral tissue injury, thus the net effect of exposure to febrile range temperature depends in part on the site and nature of the pathologic process and the specific treatment provided. PMID:24692136

  4. New concepts in immunity to Neisseria gonorrhoeae: innate responses and suppression of adaptive immunity favor the pathogen, not the host.

    PubMed

    Liu, Yingru; Feinen, Brandon; Russell, Michael W

    2011-01-01

    It is well-known that gonorrhea can be acquired repeatedly with no apparent development of protective immunity arising from previous episodes of infection. Symptomatic infection is characterized by a purulent exudate, but the host response mechanisms are poorly understood. While the remarkable antigenic variability displayed by Neisseria gonorrhoeae and its capacity to inhibit complement activation allow it to evade destruction by the host's immune defenses, we propose that it also has the capacity to avoid inducing specific immune responses. In a mouse model of vaginal gonococcal infection, N. gonorrhoeae elicits Th17-driven inflammatory-immune responses, which recruit innate defense mechanisms including an influx of neutrophils. Concomitantly, N. gonorrhoeae suppresses Th1- and Th2-dependent adaptive immunity, including specific antibody responses, through a mechanism involving TGF-β and regulatory T cells. Blockade of TGF-β alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with the generation of immune memory and protective immunity. Genital tract tissues are naturally rich in TGF-β, which fosters an immunosuppressive environment that is important in reproduction. In exploiting this niche, N. gonorrhoeae exemplifies a well-adapted pathogen that proactively elicits from its host innate responses that it can survive and concomitantly suppresses adaptive immunity. Comprehension of these mechanisms of gonococcal pathogenesis should allow the development of novel approaches to therapy and facilitate the development of an effective vaccine. PMID:21833308

  5. Evasion of Innate and Adaptive Immune Responses by Influenza A Virus

    PubMed Central

    Schmolke, Mirco; García-Sastre, Adolfo

    2010-01-01

    Summary Host organisms have developed sophisticated antiviral responses in order to defeat emerging influenza A viruses (IAV). At the same time IAV have evolved immune evasion strategies. The immune system of mammals provides several lines of defense to neutralize invading pathogens or limit their replication. Here, we summarize the mammalian innate and adaptive immune mechanisms involved in host defense against viral infection and review strategies by which IAV avoid, circumvent or subvert these mechanisms. We highlight well-characterized, as well as recently described features of this intriguing virus-host molecular battle. PMID:20482552

  6. Antibody Fc: Linking Adaptive and Innate Immunity

    PubMed Central

    Reichert, Janice M.

    2014-01-01

    Antibody Fc: Linking Adaptive and Innate Immunity, edited by Margaret E. Ackerman and Falk Nimmerjahn and published by Academic Press, provides a highly detailed examination of the involvement of the antibody Fc in mechanisms critical to both innate and adaptive immune responses. Despite a recent increase in format diversity, most marketed antibodies are full-length IgG molecules and the majority of the commercial clinical pipeline of antibody therapeutics is composed of Fc-containing IgG molecules, which underscores the importance of understanding how the Fc domain affects biological responses. The book is divided into six sections that include a total of 20 chapters. In order of their appearance, the sections provide extensive coverage of effector mechanisms, effector cells, Fc receptors, variability of the Fc domain, genetic associations, and evolving areas.

  7. Systems integration of innate and adaptive immunity.

    PubMed

    Zak, Daniel E; Aderem, Alan

    2015-09-29

    The pathogens causing AIDS, malaria, and tuberculosis have proven too complex to be overcome by classical approaches to vaccination. The complexities of human immunology and pathogen-induced modulation of the immune system mandate new approaches to vaccine discovery and design. A new field, systems vaccinology, weds holistic analysis of innate and adaptive immunity within a quantitative framework to enable rational design of new vaccines that elicit tailored protective immune responses. A key step in the approach is to discover relationships between the earliest innate inflammatory responses to vaccination and the subsequent vaccine-induced adaptive immune responses and efficacy. Analysis of these responses in clinical studies is complicated by the inaccessibility of relevant tissue compartments (such as the lymph node), necessitating reliance upon peripheral blood responses as surrogates. Blood transcriptomes, although indirect to vaccine mechanisms, have proven very informative in systems vaccinology studies. The approach is most powerful when innate and adaptive immune responses are integrated with vaccine efficacy, which is possible for malaria with the advent of a robust human challenge model. This is more difficult for AIDS and tuberculosis, given that human challenge models are lacking and efficacy observed in clinical trials has been low or highly variable. This challenge can be met by appropriate clinical trial design for partially efficacious vaccines and by analysis of natural infection cohorts. Ultimately, systems vaccinology is an iterative approach in which mechanistic hypotheses-derived from analysis of clinical studies-are evaluated in model systems, and then used to guide the development of new vaccine strategies. In this review, we will illustrate the above facets of the systems vaccinology approach with case studies.

  8. HDL in innate and adaptive immunity.

    PubMed

    Catapano, Alberico Luigi; Pirillo, Angela; Bonacina, Fabrizia; Norata, Giuseppe Danilo

    2014-08-01

    During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond. PMID:24935428

  9. Strategic Defense Initiative Organization adaptive structures program overview

    NASA Astrophysics Data System (ADS)

    Obal, Michael; Sater, Janet M.

    In the currently envisioned architecture none of the Strategic Defense System (SDS) elements to be deployed will receive scheduled maintenance. Assessments of performance capability due to changes caused by the uncertain effects of environments will be difficult, at best. In addition, the system will have limited ability to adjust in order to maintain its required performance levels. The Materials and Structures Office of the Strategic Defense Initiative Organization (SDIO) has begun to address solutions to these potential difficulties via an adaptive structures technology program that combines health and environment monitoring with static and dynamic structural control. Conceivable system benefits include improved target tracking and hit-to-kill performance, on-orbit system health monitoring and reporting, and threat attack warning and assessment.

  10. Trade-offs between acquired and innate immune defenses in humans

    PubMed Central

    McDade, Thomas W.; Georgiev, Alexander V.; Kuzawa, Christopher W.

    2016-01-01

    Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID:26739325

  11. Origins and evolutionary relationships between the innate and adaptive arms of immune systems.

    PubMed

    Bayne, Christopher J

    2003-04-01

    Long before vertebrates first appeared, protists, plants and animals had evolved diverse, effective systems of innate immunity. Ancestors of the vertebrates utilized components of the complement system, protease-inhibitors, metal-binding proteins, carbohydrate-binding proteins and other plasma-born molecules as humoral agents of defense. In these same animals, immunocytes endowed with a repertoire of defensive behaviors expressed Toll-like receptors. They made NADPH oxidase, superoxide dismutase and other respiratory burst enzymes to produce toxic oxygen radicals, and nitric oxide synthase to produce nitric oxide. Antimicrobial peptides and lytic enzymes were in their armory. Immune responses were orchestrated by cytokines. Furthermore, genes within the immunoglobulin superfamily were expressed to meet a variety of needs possibly including defense. However, recombination activating genes played no role. With the acquisition of one or more transposases and the resulting capacity to generate diverse receptors from immunoglobulin gene fragments, the adaptive (lymphoid) arm of the immune system was born. This may have coincided with the elaboration of the neural crest. Naturally, the role of the adaptive arm was initially subservient to the defensive functions of the pre-existing innate arm. The strong selective advantages that stemmed from having "sharp-shooters" (cells making antigen-specific receptors) on the defense team ensured their retention. Refined through evolution, adaptive immunity, even in mammals, remains dependent upon cells of the innate series (e.g., dendritic cells) for signals driving their functional maturation. This paper calls for some fresh thinking leading to a clearer vision of the origins and co-evolution of the two arms of modern immune systems, and suggests a possible neural origin for the adaptive immune system.

  12. Adaptive immune regulation in autoimmune diabetes.

    PubMed

    Ferretti, Concetta; La Cava, Antonio

    2016-03-01

    Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. This review discusses how adaptive immunoregulatory T cells contribute to the modulation of the development and evolution of T1D, together with potential approaches that target these cells for new therapies in the disease. PMID:26631820

  13. ALD1 Regulates Basal Immune Components and Early Inducible Defense Responses in Arabidopsis.

    PubMed

    Cecchini, Nicolás M; Jung, Ho Won; Engle, Nancy L; Tschaplinski, Timothy J; Greenberg, Jean T

    2015-04-01

    Robust immunity requires basal defense machinery to mediate timely responses and feedback cycles to amplify defenses against potentially spreading infections. AGD2-LIKE DEFENSE RESPONSE PROTEIN 1 (ALD1) is needed for the accumulation of the plant defense signal salicylic acid (SA) during the first hours after infection with the pathogen Pseudomonas syringae and is also upregulated by infection and SA. ALD1 is an aminotransferase with multiple substrates and products in vitro. Pipecolic acid (Pip) is an ALD1-dependent bioactive product induced by P. syringae. Here, we addressed roles of ALD1 in mediating defense amplification as well as the levels and responses of basal defense machinery. ALD1 needs immune components PAD4 and ICS1 (an SA synthesis enzyme) to confer disease resistance, possibly through a transcriptional amplification loop between them. Furthermore, ALD1 affects basal defense by controlling microbial-associated molecular pattern (MAMP) receptor levels and responsiveness. Vascular exudates from uninfected ALD1-overexpressing plants confer local immunity to the wild type and ald1 mutants yet are not enriched for Pip. We infer that, in addition to affecting Pip accumulation, ALD1 produces non-Pip metabolites that play roles in immunity. Thus, distinct metabolite signals controlled by the same enzyme affect basal and early defenses versus later defense responses, respectively.

  14. Intercellular Communication in the Adaptive Immune System

    NASA Astrophysics Data System (ADS)

    Chakraborty, Arup

    2004-03-01

    Higher organisms, like humans, have an adaptive immune system that can respond to pathogens that have not been encountered before. T lymphocytes (T cells) are the orchestrators of the adaptive immune response. They interact with cells, called antigen presenting cells (APC), that display molecular signatures of pathogens. Recently, video microscopy experiments have revealed that when T cells detect antigen on APC surfaces, a spatially patterned supramolecular assembly of different types of molecules forms in the junction between cell membranes. This recognition motif is implicated in information transfer between APC and T cells, and so, is labeled the immunological synapse. The observation of synapse formation sparked two broad questions: How does the synapse form? Why does the synapse form? I will describe progress made in answering these fundamental questions in biology by synergistic use of statistical mechanical theory/computation, chemical engineering principles, and genetic and biochemical experiments. The talk will also touch upon mechanisms that may underlie the extreme sensitivity with which T cells discriminate between self and non-self.

  15. Antigen translocation machineries in adaptive immunity and viral immune evasion.

    PubMed

    Mayerhofer, Peter U; Tampé, Robert

    2015-03-13

    Protein homeostasis results in a steady supply of peptides, which are further degraded to fuel protein synthesis or metabolic needs of the cell. In higher vertebrates, a small fraction of the resulting peptidome, however, is translocated into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Antigenic peptides are guided to major histocompatibility complex class I (MHC I) molecules and are finally displayed on the cell surface, where they mount an adaptive immune response against viral infected or malignantly transformed cells. Here, we review the structural organization and the molecular mechanism of this specialized antigen translocon. We discuss how the ATP-binding cassette (ABC) transporter TAP communicates and cooperates within the multi-component peptide loading machinery, mediating the proper assembly and editing of kinetically stable peptide/MHC I complexes. In light of its important role within the MHC I antigen processing pathway, TAP is a prime target for viral immune evasion strategies, and we summarize how this antigen translocation machinery is sabotaged by viral factors. Finally, we compare TAP with other ABC systems that facilitate peptide translocation.

  16. Adaptive immunity and histopathology in frog virus 3-infected Xenopus

    SciTech Connect

    Robert, Jacques . E-mail: robert@mail.rochester.edu; Morales, Heidi; Buck, Wayne; Cohen, Nicholas; Marr, Shauna; Gantress, Jennifer

    2005-02-20

    Xenopus has been used as an experimental model to evaluate the contribution of adaptive cellular immunity in amphibian host susceptibility to the emerging ranavirus FV3. Conventional histology and immunohistochemistry reveal that FV3 has a strong tropism for the proximal tubular epithelium of the kidney and is rarely disseminated elsewhere in Xenopus hosts unless their immune defenses are impaired or developmentally immature as in larvae. In such cases, virus is found widespread in most tissues. Adults, immunocompromised by depletion of CD8{sup +} T cells or by sub-lethal {gamma}-irradiation, show increased susceptibility to FV3 infection. Larvae and irradiated (but not normal) adults can be cross-infected through water by infected adult conspecifics (irradiated or not). The natural MHC class I deficiency and the absence of effect of anti-CD8 treatment on both larval CD8{sup +} T cells and larval susceptibility to FV3 are consistent with an inefficient CD8{sup +} T cell effector function during this developmental period.

  17. Evolutionary insights into the origin of innate and adaptive immune systems: different shades of grey.

    PubMed

    Sirisinha, Stitaya

    2014-03-01

    To struggle for survival, all living organisms, from protists to humans, must defend themselves from attack by predators. From the time when life began around 3,500 million years ago, all living cells have evolved mechanisms and strategies to optimally defend themselves, while the invaders also need to survive by evading these immune defenses. The end results would be healthy co-evolution of both parties. Classically, immune host defense is divided into two main categories, namely, innate and adaptive systems. It is well documented that while vertebrates possess both systems, invertebrates and prokaryotes like bacteria and archaea depend almost exclusively on the innate immune functions. Although the adaptive immune system like antibodies and cellular immunity or their equivalents are believed to have evolved at the time when the vertebrates first appeared about 550 million years ago, more recent information from molecular and genomic studies suggest that different forms of adaptive immune system may also be present in the invertebrates as well. These forms of "adaptive" immune system exhibit, for instance, limited degrees of memory, diversity and similarities of their immune receptors with the immunoglobulin domains of the conventional adaptive immune system of vertebrates. Organized lymphoid tissues have been identified in all vertebrates. Very recent molecular and genetic data further suggest that a special type of adaptive system functioning like RNAi of vertebrates is also present in the very ancient form of life like the bacteria and archaea. In this review, I provide some insights, based on recent information gathering from evolutionary data of innate and adaptive immune receptors of invertebrate and vertebrate animals that should convince the readers that our current view on the innate and adaptive immunity may need to be modified. The distinction between the two systems should not be thought of in terms of a "black and white" phenomenon anymore, as recent

  18. Antiviral defense in shrimp: from innate immunity to viral infection.

    PubMed

    Wang, Pei-Hui; Huang, Tianzhi; Zhang, Xiaobo; He, Jian-Guo

    2014-08-01

    The culture of penaeid shrimp is rapidly developing as a major business endeavor worldwide. However, viral diseases have caused huge economic loss in penaeid shrimp culture industries. Knowledge of shrimp innate immunity and antiviral responses has made important progress in recent years, allowing the design of better strategies for the prevention and control of shrimp diseases. In this study, we have updated information on shrimp antiviral immunity and interactions between shrimp hosts and viral pathogens. Current knowledge and recent progress in immune signaling pathways (e.g., Toll/IMD-NF-κB and JAK-STAT signaling pathways), RNAi, phagocytosis, and apoptosis in shrimp antiviral immunity are discussed. The mechanism of viral infection in shrimp hosts and the interactions between viruses and shrimp innate immune systems are also analyzed.

  19. DNA Damage Response and Immune Defense: Links and Mechanisms.

    PubMed

    Nakad, Rania; Schumacher, Björn

    2016-01-01

    DNA damage plays a causal role in numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signaling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signaling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signaling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans. PMID:27555866

  20. DNA Damage Response and Immune Defense: Links and Mechanisms

    PubMed Central

    Nakad, Rania; Schumacher, Björn

    2016-01-01

    DNA damage plays a causal role in numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signaling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signaling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signaling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans. PMID:27555866

  1. Mast cells as effector cells of innate immunity and regulators of adaptive immunity.

    PubMed

    Cardamone, Chiara; Parente, Roberta; Feo, Giulia De; Triggiani, Massimo

    2016-10-01

    Mast cells are widely distributed in human organs and tissues and they are particularly abundant at major body interfaces with the external environment such as the skin, the lung and the gastrointestinal tract. Moreover, mast cells are located around blood vessels and are highly represented within central and peripheral lymphoid organs. The strategic distribution of mast cells closely reflects the primary role of these cells in providing first-line defense against environmental dangers, in regulating local and systemic inflammatory reactions and in shaping innate and adaptive immune responses. Human mast cells have pleiotropic and multivalent functions that make them highly versatile cells able to rapidly adapt responses to microenvironmental changes. They express a wide variety of surface receptors including immunoglobulin receptors, pathogen-associated molecular pattern receptors and danger signal receptors. The abundance of these receptors makes mast cells unique and effective surveillance cells able to detect promptly aggression by viral, bacterial and parasitic agents. In addition, mast cells express multiple receptors for cytokines and chemokines that confer them the capacity of being recruited and activated at sites of inflammation. Once activated by immunological or nonimmunological stimuli mast cells secrete a wide spectrum of preformed (early) and de novo synthesized (late) mediators. Preformed mediators are stored within granules and are rapidly released in the extracellular environment to provide a fast vascular response that promotes inflammation and local recruitment of other innate immunity cells such as neutrophils, eosinophils, basophils and monocyte/macrophages. Later on, delayed release of multiple cytokines and chemokines from mast cells further induce modulation of cells of adaptive immunity and regulates tissue injury and, eventually, resolution of inflammation. Finally, mast cells express several costimulatory and inhibitory surface molecules

  2. 75 FR 34988 - Federal Advisory Committee; Defense Science Board 2010 Summer Study on Enhancing Adaptability of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-21

    ... of the Secretary Federal Advisory Committee; Defense Science Board 2010 Summer Study on Enhancing... meeting. SUMMARY: The Defense Science Board 2010 Summer Study on Enhancing Adaptability of our Military... of adaptation, both commercial and non-commercial, and what made them successful and...

  3. Linear ubiquitination signals in adaptive immune responses

    PubMed Central

    Ikeda, Fumiyo

    2015-01-01

    Summary Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage-type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized Tumor Necrosis Factor (TNF) -induced canonical nuclear factor-kappa B (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways. PMID:26085218

  4. Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders.

    PubMed

    Mosley, R Lee

    2015-12-01

    Neurodegenerative and neuropsychological disorders are becoming a greater proportion of the global disease burden; however the pathogenic mechanisms by which these disorders originate and contribute to disease progression are not well-described. Increasing evidence supports neuroinflammation as a common underlying component associated with the neuropathological processes that effect disease progression. This collection of articles explores the role of adaptive immunity in autoimmunity, neurodegeneration, neurotrauma, and psychological disorders. The section emphasizes the interactions of T cells with innate cellular responses within the CNS and the effects on neurological functions. One recurrent theme is that modified and aggregated self-proteins upregulate innate-mediated inflammation and provide a permissive environment for polarization of T cells to proinflammatory effector cells. Moreover, infiltration and reactivation of those T effector cells exacerbate neuroinflammation and oxidative stress to greater neurotoxic levels. Another recurrent theme in these disorders promotes diminished regulatory functions that reduce control over activated T effector cells and microglia, and ultimately augment proinflammatory conditions. Augmentation of regulatory control is discussed as therapeutic strategies to attenuate neuroinflammation, mitigate neurodegeneration or neuronal dysfunction, and lessen disease progression.

  5. Modulatory effects of defense and coping on stress-induced changes in endocrine and immune parameters.

    PubMed

    Olff, M; Brosschot, J F; Godaert, G; Benschop, R J; Ballieux, R E; Heijnen, C J; de Smet, M B; Ursin, H

    1995-01-01

    We examined whether habitual defense and coping affect the response of hormones (ACTH. cortisol, prolactin. endorphins, and noradrenaline) and immune parameters (numbers of T cells. B cells. natural killer [NK] cells, and proliferative responses to mitogens or antigens) to an acute laboratory stressor (i.e., solving a 3-dimensional puzzle and explaining it to a confederate) in 86 male high school teachers. Defense and coping were assessed by Kragh's tachistoscopic Defense Mechanism Test (a measure of perceptual defense) and by 4 questionnaire-based coping styles assessing instrumental mastery-oriented coping, emotion-focused coping, cognitive defense, and defensive hostility. The laboratory stressor per se caused a relative increase in immunological (in particular NK cells) and endocrine (cortisol, prolactin) parameters. Defense and coping, however, significantly codetermined the response to the stressor. In particular, instrumental mastery-oriented coping and perceptual defense were related to stress-induced changes in numbers of B cells and in the pituitary-adrenal hormones. The results indicate that the impact of a mild psychological stressor on the immune and endocrine system depends to a considerable extent on the specific ways people deal with stressors.

  6. Immune defenses against Batrachochytrium dendrobatidis, a fungus linked to global amphibian declines, in the South African clawed frog, Xenopus laevis.

    PubMed

    Ramsey, Jeremy P; Reinert, Laura K; Harper, Laura K; Woodhams, Douglas C; Rollins-Smith, Louise A

    2010-09-01

    Batrachochytrium dendrobatidis is a chytrid fungus that causes the lethal skin disease chytridiomycosis in amphibians. It is regarded as an emerging infectious disease affecting diverse amphibian populations in many parts of the world. Because there are few model amphibian species for immunological studies, little is known about immune defenses against B. dendrobatidis. We show here that the South African clawed frog, Xenopus laevis, is a suitable model for investigating immunity to this pathogen. After an experimental exposure, a mild infection developed over 20 to 30 days and declined by 45 days postexposure. Either purified antimicrobial peptides or mixtures of peptides in the skin mucus inhibited B. dendrobatidis growth in vitro. Skin peptide secretion was maximally induced by injection of norepinephrine, and this treatment resulted in sustained skin peptide depletion and increased susceptibility to infection. Sublethal X-irradiation of frogs decreased leukocyte numbers in the spleen and resulted in greater susceptibility to infection. Immunization against B. dendrobatidis induced elevated pathogen-specific IgM and IgY serum antibodies. Mucus secretions from X. laevis previously exposed to B. dendrobatidis contained significant amounts of IgM, IgY, and IgX antibodies that bind to B. dendrobatidis. These data strongly suggest that both innate and adaptive immune defenses are involved in the resistance of X. laevis to lethal B. dendrobatidis infections.

  7. Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

    PubMed Central

    Gjini, Erida; Brito, Patricia H.

    2016-01-01

    Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. We use mathematical modelling of within-host infection dynamics to study the interplay between pathogen-dependent host immune responses and antibiotic treatment. We compare classical (fixed dose and duration) and adaptive (coupled to pathogen load) treatment regimes, exploring systematically infection outcomes such as time to clearance, immunopathology, host immunization, and selection of resistant bacteria. Our analysis and simulations uncover effective treatment strategies that promote synergy between the host immune system and the antimicrobial drug in clearing infection. Both in classical and adaptive treatment, we quantify how treatment timing and the strength of the immune response determine the success of moderate therapies. We explain key parameters and dimensions, where an adaptive regime differs from classical treatment, bringing new insight into the ongoing debate of resistance management. Emphasizing the sensitivity of treatment outcomes to the balance between external antibiotic intervention and endogenous natural defenses, our study calls for more empirical attention to host immunity processes. PMID:27078624

  8. Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment.

    PubMed

    Gjini, Erida; Brito, Patricia H

    2016-04-01

    Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. We use mathematical modelling of within-host infection dynamics to study the interplay between pathogen-dependent host immune responses and antibiotic treatment. We compare classical (fixed dose and duration) and adaptive (coupled to pathogen load) treatment regimes, exploring systematically infection outcomes such as time to clearance, immunopathology, host immunization, and selection of resistant bacteria. Our analysis and simulations uncover effective treatment strategies that promote synergy between the host immune system and the antimicrobial drug in clearing infection. Both in classical and adaptive treatment, we quantify how treatment timing and the strength of the immune response determine the success of moderate therapies. We explain key parameters and dimensions, where an adaptive regime differs from classical treatment, bringing new insight into the ongoing debate of resistance management. Emphasizing the sensitivity of treatment outcomes to the balance between external antibiotic intervention and endogenous natural defenses, our study calls for more empirical attention to host immunity processes.

  9. [Adaptive immune response of people living near chemically hazardous object].

    PubMed

    Petlenko, S V; Ivanov, M B; Goverdovskiĭ, Iu B; Bogdanova, E G; Golubkov, A V

    2011-10-01

    The article presents data dynamics of adaptive immune responses of people for a long time living in adverse environmental conditions caused by pollution of the environment by industrial toxic waste. It is shown that in the process of adaptation to adverse environmental factors, changes in the immune system are in the phase fluctuations of immunological parameters that are accompanied by changes in the structure of immunodependent pathology. Most sensitive to prolonged exposure to toxic compounds are the cellular mechanisms of immune protection. Violations of the structural and quantitative and functional parameters of the link of the immune system are leading to the formation of immunopathological processes.

  10. [Immune defense is both stimulated and inhibited by physical activity].

    PubMed

    Malm, Christer; Celsing, Fredrik; Friman, Göran

    Physical exercise may enhance some and depress other immune functions. The biological importance of these changes is not fully elucidated. Acute endurance exercise results in a relatively large redistribution of leukocytes between circulating blood and other tissues, as well as an increase in circulating cytokines. Some of these changes have been related to energy metabolism. A temporal correlation has been observed between altered immune functions and resistance to infections. A post-exercise infection can be either the result of a pre-exercise, sub-clinical infection amplified by the performed work or a novel infection, acquired during a period of decreased immune function shortly after exercise. Animal experiments have demonstrated that the susceptibility to infections after exercise depends on exercise intensity and duration, type of pathogen and time of inoculation. Exercise before inoculation with some bacterial agents can enhance resistance to infection, while exercise during an ongoing viral or bacterial infection worsens symptoms and enhances the risk for complications. Most studies demonstrate a deleterious effect of physical exercise in conjunction with infectious episodes.

  11. Hemocyanins and the immune response: defense against the dark arts.

    PubMed

    Terwilliger, Nora B

    2007-10-01

    The innate immune response is a conserved trait shared by invertebrates and vertebrates. In crustaceans, circulating hemocytes play significant roles in the immune response, including the release of prophenoloxidases. Activated phenoloxidase (tyrosinase) participates in encapsulation and melanization of foreign organisms as well as sclerotization of the new exoskeleton after wound-repair or molting. Hemocyanin functions as a phenoloxidase under certain conditions and thus also participates in the immune response and molting. The relative contributions of hemocyte phenoloxidase and hemocyanin in the physiological ratio at which they occur in hemolymph have been investigated in the crab Cancer magister. Differences in activity, substrate affinity, and catalytic ability between the two enzymes indicate that hemocytes are the predominant source of phenoloxidase activity in crabs. In contrast, hemocyanin is the primary source of phenoloxidase activity in isopods and chelicerates whose hemocytes show no phenoloxidase activity. Quantitative PCR studies on the distribution of prophenoloxidase mRNA in the tissues of Carcinus maenas showed little effect relative to salinity stress. Phylogenetic analysis of hemocyanin, phenoloxidase, and other members of this arthropod gene family are consistent with the possibility that a common ancestral molecule had both phenoloxidase and oxygen-binding capabilities.

  12. Immunity and emotions: lipopolysaccharide increases defensive behaviours and potentiates despair in mice.

    PubMed

    Renault, Julien; Aubert, Arnaud

    2006-11-01

    Many studies have pointed out the relationships between immunity and depression, supporting a neuroimmune hypothesis of depressive disorders. However, despite the growing interest for such a hypothesis and the amount of clinical and experimental data available, the precise nature of this relationship between immunity and depression remains unclear. The present study aimed to investigate further the link between depression and immunity in mice using the modified version of the forced-swimming test. Based on a two-session test, results from our first experiment showed that endotoxin enhanced active defensive behaviours in mice during the first exposure to water, but was associated with increased immobility (i.e., 'behavioural despair') in the subsequent session. In our second experiment, we showed that these effects were blocked by a chronic antidepressant treatment with imipramine. Finally, we suggest a link between immunity and depression, based on the behavioural context in which immune activation takes place. We hypothesize that immune activation, by enhancing reactivity to the negative features of a given situation, increases defensive motivation of subjects, but therefore makes them more vulnerable to the deleterious emotional consequences of failure in defensive strategies. PMID:16647244

  13. The coagulation system and its function in early immune defense.

    PubMed

    van der Poll, Tom; Herwald, Heiko

    2014-10-01

    Blood coagulation has a Janus-faced role in infectious diseases. When systemically activated, it can cause serious complications associated with high morbidity and mortality. However, coagulation is also part of the innate immune system and its local activation has been found to play an important role in the early host response to infection. Though the latter aspect has been less investigated, phylogenetic studies have shown that many factors involved in coagulation have ancestral origins which are often combined with anti-microbial features. This review gives a general overview about the most recent advances in this area of research also referred to as immunothrombosis.

  14. Diversity of immune strategies explained by adaptation to pathogen statistics

    PubMed Central

    Mayer, Andreas; Mora, Thierry; Rivoire, Olivier; Walczak, Aleksandra M.

    2016-01-01

    Biological organisms have evolved a wide range of immune mechanisms to defend themselves against pathogens. Beyond molecular details, these mechanisms differ in how protection is acquired, processed, and passed on to subsequent generations—differences that may be essential to long-term survival. Here, we introduce a mathematical framework to compare the long-term adaptation of populations as a function of the pathogen dynamics that they experience and of the immune strategy that they adopt. We find that the two key determinants of an optimal immune strategy are the frequency and the characteristic timescale of the pathogens. Depending on these two parameters, our framework identifies distinct modes of immunity, including adaptive, innate, bet-hedging, and CRISPR-like immunities, which recapitulate the diversity of natural immune systems. PMID:27432970

  15. Inducible defenses stay up late: temporal patterns of immune gene expression in Tenebrio molitor.

    PubMed

    Johnston, Paul R; Makarova, Olga; Rolff, Jens

    2014-06-01

    The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo. PMID:24318927

  16. Host defense peptides as effector molecules of the innate immune response: a sledgehammer for drug resistance?

    PubMed

    Steinstraesser, Lars; Kraneburg, Ursula M; Hirsch, Tobias; Kesting, Marco; Steinau, Hans-Ulrich; Jacobsen, Frank; Al-Benna, Sammy

    2009-09-09

    Host defense peptides can modulate the innate immune response and boost infection-resolving immunity, while dampening potentially harmful pro-inflammatory (septic) responses. Both antimicrobial and/or immunomodulatory activities are an integral part of the process of innate immunity, which itself has many of the hallmarks of successful anti-infective therapies, namely rapid action and broad-spectrum antimicrobial activities. This gives these peptides the potential to become an entirely new therapeutic approach against bacterial infections. This review details the role and activities of these peptides, and examines their applicability as development candidates for use against bacterial infections.

  17. Oil and related toxicant effects on mallard immune defenses

    SciTech Connect

    Rocke, T.E.; Yuill, T.M.; Hinsdill, R.D.

    1984-04-01

    A crude oil, a petroleum distillate, and chemically dispersed oil were tested for their effects on resistance to bacterial infection and the immune response in waterfowl. Sublethal oral doses for mallards were determined for South Louisiana crude oil, Bunker C fuel oil a dispersant-Corexit 9527, and oil/Corexit combinations by gizzard intubation. Resistance to bacterial challange (Pasteurella multocida) was significantly lowered in mallards receiving 2.5 or 4.0 ml/kg of Bunker C fuel oil, 4.0 ml/kg of South Louisiana crude oil, and 4.0 ml/kg of a 50:1 Bunker C fuel oil/Corexit mixture daily for 28 days. Ingestion of oil or oil/Corexit mixtures had no effect on mallard antibody-producing capability as measured by the direct spleen plaque-forming assay.

  18. The immune system, adaptation, and machine learning

    NASA Astrophysics Data System (ADS)

    Farmer, J. Doyne; Packard, Norman H.; Perelson, Alan S.

    1986-10-01

    The immune system is capable of learning, memory, and pattern recognition. By employing genetic operators on a time scale fast enough to observe experimentally, the immune system is able to recognize novel shapes without preprogramming. Here we describe a dynamical model for the immune system that is based on the network hypothesis of Jerne, and is simple enough to simulate on a computer. This model has a strong similarity to an approach to learning and artificial intelligence introduced by Holland, called the classifier system. We demonstrate that simple versions of the classifier system can be cast as a nonlinear dynamical system, and explore the analogy between the immune and classifier systems in detail. Through this comparison we hope to gain insight into the way they perform specific tasks, and to suggest new approaches that might be of value in learning systems.

  19. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells

    PubMed Central

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines. PMID:26258152

  20. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells.

    PubMed

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines.

  1. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells.

    PubMed

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines. PMID:26258152

  2. Effects of generalized and specialized adaptive defense by shared prey on intra-guild predation.

    PubMed

    Ikegawa, Yusuke; Ezoe, Hideo; Namba, Toshiyuki

    2015-01-01

    Intra-guild predation (IGP), predation on consumers which share common prey with the predators, is an important community module to understand a mechanism for persistence of complex food webs. However, classical theory suggests that persistence of an IGP system is unlikely particularly at high productivity, while empirical data do not support the prediction. Recently, adaptive defense by shared prey has been recognized to enhance coexistence of species and stability of the system. Some organisms having multiple predators in IGP systems employ two types of defenses; generalized defense that is effective against multiple predators and specialized one that is effective against only a specific predator species. We consider an IGP model including shared prey that can use the two types of defenses in combination against the consumer or omnivore. Assuming that the shared prey can change the allocation of defensive effort to increase its fitness, we show that the joint use of two types of adaptive defenses promotes three species coexistence and enhances stability of the IGP system when the specialized defense is more effective than the generalized one. When the system is unstable, a variety of oscillations appear and both the population densities and defensive efforts or only the population densities oscillate. Joint use of defenses against the consumer tends to increase the equilibrium population density of the shared prey with the defense efficiencies. In contrast, efficient generalized and specialized defenses against the omnivore often decrease the prey population. Consequently, adaptive defense by shared prey may not necessarily heighten the population size of the defender but sometimes increases densities of both the attackers and defender in IGP systems.

  3. CD98 at the crossroads of adaptive immunity and cancer

    PubMed Central

    Cantor, Joseph M.; Ginsberg, Mark H.

    2012-01-01

    Adaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer. PMID:22499670

  4. Staphylococcal biofilm exopolysaccharide protects against Caenorhabditis elegans immune defenses.

    PubMed

    Begun, Jakob; Gaiani, Jessica M; Rohde, Holger; Mack, Dietrich; Calderwood, Stephen B; Ausubel, Frederick M; Sifri, Costi D

    2007-04-01

    Staphylococcus epidermidis and Staphylococcus aureus are leading causes of hospital-acquired infections that have become increasingly difficult to treat due to the prevalence of antibiotic resistance in these organisms. The ability of staphylococci to produce biofilm is an important virulence mechanism that allows bacteria both to adhere to living and artificial surfaces and to resist host immune factors and antibiotics. Here, we show that the icaADBC locus, which synthesizes the biofilm-associated polysaccharide intercellular adhesin (PIA) in staphylococci, is required for the formation of a lethal S. epidermidis infection in the intestine of the model nematode Caenorhabditis elegans. Susceptibility to S. epidermidis infection is influenced by mutation of the C. elegans PMK-1 p38 mitogen-activated protein (MAP) kinase or DAF-2 insulin-signaling pathways. Loss of PIA production abrogates nematocidal activity and leads to reduced bacterial accumulation in the C. elegans intestine, while overexpression of the icaADBC locus in S. aureus augments virulence towards nematodes. PIA-producing S. epidermidis has a significant survival advantage over ica-deficient S. epidermidis within the intestinal tract of wild-type C. elegans, but not in immunocompromised nematodes harboring a loss-of-function mutation in the p38 MAP kinase pathway gene sek-1. Moreover, sek-1 and pmk-1 mutants are equally sensitive to wild-type and icaADBC-deficient S. epidermidis. These results suggest that biofilm exopolysaccharide enhances virulence by playing an immunoprotective role during colonization of the C. elegans intestine. These studies demonstrate that C. elegans can serve as a simple animal model for studying host-pathogen interactions involving staphylococcal biofilm exopolysaccharide and suggest that the protective activity of biofilm matrix represents an ancient conserved function for resisting predation.

  5. Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina.

    PubMed

    Rapaka, Rekha R; Ricks, David M; Alcorn, John F; Chen, Kong; Khader, Shabaana A; Zheng, Mingquan; Plevy, Scott; Bengtén, Eva; Kolls, Jay K

    2010-12-20

    Host defense against opportunistic fungi requires coordination between innate and adaptive immunity for resolution of infection. Antibodies generated in mice vaccinated with the fungus Pneumocystis prevent growth of Pneumocystis organisms within the lungs, but the mechanisms whereby antibodies enhance antifungal host defense are poorly defined. Nearly all species of fungi contain the conserved carbohydrates β-glucan and chitin within their cell walls, which may be targets of innate and adaptive immunity. In this study, we show that natural IgM antibodies targeting these fungal cell wall carbohydrates are conserved across many species, including fish and mammals. Natural antibodies bind fungal organisms and enhance host defense against Pneumocystis in early stages of infection. IgM antibodies influence recognition of fungal antigen by dendritic cells, increasing their migration to draining pulmonary lymph nodes. IgM antibodies are required for adaptive T helper type 2 (Th2) and Th17 cell differentiation and guide B cell isotype class-switch recombination during host defense against Pneumocystis. These experiments suggest a novel role for the IgM isotype in shaping the earliest steps in recognition and clearance of this fungus. We outline a mechanism whereby serum IgM, containing ancient specificities against conserved fungal antigens, bridges innate and adaptive immunity against fungal organisms.

  6. Evolution of adaptive immunity from transposable elements combined with innate immune systems.

    PubMed

    Koonin, Eugene V; Krupovic, Mart

    2015-03-01

    Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems.

  7. Consequences of Food Restriction for Immune Defense, Parasite Infection, and Fitness in Monarch Butterflies.

    PubMed

    McKay, Alexa Fritzsche; Ezenwa, Vanessa O; Altizer, Sonia

    2016-01-01

    Organisms have a finite pool of resources to allocate toward multiple competing needs, such as development, reproduction, and enemy defense. Abundant resources can support investment in multiple traits simultaneously, but limited resources might promote trade-offs between fitness-related traits and immune defenses. We asked how food restriction at both larval and adult life stages of the monarch butterfly (Danaus plexippus) affected measures of immunity, fitness, and immune-fitness interactions. We experimentally infected a subset of monarchs with a specialist protozoan parasite to determine whether parasitism further affected these relationships and whether food restriction influenced the outcome of infection. Larval food restriction reduced monarch fitness measures both within the same life stage (e.g., pupal mass) as well as later in life (e.g., adult lifespan); adult food restriction further reduced adult lifespan. Larval food restriction lowered both hemocyte concentration and phenoloxidase activity at the larval stage, and the effects of larval food restriction on phenoloxidase activity persisted when immunity was sampled at the adult stage. Adult food restriction reduced only adult phenoloxidase activity but not hemocyte concentration. Parasite spore load decreased with one measure of larval immunity, but food restriction did not increase the probability of parasite infection. Across monarchs, we found a negative relationship between larval hemocyte concentration and pupal mass, and a trade-off between adult hemocyte concentration and adult life span was evident in parasitized female monarchs. Adult life span increased with phenoloxidase activity in some subsets of monarchs. Our results emphasize that food restriction can alter fitness and immunity across multiple life stages. Understanding the consequences of resource limitation for immune defense is therefore important for predicting how increasing constraints on wildlife resources will affect fitness and

  8. Innate and adaptive immune responses in neurodegeneration and repair.

    PubMed

    Amor, Sandra; Woodroofe, M Nicola

    2014-03-01

    Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases.

  9. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview

    PubMed Central

    Dotzauer, Andreas; Kraemer, Leena

    2012-01-01

    Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses. PMID:24175214

  10. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview.

    PubMed

    Dotzauer, Andreas; Kraemer, Leena

    2012-06-12

    Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.

  11. Generation of Individual Diversity: A Too Neglected Fundamental Property of Adaptive Immune System

    PubMed Central

    Muraille, Eric

    2014-01-01

    The fitness gains resulting from development of the adaptive immune system (AIS) during evolution are still the subject of hot debate. A large random repertoire of antigenic receptors is costly to develop and could be the source of autoimmune reactions. And yet, despite their drawbacks, AIS-like systems seem to have been independently acquired in several phyla of metazoans with very different anatomies, longevities, and lifestyles. This article is a speculative attempt to explore the selective pressures, which favored this striking convergent evolution. It is well known that the AIS enables an organism to produce a specific immune response against all natural or artificial antigenic structures. However, it is frequently neglected that this response is highly variable among individuals. In practice, each individual possesses a “private” adaptive immune repertoire. This individualization of immune defenses implies that invasion and escape immune mechanisms developed by pathogens will certainly not always be successful as the specific targets and organization of the immune response are somewhat unpredictable. In a population, where individuals display heterogeneous immune responses to infection, the probability that a pathogen is able to infect all individuals could be reduced compared to a homogeneous population. This suggests that the individual diversity of the immune repertoire is not a by-product of the AIS but of its fundamental properties and could be in part responsible for repeated selection and conservation of the AIS during metazoan evolution. The capacity of the AIS to improve the management of cooperative or parasitic symbiotic relationships at the individual level could be a secondary development due to its progressive integration into the innate immune system. This hypothesis constitutes a new scenario for AIS emergence and explains the selection of MHC restriction and MHC diversification. PMID:24860570

  12. CRISPR-Based Adaptive Immune Systems

    PubMed Central

    Terns, Michael P.; Terns, Rebecca M.

    2011-01-01

    CRISPR-Cas systems are recently discovered, RNA-based immune systems that control invasions of viruses and plasmids in archaea and bacteria. Prokaryotes with CRISPR-Cas immune systems capture short invader sequences within the CRISPR loci in their genomes, and small RNAs produced from the CRISPR loci (CRISPR (cr)RNAs) guide Cas proteins to recognize and degrade (or otherwise silence) the invading nucleic acids. There are multiple variations of the pathway found among prokaryotes, each mediated by largely distinct components and mechanisms that we are only beginning to delineate. Here we will review our current understanding of the remarkable CRISPR-Cas pathways with particular attention to studies relevant to systems found in the archaea. PMID:21531607

  13. CRISPR-Cas systems: Prokaryotes upgrade to adaptive immunity.

    PubMed

    Barrangou, Rodolphe; Marraffini, Luciano A

    2014-04-24

    Clustered regularly interspaced short palindromic repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against exogenic elements in many bacteria and most archaea. CRISPR-mediated immunization occurs through the uptake of DNA from invasive genetic elements such as plasmids and viruses, followed by its integration into CRISPR loci. These loci are subsequently transcribed and processed into small interfering RNAs that guide nucleases for specific cleavage of complementary sequences. Conceptually, CRISPR-Cas shares functional features with the mammalian adaptive immune system, while also exhibiting characteristics of Lamarckian evolution. Because immune markers spliced from exogenous agents are integrated iteratively in CRISPR loci, they constitute a genetic record of vaccination events and reflect environmental conditions and changes over time. Cas endonucleases, which can be reprogrammed by small guide RNAs have shown unprecedented potential and flexibility for genome editing and can be repurposed for numerous DNA targeting applications including transcriptional control.

  14. CRISPR-Cas systems: prokaryotes upgrade to adaptive immunity

    PubMed Central

    Barrangou, Rodolphe; Marraffini, Luciano A.

    2014-01-01

    Summary Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against exogenic elements in many bacteria and most archaea. CRISPR-mediated immunization occurs through the uptake of DNA from invasive genetic elements such as plasmids and viruses, followed by its integration into CRISPR loci. These loci are subsequently transcribed and processed into small interfering RNAs that guide nucleases for specific cleavage of complementary sequences. Conceptually, CRISPR-Cas shares functional features with the mammalian adaptive immune system, while also exhibiting characteristics of Lamarckian evolution. Because immune markers spliced from exogenous agents are integrated iteratively in CRISPR loci, they constitute a genetic record of vaccination events and reflect environmental conditions and changes over time. Cas endonucleases, which can be reprogrammed by small guide RNAs have shown unprecedented potential and flexibility for genome editing, and can be repurposed for numerous DNA targeting applications including transcriptional control. PMID:24766887

  15. Platelets as immune mediators: their role in host defense responses and sepsis.

    PubMed

    Li, Zhenyu; Yang, Fanmuyi; Dunn, Steve; Gross, A Kendall; Smyth, Susan S

    2011-03-01

    Platelets occupy a central role at the interface between thrombosis and inflammation. At sites of vascular damage, adherent platelets physically and functionally interact with circulating leukocytes. Activated platelets release soluble factors into circulation that may have local and systemic effects on blood and vascular cells. Platelets can also interact with a wide variety of microbial pathogens. Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes involving tissue injury, immune responses and repair that underlie diverse diseases such as atherosclerosis, autoimmune disorders, inflammatory lung and bowel disorders, host-defense responses and sepsis. In this review, we summarize the general mechanisms by which platelets may contribute to immune function, and then discuss evidence for their role in host defense responses and sepsis from preclinical and clinical studies.

  16. Larval Environment Alters Amphibian Immune Defenses Differentially across Life Stages and Populations.

    PubMed

    Krynak, Katherine L; Burke, David J; Benard, Michael F

    2015-01-01

    Recent global declines, extirpations and extinctions of wildlife caused by newly emergent diseases highlight the need to improve our knowledge of common environmental factors that affect the strength of immune defense traits. To achieve this goal, we examined the influence of acidification and shading of the larval environment on amphibian skin-associated innate immune defense traits, pre and post-metamorphosis, across two populations of American Bullfrogs (Rana catesbeiana), a species known for its wide-ranging environmental tolerance and introduced global distribution. We assessed treatment effects on 1) skin-associated microbial communities and 2) post-metamorphic antimicrobial peptide (AMP) production and 3) AMP bioactivity against the fungal pathogen Batrachochytrium dendrobatidis (Bd). While habitat acidification did not affect survival, time to metamorphosis or juvenile mass, we found that a change in average pH from 7 to 6 caused a significant shift in the larval skin microbial community, an effect which disappeared after metamorphosis. Additionally, we found shifts in skin-associated microbial communities across life stages suggesting they are affected by the physiological or ecological changes associated with amphibian metamorphosis. Moreover, we found that post-metamorphic AMP production and bioactivity were significantly affected by the interactions between pH and shade treatments and interactive effects differed across populations. In contrast, there were no significant interactions between treatments on post-metamorphic microbial community structure suggesting that variation in AMPs did not affect microbial community structure within our study. Our findings indicate that commonly encountered variation in the larval environment (i.e. pond pH and degree of shading) can have both immediate and long-term effects on the amphibian innate immune defense traits. Our work suggests that the susceptibility of amphibians to emerging diseases could be related to

  17. Larval Environment Alters Amphibian Immune Defenses Differentially across Life Stages and Populations

    PubMed Central

    2015-01-01

    Recent global declines, extirpations and extinctions of wildlife caused by newly emergent diseases highlight the need to improve our knowledge of common environmental factors that affect the strength of immune defense traits. To achieve this goal, we examined the influence of acidification and shading of the larval environment on amphibian skin-associated innate immune defense traits, pre and post-metamorphosis, across two populations of American Bullfrogs (Rana catesbeiana), a species known for its wide-ranging environmental tolerance and introduced global distribution. We assessed treatment effects on 1) skin-associated microbial communities and 2) post-metamorphic antimicrobial peptide (AMP) production and 3) AMP bioactivity against the fungal pathogen Batrachochytrium dendrobatidis (Bd). While habitat acidification did not affect survival, time to metamorphosis or juvenile mass, we found that a change in average pH from 7 to 6 caused a significant shift in the larval skin microbial community, an effect which disappeared after metamorphosis. Additionally, we found shifts in skin-associated microbial communities across life stages suggesting they are affected by the physiological or ecological changes associated with amphibian metamorphosis. Moreover, we found that post-metamorphic AMP production and bioactivity were significantly affected by the interactions between pH and shade treatments and interactive effects differed across populations. In contrast, there were no significant interactions between treatments on post-metamorphic microbial community structure suggesting that variation in AMPs did not affect microbial community structure within our study. Our findings indicate that commonly encountered variation in the larval environment (i.e. pond pH and degree of shading) can have both immediate and long-term effects on the amphibian innate immune defense traits. Our work suggests that the susceptibility of amphibians to emerging diseases could be related to

  18. Larval Environment Alters Amphibian Immune Defenses Differentially across Life Stages and Populations.

    PubMed

    Krynak, Katherine L; Burke, David J; Benard, Michael F

    2015-01-01

    Recent global declines, extirpations and extinctions of wildlife caused by newly emergent diseases highlight the need to improve our knowledge of common environmental factors that affect the strength of immune defense traits. To achieve this goal, we examined the influence of acidification and shading of the larval environment on amphibian skin-associated innate immune defense traits, pre and post-metamorphosis, across two populations of American Bullfrogs (Rana catesbeiana), a species known for its wide-ranging environmental tolerance and introduced global distribution. We assessed treatment effects on 1) skin-associated microbial communities and 2) post-metamorphic antimicrobial peptide (AMP) production and 3) AMP bioactivity against the fungal pathogen Batrachochytrium dendrobatidis (Bd). While habitat acidification did not affect survival, time to metamorphosis or juvenile mass, we found that a change in average pH from 7 to 6 caused a significant shift in the larval skin microbial community, an effect which disappeared after metamorphosis. Additionally, we found shifts in skin-associated microbial communities across life stages suggesting they are affected by the physiological or ecological changes associated with amphibian metamorphosis. Moreover, we found that post-metamorphic AMP production and bioactivity were significantly affected by the interactions between pH and shade treatments and interactive effects differed across populations. In contrast, there were no significant interactions between treatments on post-metamorphic microbial community structure suggesting that variation in AMPs did not affect microbial community structure within our study. Our findings indicate that commonly encountered variation in the larval environment (i.e. pond pH and degree of shading) can have both immediate and long-term effects on the amphibian innate immune defense traits. Our work suggests that the susceptibility of amphibians to emerging diseases could be related to

  19. Proteasome function shapes innate and adaptive immune responses.

    PubMed

    Kammerl, Ilona E; Meiners, Silke

    2016-08-01

    The proteasome system degrades more than 80% of intracellular proteins into small peptides. Accordingly, the proteasome is involved in many essential cellular functions, such as protein quality control, transcription, immune responses, cell signaling, and apoptosis. Moreover, degradation products are loaded onto major histocompatibility class I molecules to communicate the intracellular protein composition to the immune system. The standard 20S proteasome core complex contains three distinct catalytic active sites that are exchanged upon stimulation with inflammatory cytokines to form the so-called immunoproteasome. Immunoproteasomes are constitutively expressed in immune cells and have different proteolytic activities compared with standard proteasomes. They are rapidly induced in parenchymal cells upon intracellular pathogen infection and are crucial for priming effective CD8(+) T-cell-mediated immune responses against infected cells. Beyond shaping these adaptive immune reactions, immunoproteasomes also regulate the function of immune cells by degradation of inflammatory and immune mediators. Accordingly, they emerge as novel regulators of innate immune responses. The recently unraveled impairment of immunoproteasome function by environmental challenges and by genetic variations of immunoproteasome genes might represent a currently underestimated risk factor for the development and progression of lung diseases. In particular, immunoproteasome dysfunction will dampen resolution of infections, thereby promoting exacerbations, may foster autoimmunity in chronic lung diseases, and possibly contributes to immune evasion of tumor cells. Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, however, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively. PMID:27343191

  20. Proteasome function shapes innate and adaptive immune responses.

    PubMed

    Kammerl, Ilona E; Meiners, Silke

    2016-08-01

    The proteasome system degrades more than 80% of intracellular proteins into small peptides. Accordingly, the proteasome is involved in many essential cellular functions, such as protein quality control, transcription, immune responses, cell signaling, and apoptosis. Moreover, degradation products are loaded onto major histocompatibility class I molecules to communicate the intracellular protein composition to the immune system. The standard 20S proteasome core complex contains three distinct catalytic active sites that are exchanged upon stimulation with inflammatory cytokines to form the so-called immunoproteasome. Immunoproteasomes are constitutively expressed in immune cells and have different proteolytic activities compared with standard proteasomes. They are rapidly induced in parenchymal cells upon intracellular pathogen infection and are crucial for priming effective CD8(+) T-cell-mediated immune responses against infected cells. Beyond shaping these adaptive immune reactions, immunoproteasomes also regulate the function of immune cells by degradation of inflammatory and immune mediators. Accordingly, they emerge as novel regulators of innate immune responses. The recently unraveled impairment of immunoproteasome function by environmental challenges and by genetic variations of immunoproteasome genes might represent a currently underestimated risk factor for the development and progression of lung diseases. In particular, immunoproteasome dysfunction will dampen resolution of infections, thereby promoting exacerbations, may foster autoimmunity in chronic lung diseases, and possibly contributes to immune evasion of tumor cells. Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, however, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively.

  1. Mitochondria in the regulation of innate and adaptive immunity.

    PubMed

    Weinberg, Samuel E; Sena, Laura A; Chandel, Navdeep S

    2015-03-17

    Mitochondria are well appreciated for their role as biosynthetic and bioenergetic organelles. In the past two decades, mitochondria have emerged as signaling organelles that contribute critical decisions about cell proliferation, death, and differentiation. Mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and their function. Mitochondria can rapidly switch from primarily being catabolic organelles generating ATP to anabolic organelles that generate both ATP and building blocks for macromolecule synthesis. This enables them to fulfill appropriate metabolic demands of different immune cells. Mitochondria have multiple mechanisms that allow them to activate signaling pathways in the cytosol including altering in AMP/ATP ratio, the release of ROS and TCA cycle metabolites, as well as the localization of immune regulatory proteins on the outer mitochondrial membrane. In this Review, we discuss the evidence and mechanisms that mitochondrial dependent signaling controls innate and adaptive immune responses.

  2. Glassy Dynamics in the Adaptive Immune Response Prevents Autoimmune Disease

    NASA Astrophysics Data System (ADS)

    Sun, Jun; Earl, David J.; Deem, Michael W.

    2005-09-01

    The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self-antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely, gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system’s search for antibodies, a balance has evolved between binding affinity and specificity.

  3. Roles of small RNAs in the immune defense mechanisms of crustaceans.

    PubMed

    He, Yaodong; Ju, Chenyu; Zhang, Xiaobo

    2015-12-01

    Small RNAs, 21-24 nucleotides in length, are non-coding RNAs found in most multicellular organisms, as well as in some viruses. There are three main types of small RNAs including microRNA (miRNA), small-interfering RNA (siRNA), and piwi-interacting RNA (piRNA). Small RNAs play key roles in the genetic regulation of eukaryotes; at least 50% of all eukaryote genes are the targets of small RNAs. In recent years, studies have shown that some unique small RNAs are involved in the immune response of crustaceans, leading to lower or higher immune responses to infections and diseases. SiRNAs could be used as therapy for virus infection. In this review, we provide an overview of the diverse roles of small RNAs in the immune defense mechanisms of crustaceans. PMID:26210184

  4. Obligate Biotroph Pathogens of the Genus Albugo Are Better Adapted to Active Host Defense Compared to Niche Competitors.

    PubMed

    Ruhe, Jonas; Agler, Matthew T; Placzek, Aleksandra; Kramer, Katharina; Finkemeier, Iris; Kemen, Eric M

    2016-01-01

    Recent research suggested that plants behave differently under combined versus single abiotic and biotic stress conditions in controlled environments. While this work has provided a glimpse into how plants might behave under complex natural conditions, it also highlights the need for field experiments using established model systems. In nature, diverse microbes colonize the phyllosphere of Arabidopsis thaliana, including the obligate biotroph oomycete genus Albugo, causal agent of the common disease white rust. Biotrophic, as well as hemibiotrophic plant pathogens are characterized by efficient suppression of host defense responses. Lab experiments have even shown that Albugo sp. can suppress non-host resistance, thereby enabling otherwise avirulent pathogen growth. We asked how a pathogen that is vitally dependent on a living host can compete in nature for limited niche space while paradoxically enabling colonization of its host plant for competitors? To address this question, we used a proteomics approach to identify differences and similarities between lab and field samples of Albugo sp.-infected and -uninfected A. thaliana plants. We could identify highly similar apoplastic proteomic profiles in both infected and uninfected plants. In wild plants, however, a broad range of defense-related proteins were detected in the apoplast regardless of infection status, while no or low levels of defense-related proteins were detected in lab samples. These results indicate that Albugo sp. do not strongly affect immune responses and leave distinct branches of the immune signaling network intact. To validate our findings and to get mechanistic insights, we tested a panel of A. thaliana mutant plants with induced or compromised immunity for susceptibility to different biotrophic pathogens. Our findings suggest that the biotroph pathogen Albugo selectively interferes with host defense under different environmental and competitive pressures to maintain its ecological niche

  5. Obligate Biotroph Pathogens of the Genus Albugo Are Better Adapted to Active Host Defense Compared to Niche Competitors.

    PubMed

    Ruhe, Jonas; Agler, Matthew T; Placzek, Aleksandra; Kramer, Katharina; Finkemeier, Iris; Kemen, Eric M

    2016-01-01

    Recent research suggested that plants behave differently under combined versus single abiotic and biotic stress conditions in controlled environments. While this work has provided a glimpse into how plants might behave under complex natural conditions, it also highlights the need for field experiments using established model systems. In nature, diverse microbes colonize the phyllosphere of Arabidopsis thaliana, including the obligate biotroph oomycete genus Albugo, causal agent of the common disease white rust. Biotrophic, as well as hemibiotrophic plant pathogens are characterized by efficient suppression of host defense responses. Lab experiments have even shown that Albugo sp. can suppress non-host resistance, thereby enabling otherwise avirulent pathogen growth. We asked how a pathogen that is vitally dependent on a living host can compete in nature for limited niche space while paradoxically enabling colonization of its host plant for competitors? To address this question, we used a proteomics approach to identify differences and similarities between lab and field samples of Albugo sp.-infected and -uninfected A. thaliana plants. We could identify highly similar apoplastic proteomic profiles in both infected and uninfected plants. In wild plants, however, a broad range of defense-related proteins were detected in the apoplast regardless of infection status, while no or low levels of defense-related proteins were detected in lab samples. These results indicate that Albugo sp. do not strongly affect immune responses and leave distinct branches of the immune signaling network intact. To validate our findings and to get mechanistic insights, we tested a panel of A. thaliana mutant plants with induced or compromised immunity for susceptibility to different biotrophic pathogens. Our findings suggest that the biotroph pathogen Albugo selectively interferes with host defense under different environmental and competitive pressures to maintain its ecological niche

  6. Obligate Biotroph Pathogens of the Genus Albugo Are Better Adapted to Active Host Defense Compared to Niche Competitors

    PubMed Central

    Ruhe, Jonas; Agler, Matthew T.; Placzek, Aleksandra; Kramer, Katharina; Finkemeier, Iris; Kemen, Eric M.

    2016-01-01

    Recent research suggested that plants behave differently under combined versus single abiotic and biotic stress conditions in controlled environments. While this work has provided a glimpse into how plants might behave under complex natural conditions, it also highlights the need for field experiments using established model systems. In nature, diverse microbes colonize the phyllosphere of Arabidopsis thaliana, including the obligate biotroph oomycete genus Albugo, causal agent of the common disease white rust. Biotrophic, as well as hemibiotrophic plant pathogens are characterized by efficient suppression of host defense responses. Lab experiments have even shown that Albugo sp. can suppress non-host resistance, thereby enabling otherwise avirulent pathogen growth. We asked how a pathogen that is vitally dependent on a living host can compete in nature for limited niche space while paradoxically enabling colonization of its host plant for competitors? To address this question, we used a proteomics approach to identify differences and similarities between lab and field samples of Albugo sp.-infected and -uninfected A. thaliana plants. We could identify highly similar apoplastic proteomic profiles in both infected and uninfected plants. In wild plants, however, a broad range of defense-related proteins were detected in the apoplast regardless of infection status, while no or low levels of defense-related proteins were detected in lab samples. These results indicate that Albugo sp. do not strongly affect immune responses and leave distinct branches of the immune signaling network intact. To validate our findings and to get mechanistic insights, we tested a panel of A. thaliana mutant plants with induced or compromised immunity for susceptibility to different biotrophic pathogens. Our findings suggest that the biotroph pathogen Albugo selectively interferes with host defense under different environmental and competitive pressures to maintain its ecological niche

  7. An Adaptive Immune Genetic Algorithm for Edge Detection

    NASA Astrophysics Data System (ADS)

    Li, Ying; Bai, Bendu; Zhang, Yanning

    An adaptive immune genetic algorithm (AIGA) based on cost minimization technique method for edge detection is proposed. The proposed AIGA recommends the use of adaptive probabilities of crossover, mutation and immune operation, and a geometric annealing schedule in immune operator to realize the twin goals of maintaining diversity in the population and sustaining the fast convergence rate in solving the complex problems such as edge detection. Furthermore, AIGA can effectively exploit some prior knowledge and information of the local edge structure in the edge image to make vaccines, which results in much better local search ability of AIGA than that of the canonical genetic algorithm. Experimental results on gray-scale images show the proposed algorithm perform well in terms of quality of the final edge image, rate of convergence and robustness to noise.

  8. The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans.

    PubMed

    Soltész, Beáta; Tóth, Beáta; Sarkadi, Adrien Katalin; Erdős, Melinda; Maródi, László

    2015-01-01

    The discovery of interleukin (IL)-17-mediated immunity has provided a robust framework upon which our current understanding of the mechanism involved in host defense against mucocutaneous candidiasis (CMC) has been built. Studies have shed light on how pattern recognition receptors expressed by innate immune cells recognize various components of Candida cell wall. Inborn errors of immunity affecting IL-17+ T cell differentiation have recently been defined, such as deficiencies of signal transducer and activator of transcription (STAT)3, STAT1, IL-12Rβ1 and IL-12p40, and caspase recruitment domain 9. Impaired receptor-ligand coupling was identified in patients with IL-17F and IL-17 receptor A (IL17RA) deficiency and autoimmune polyendocrine syndrome (APS) type 1. Mutation in the nuclear factor kappa B activator (ACT) 1 was described as a cause of impaired IL-17R-mediated signaling. CMC may be part of a complex clinical phenotype like in patients with deficiencies of STAT3, IL-12Rβ1/IL-12p40 and APS-1 or may be the only or dominant phenotypic manifestation of disease which is referred to as CMC disease. CMCD may result from deficiencies of STAT1, IL-17F, IL-17RA and ACT1. In this review we discuss how recent research on IL-17-mediated immunity shed light on host defense against mucocutaneous infection by Candida and how the discovery of various germ-line mutations and the characterization of associated clinical phenotypes have provided insights into the role of CD4+IL-17+ lymphocytes in the regulation of anticandidal defense of body surfaces.

  9. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response.

    PubMed

    de Brito, Cyro Alves; Goldoni, Adriana Letícia; Sato, Maria Notomi

    2009-09-01

    The neonatal phase is a transitory period characterized by an absence of memory cells, favoring a slow adaptive response prone to tolerance effects and the development of Th2-type responses. However, when appropriately stimulated, neonates may achieve an immune response comparable with adult counterparts. One strategy to stimulate the immunological response of neonates or children in early infancy has been to explore natural or synthetic ligands of cell receptors to stimulate innate immunity. The use of adjuvants for activating different cell receptors may be the key to enhancing neonatal adaptive immunity. This review highlights recent advances in the emerging field of molecular adjuvants of innate immune response and their implications for the development of immunotherapies, with particular focus on the neonatal period.

  10. Connecting growth and defense: the emerging roles of brassinosteroids and gibberellins in plant innate immunity.

    PubMed

    De Bruyne, Lieselotte; Höfte, Monica; De Vleesschauwer, David

    2014-06-01

    Brassinosteroids (BRs) and gibberellins (GAs) are two groups of phytohormones that regulate many common developmental processes throughout the plant life cycle. Fueled by large-scale 'omics' technologies and the burgeoning field of plant computational biology, the past few years have witnessed paradigm-shifting advances in our understanding of how BRs and GA are perceived and their signals transduced. Accumulating evidence also implicates BR and GA in the coordination and integration of plant immune responses. Similarly to other growth regulators, BR and GA play ambiguous roles in molding pathological outcomes, the effects of which may depend not only on the pathogen's lifestyle and infection strategy, but also on specialized features of each interaction. Analysis of the underpinning molecular mechanisms points to a crucial role of GA-inhibiting DELLA proteins and the BR-regulated transcription factor BZR1. Acting at the interface of developmental and defense signaling, these proteins likely serve as central hubs for pathway crosstalk and signal integration, allowing appropriate modulation of plant growth and defense in response to various stimuli. In this review, we outline the latest discoveries dealing with BR and GA modulation of plant innate immunity and highlight interactions between BR and GA signaling, plant defense, and microbial virulence.

  11. Multifaceted interactions between adaptive immunity and the central nervous system.

    PubMed

    Kipnis, Jonathan

    2016-08-19

    Neuroimmunologists seek to understand the interactions between the central nervous system (CNS) and the immune system, both under homeostatic conditions and in diseases. Unanswered questions include those relating to the diversity and specificity of the meningeal T cell repertoire; the routes taken by immune cells that patrol the meninges under healthy conditions and invade the parenchyma during pathology; the opposing effects (beneficial or detrimental) of these cells on CNS function; the role of immune cells after CNS injury; and the evolutionary link between the two systems, resulting in their tight interaction and interdependence. This Review summarizes the current standing of and challenging questions related to interactions between adaptive immunity and the CNS and considers the possible directions in which these aspects of neuroimmunology will be heading over the next decade. PMID:27540163

  12. Unravelling the Costs of Flight for Immune Defenses in the Migratory Monarch Butterfly.

    PubMed

    Fritzsche McKay, Alexa; Ezenwa, Vanessa O; Altizer, Sonia

    2016-08-01

    Migratory animals undergo extreme physiological changes to prepare for and sustain energetically costly movements; one potential change is reduced investment in immune defenses. However, because some migrants have evolved to minimize the energetic demands of movement (for example, through the temporary atrophy of non-essential organs such as those involved in reproduction), migratory animals could potentially avoid immunosuppression during long-distance journeys. In this study, we used a tethered flight mill to examine immune consequences of experimentally induced powered flight in eastern North American monarch butterflies. These butterflies undergo an annual two-way long-distance migration each year from as far north as Canada to wintering sites in Central Mexico. We quantified immune measures as a function of categorical flight treatment (flown versus control groups) and continuous measures of flight effort (e.g., flight distance, duration, and measures of efficiency). We also examined whether relationships between flight and immune measures depended on reproductive investment by experimentally controlling whether monarchs were reproductive or in state of reproductive diapause (having atrophied reproductive organs) prior to flight. Of the three immune responses we measured, hemocyte concentration (the number of immune cells) was lower in flown monarchs relative to controls but increased with flight distance among flown monarchs; the other two immune measures showed no relationship to monarch flight. We also found that monarchs that were reproductively active were less efficient fliers, as they exerted more power during flight than monarchs in reproductive diapause. However, reproductive status did not modify relationships between flight and immune measures. Results of this study add to a growing body of work suggesting that migratory monarchs-like some other animals that travel vast distances-can complete their journeys with efficient use of resources and

  13. Unravelling the Costs of Flight for Immune Defenses in the Migratory Monarch Butterfly.

    PubMed

    Fritzsche McKay, Alexa; Ezenwa, Vanessa O; Altizer, Sonia

    2016-08-01

    Migratory animals undergo extreme physiological changes to prepare for and sustain energetically costly movements; one potential change is reduced investment in immune defenses. However, because some migrants have evolved to minimize the energetic demands of movement (for example, through the temporary atrophy of non-essential organs such as those involved in reproduction), migratory animals could potentially avoid immunosuppression during long-distance journeys. In this study, we used a tethered flight mill to examine immune consequences of experimentally induced powered flight in eastern North American monarch butterflies. These butterflies undergo an annual two-way long-distance migration each year from as far north as Canada to wintering sites in Central Mexico. We quantified immune measures as a function of categorical flight treatment (flown versus control groups) and continuous measures of flight effort (e.g., flight distance, duration, and measures of efficiency). We also examined whether relationships between flight and immune measures depended on reproductive investment by experimentally controlling whether monarchs were reproductive or in state of reproductive diapause (having atrophied reproductive organs) prior to flight. Of the three immune responses we measured, hemocyte concentration (the number of immune cells) was lower in flown monarchs relative to controls but increased with flight distance among flown monarchs; the other two immune measures showed no relationship to monarch flight. We also found that monarchs that were reproductively active were less efficient fliers, as they exerted more power during flight than monarchs in reproductive diapause. However, reproductive status did not modify relationships between flight and immune measures. Results of this study add to a growing body of work suggesting that migratory monarchs-like some other animals that travel vast distances-can complete their journeys with efficient use of resources and

  14. Type I interferon as a link between innate and adaptive immunity through dendritic cell stimulation.

    PubMed

    Tough, David F

    2004-02-01

    Type I interferon (IFN-alpha/beta) is expressed rapidly after infection and plays a key role in innate defense against pathogens. Recent studies have shown that a connection exists between IFN-alpha/beta and antigen-presenting dendritic cells (DCs) at two levels. Firstly, a specific DC precursor, the plasmacytoid pre-DC (p-preDC), was identified as a cell type able to secrete very high amounts of IFN-alpha/beta following stimulation with infectious agents. Secondly, IFN-alpha/beta has been shown to act as a differentiation/maturation factor for DCs. These findings will be discussed in association with evidence indicating that IFN-alpha/beta can enhance and modulate immune responses in vivo. Taken together, the available data suggest that IFN-alpha/beta serves as a link between the innate response to infection and the adaptive immune response. PMID:15101709

  15. Immunity comes first: the effect of parasite genotypes on adaptive immunity and immunization in three-spined sticklebacks.

    PubMed

    Haase, David; Rieger, Jennifer K; Witten, Anika; Stoll, Monika; Bornberg-Bauer, Erich; Kalbe, Martin; Reusch, Thorsten B H

    2016-01-01

    Adaptive immunity in vertebrates can confer increased resistance against invading pathogens upon re-infection. But how specific parasite genotypes affect the temporal transition from innate to adaptive immunity under continual exposure to parasites is poorly understood. Here, we investigated the effects of homologous and heterologous exposures of genetically distinct parasite lineages of the eye fluke Diplostomum pseudospathaceum on gene expression patterns of adaptive immunity in sticklebacks (Gasterosteus aculeatus). Observable differences in gene expression were largely attributable to final exposures while there was no transcription pattern characteristic for a general response to repeated infections with D. pseudospathaceum. None of the final exposure treatments was able to erase the distinct expression patterns resulting from a heterologous pre-exposed fish. Interestingly, heterologous final exposures showed similarities between different treatment groups subjected to homologous pre-exposure. The observed pattern was supported by parasite infection rates and suggests that host immunization was optimized towards an adaptive immune response that favored effectiveness against parasite diversity over specificity.

  16. Epithelium: At the interface of innate and adaptive immune responses

    PubMed Central

    Schleimer, Robert P.; Kato, Atsushi; Kern, Robert; Kuperman, Douglas; Avila, Pedro C.

    2009-01-01

    Several diseases of the airways have a strong component of allergic inflammation in their cause, including allergic rhinitis, asthma, polypoid chronic rhinosinusitis, eosinophilic bronchitis, and others. Although the roles played by antigens and pathogens vary, these diseases have in common a pathology that includes marked activation of epithelial cells in the upper airways, the lower airways, or both. Substantial new evidence indicates an important role of epithelial cells as both mediators and regulators of innate immune responses and adaptive immune responses, as well as the transition from innate immunity to adaptive immunity. The purpose of this review is to discuss recent studies that bear on the molecular and cellular mechanisms by which epithelial cells help to shape the responses of dendritic cells, T cells, and B cells and inflammatory cell recruitment in the context of human disease. Evidence will be discussed that suggests that secreted products of epithelial cells and molecules expressed on their cell surfaces can profoundly influence both immunity and inflammation in the airways. PMID:17949801

  17. Adaptive resistance: A tumor strategy to evade immune attack

    PubMed Central

    Yao, Sheng; Chen, Lieping

    2014-01-01

    A dilemma in cancer immunology is that, although patients often develop active anti-tumor immune responses, the tumor still outgrows. It has become clear that under the pressure of the host’s immune system, cancer cells have adapted elaborate tactics to reduce their immunogenicity (also known as immunoselection) and/or to actively suppress immune cells and promote immune tolerance (also known as immunosubversion). In this issue of the European Journal of Immunology, Dolen and Esendagli [Eur. J. Immunol. 2013. 43: 747–757] show that acute myeloid leukemia (AML) cells develop an adaptive immune phenotype switching mechanism: In response to attack by activated T cells, the leukemia cells quickly downregulate the T-cell costimulatory ligand B7-H2 and reciprocally upregulate the coinhibitory ligands B7-H1 and B7-DC in order to shut down T-cell activation via the PD-1 pathway. These novel findings and their relevance for cancer immunotherapy, especially potential applications in PD-1 check-point blockade therapy are discussed in this Commentary. PMID:23381914

  18. Control of commensal microbiota by the adaptive immune system.

    PubMed

    Zhang, Husen; Luo, Xin M

    2015-01-01

    The symbiotic relationship between the mammalian host and gut microbes has fascinated many researchers in recent years. Use of germ-free animals has contributed to our understanding of how commensal microbes affect the host. Immunodeficiency animals lacking specific components of the mammalian immune system, on the other hand, enable studying of the reciprocal function-how the host controls which microbes to allow for symbiosis. Here we review the recent advances and discuss our perspectives of how to better understand the latter, with an emphasis on the effects of adaptive immunity on the composition and diversity of gut commensal bacteria. PMID:25901893

  19. Links between innate and adaptive immunity via type I interferon.

    PubMed

    Le Bon, Agnes; Tough, David F

    2002-08-01

    Type I interferon (IFN-alpha/beta) is expressed rapidly following exposure to a wide variety of infectious agents and plays a key role in innate control of virus replication. Recent studies have demonstrated that dendritic cells both produce IFN-alpha/beta and undergo maturation in response to IFN-alpha/beta. Moreover, IFN-alpha/beta has been shown to potently enhance immune responses in vivo through the stimulation of dendritic cells. These findings indicate that IFN-alpha/beta serves as a signal linking innate and adaptive immunity. PMID:12088676

  20. NIK1, a host factor specialized in antiviral defense or a novel general regulator of plant immunity?

    PubMed

    Machado, Joao P B; Brustolini, Otavio J B; Mendes, Giselle C; Santos, Anésia A; Fontes, Elizabeth P B

    2015-11-01

    NIK1 is a receptor-like kinase involved in plant antiviral immunity. Although NIK1 is structurally similar to the plant immune factor BAK1, which is a key regulator in plant immunity to bacterial pathogens, the NIK1-mediated defenses do not resemble BAK1 signaling cascades. The underlying mechanism for NIK1 antiviral immunity has recently been uncovered. NIK1 activation mediates the translocation of RPL10 to the nucleus, where it interacts with LIMYB to fully down-regulate translational machinery genes, resulting in translation inhibition of host and viral mRNAs and enhanced tolerance to begomovirus. Therefore, the NIK1 antiviral immunity response culminates in global translation suppression, which represents a new paradigm for plant antiviral defenses. Interestingly, transcriptomic analyses in nik1 mutant suggest that NIK1 may suppress antibacterial immune responses, indicating a possible opposite effect of NIK1 in bacterial and viral infections.

  1. The appearance of the thymus and the integrated evolution of adaptive immune and neuroendocrine systems.

    PubMed

    Geenen, V

    2012-01-01

    The immune system may be considered as a sensory organ able to respond to different kinds of danger signals that are not detected by nervous cells. The immune response is not autonomous but also regulated by the central and peripheral nervous system, as well as by neuropeptides, vitamin D and neuroendocrine axes such as the corticotrope, somatotrope, thyrotrope and gonadotrope axes. During evolution, the thymus emerged concomitantly with recombinase-dependent adaptive immunity as an'immune brain' or a'master class' highly specialized in the orchestration of central immunological self-tolerance. This was an absolute requirement for survival of species because of the high risk of autotoxicity inherent to the stochastic generation of extreme diversity characterizing this novel adaptive type of immune defenses against non-self. The thymus now appears to be an obligatory intersection for the integrated evolution of the major systems of cell-to-cell signalling, the nervous, endocrine and immune systems. The presentation of many self-peptides by thymic major histocompatibility complex (MHC) proteins is controlled by the autoimmune regulator (AIRE) gene/protein and is responsible for the clonal deletion of self-reactive T cells. In the same time, by still unexplained mechanisms, MHC presentation of the same self-peptides in the thymus promotes the generation of self-specific FOXP3+ CD4+CD25+ natural regulatory T cells (nTreg) that are able to inhibit in periphery self-reactive CD4+ and CD8+ T cells having escaped the thymus censorship. Moreover, a thymus dysfunction is more and more established as the primary event driving the development of organ-specific autoimmunity, which is the tribute paid, mainly by mankind, for the preservation of self against non-self. Our novel knowledge about thymus physiology and physiopathology already serves as the basis for the development of various innovative and efficient immunomodulating strategies in pharmacology. PMID:22897070

  2. Drosophila Adaptation to Viral Infection through Defensive Symbiont Evolution

    PubMed Central

    Faria, Vitor G.; Magalhães, Sara; Paulo, Tânia F.; Nolte, Viola; Schlötterer, Christian

    2016-01-01

    Microbial symbionts can modulate host interactions with biotic and abiotic factors. Such interactions may affect the evolutionary trajectories of both host and symbiont. Wolbachia protects Drosophila melanogaster against several viral infections and the strength of the protection varies between variants of this endosymbiont. Since Wolbachia is maternally transmitted, its fitness depends on the fitness of its host. Therefore, Wolbachia populations may be under selection when Drosophila is subjected to viral infection. Here we show that in D. melanogaster populations selected for increased survival upon infection with Drosophila C virus there is a strong selection coefficient for specific Wolbachia variants, leading to their fixation. Flies carrying these selected Wolbachia variants have higher survival and fertility upon viral infection when compared to flies with the other variants. These findings demonstrate how the interaction of a host with pathogens shapes the genetic composition of symbiont populations. Furthermore, host adaptation can result from the evolution of its symbionts, with host and symbiont functioning as a single evolutionary unit. PMID:27684942

  3. Control of the Adaptive Immune Response by Tumor Vasculature

    PubMed Central

    Mauge, Laetitia; Terme, Magali; Tartour, Eric; Helley, Dominique

    2014-01-01

    The endothelium is nowadays described as an entire organ that regulates various processes: vascular tone, coagulation, inflammation, and immune cell trafficking, depending on the vascular site and its specific microenvironment as well as on endothelial cell-intrinsic mechanisms like epigenetic changes. In this review, we will focus on the control of the adaptive immune response by the tumor vasculature. In physiological conditions, the endothelium acts as a barrier regulating cell trafficking by specific expression of adhesion molecules enabling adhesion of immune cells on the vessel, and subsequent extravasation. This process is also dependent on chemokine and integrin expression, and on the type of junctions defining the permeability of the endothelium. Endothelial cells can also regulate immune cell activation. In fact, the endothelial layer can constitute immunological synapses due to its close interactions with immune cells, and the delivery of co-stimulatory or co-inhibitory signals. In tumor conditions, the vasculature is characterized by an abnormal vessel structure and permeability, and by a specific phenotype of endothelial cells. All these abnormalities lead to a modulation of intra-tumoral immune responses and contribute to the development of intra-tumoral immunosuppression, which is a major mechanism for promoting the development, progression, and treatment resistance of tumors. The in-depth analysis of these various abnormalities will help defining novel targets for the development of anti-tumoral treatments. Furthermore, eventual changes of the endothelial cell phenotype identified by plasma biomarkers could secondarily be selected to monitor treatment efficacy. PMID:24734218

  4. Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection.

    PubMed

    Zaki, Md Hasan; Man, Si Ming; Vogel, Peter; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi

    2014-01-01

    The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella-infected macrophages induced NLRP12-dependent inhibition of NF-κB and ERK activation by suppressing phosphorylation of IκBα and ERK. NLRP12-mediated down-regulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host.

  5. A complex of genes involved in adaptation of Leptinotarsa decemlineata larvae to induced potato defense.

    PubMed

    Petek, Marko; Turnšek, Neža; Gašparič, Meti Buh; Novak, Maruša Pompe; Gruden, Kristina; Slapar, Nina; Popovič, Tatjana; Štrukelj, Borut; Gruden, Kristina; Štrukelj, Borut; Jongsma, Maarten A

    2012-03-01

    The Colorado potato beetle (Leptinotarsa decemlineata) is the most important pest of potato in many areas of the world. One of the main reasons for its success lies in the ability of its larvae to counteract plant defense compounds. Larvae adapt to protease inhibitors (PIs) produced in potato leaves through substitution of inhibitor-sensitive digestive cysteine proteases with inhibitor-insensitive cysteine proteases. To get a broader insight into the basis of larval adaptation to plant defenses, we created a "suppression subtractive hybridisation" library using cDNA from the gut of L. decemlineata larvae fed methyl jasmonate-induced or uninduced potato leaves. Four hundred clones, randomly selected from the library, were screened for their relevance to adaptation with DNA microarray hybridizations. Selected enzyme systems of beetle digestion were further inspected for changes in gene expression using quantitative PCR and enzyme activity measurements. We identified two new groups of digestive cysteine proteases, intestains D and intestains E. Intestains D represent a group of structurally distinct digestive cysteine proteases, of which the tested members are strongly upregulated in response to induced plant defenses. Moreover, we found that other digestive enzymes also participate in adaptation, namely, cellulases, serine proteases, and an endopolygalacturonase. In addition, juvenile hormone binding protein-like (JHBP-like) genes were upregulated. All studied genes were expressed specifically in larval guts. In contrast to earlier studies that reported experiments based on PI-enriched artificial diets, our results increase understanding of insect adaptation under natural conditions.

  6. Maternal adaptive immunity influences the intestinal microflora of suckling mice.

    PubMed

    Diaz, Rosa L; Hoang, Lisa; Wang, Jiafang; Vela, Jose L; Jenkins, Shannon; Aranda, Richard; Martín, Martín G

    2004-09-01

    The microflorae in the intestine of breast-fed infants are distinct from those that typically populate the intestine of formula-fed infants. Although the acquisition of passive immunity through breast-feeding may play a critical role in influencing the pattern of bacterial colonization of the gut, the precise mechanisms underlying the differences in the commensal microflorae of breast and formula-fed children have not been established. We hypothesized that the assemblage of commensal microflorae in suckling and weaned mice may be influenced by the maternal adaptive immune system. To test this hypothesis, we analyzed the intestinal microflorae of mice reared in the presence (wild-type) or absence of an intact maternal immune system (T- and B-cell deficient). Several types of bacteria (Lactobacillus, Enterococcus, Clostridium perfringens, Bifidobacterium, and Bacteroides) were isolated and enumerated from both the small and large intestine of 10-, 18-, 25- and 40- to 60-d old mice using selective media. The densities of bacteria were significantly lower in the small intestine of weaned mice that were reared by wild-type (WT) compared with immunodeficient (ID) dams. However, the microflorae were generally more abundant in the large intestine of suckling pups reared by WT compared with ID dams. Our results indicate that intestinal microflorae change throughout the suckling phase of development and that the maternal adaptive immune system influences the pattern and abundance of bacteria within the gut in an age- and site-specific manner.

  7. Evaluation of the Adaptive Immune Response to Respiratory Syncytial Virus.

    PubMed

    Knudson, Cory J; Weiss, Kayla A; Stoley, Megan E; Varga, Steven M

    2016-01-01

    Evaluation of the adaptive immune response is critical to the advancement of our basic knowledge and understanding of respiratory syncytial virus (RSV). The cellular composition in the lung following RSV infection is often evaluated using flow cytometry. However, a limitation of this approach has been the inability to readily distinguish cells that are within the lung parenchyma from cells that remain in the pulmonary blood vessels. Herein, we detail a procedure to evaluate the adaptive immune response via flow cytometric analysis that incorporates an in vivo intravascular staining technique. This technique allows for discrimination of immune cells in the lung tissue from cells that remain in the pulmonary vasculature following perfusion. Therefore at any given time point following an RSV infection, the leukocytic populations in the lung parenchyma can be quantified and phenotypically assessed with high resolution. While we focus on the T lymphocyte response in the lung, this technique can be readily adapted to examine various leukocytic cell types in the lung following RSV infection. PMID:27464699

  8. Innate immune defenses exhibit circadian rhythmicity and differential temporal sensitivity to a bacterial endotoxin in Nile tilapia (Oreochromis niloticus).

    PubMed

    Lazado, Carlo C; Skov, Peter Vilhelm; Pedersen, Per Bovbjerg

    2016-08-01

    The present study investigated the daily dynamics of humoral immune defenses and the temporal influence in the sensitivity of these responses to a bacterial endotoxin in Nile tilapia (Oreochromis niloticus). The first experiment subjected the fish to two photoperiod conditions, 12L:12D (LD) and 0L:24D (DD), for 20 days to characterize the rhythms of humoral immunity. Serum alkaline phosphatase (ALP), lysozyme (LYZ), peroxidase (PER) and protease (PRO) exhibited significant rhythmicity under LD but not in DD. No significant rhythms were observed in esterase (ESA) and anti-protease (ANTI) in both photoperiod conditions. Fish reared under LD were subsequently subjected to DD while the group previously under DD was exposed to LD, and this carried on for 3 days before another set of samples was collected. Results revealed that the rhythms of LYZ, PER and PRO but not ALP persisted when photoperiod was changed from LD to DD. Nonetheless, immune parameters remained arrhythmic in the group subjected from DD to LD. Cluster analysis of the humoral immune responses under various light conditions revealed that each photic environment had distinct daily immunological profile. In the second experiment, fish were injected with bacterial endotoxin lipopolysaccharide (LPS) either at ZT3 (day) or at ZT15 (night) to evaluate the temporal sensitivity of humoral immunity to a pathogen-associated molecular pattern. The results demonstrated that responses to LPS were gated by the time of day. LPS significantly modulated serum ALP and ANTI activities but only when the endotoxin was administered at ZT3. Serum LYZ and PER were stimulated at both injection times but with differing response profiles. Modulated LYZ activity was persistent when injected at ZT3 but transient when LPS was applied at ZT15. The magnitude of LPS-induced PER activity was higher when the endotoxin was delivered at ZT3 versus ZT15. It was further shown that plasma cortisol was significantly elevated but only when LPS

  9. Innate immune defenses exhibit circadian rhythmicity and differential temporal sensitivity to a bacterial endotoxin in Nile tilapia (Oreochromis niloticus).

    PubMed

    Lazado, Carlo C; Skov, Peter Vilhelm; Pedersen, Per Bovbjerg

    2016-08-01

    The present study investigated the daily dynamics of humoral immune defenses and the temporal influence in the sensitivity of these responses to a bacterial endotoxin in Nile tilapia (Oreochromis niloticus). The first experiment subjected the fish to two photoperiod conditions, 12L:12D (LD) and 0L:24D (DD), for 20 days to characterize the rhythms of humoral immunity. Serum alkaline phosphatase (ALP), lysozyme (LYZ), peroxidase (PER) and protease (PRO) exhibited significant rhythmicity under LD but not in DD. No significant rhythms were observed in esterase (ESA) and anti-protease (ANTI) in both photoperiod conditions. Fish reared under LD were subsequently subjected to DD while the group previously under DD was exposed to LD, and this carried on for 3 days before another set of samples was collected. Results revealed that the rhythms of LYZ, PER and PRO but not ALP persisted when photoperiod was changed from LD to DD. Nonetheless, immune parameters remained arrhythmic in the group subjected from DD to LD. Cluster analysis of the humoral immune responses under various light conditions revealed that each photic environment had distinct daily immunological profile. In the second experiment, fish were injected with bacterial endotoxin lipopolysaccharide (LPS) either at ZT3 (day) or at ZT15 (night) to evaluate the temporal sensitivity of humoral immunity to a pathogen-associated molecular pattern. The results demonstrated that responses to LPS were gated by the time of day. LPS significantly modulated serum ALP and ANTI activities but only when the endotoxin was administered at ZT3. Serum LYZ and PER were stimulated at both injection times but with differing response profiles. Modulated LYZ activity was persistent when injected at ZT3 but transient when LPS was applied at ZT15. The magnitude of LPS-induced PER activity was higher when the endotoxin was delivered at ZT3 versus ZT15. It was further shown that plasma cortisol was significantly elevated but only when LPS

  10. Glassy Dynamics in the Adaptive Immune Response Prevents Autoimmune Disease

    NASA Astrophysics Data System (ADS)

    Sun, Jun; Deem, Michael

    2006-03-01

    The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross-reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system a balance has evolved between binding affinity and specificity in the mechanism for searching the amino acid sequence space of antibodies. Our model predicts that chronic infection may lead to autoimmune disease as well due to cross-reactivity and suggests a broad distribution for the time of onset of autoimmune disease due to chronic exposure. The slow search of antibody sequence space by point mutation leads to the broad of distribution times.

  11. Microbial symbiosis with the innate immune defense system of the skin.

    PubMed

    Gallo, Richard L; Nakatsuji, Teruaki

    2011-10-01

    Skin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the unique ionic, lipid, and physical barrier of the epidermis, is the first-line defense against invading pathogens. However, recent studies have revealed that our skin's innate immune system is not solely of human origin. Staphylococcus epidermidis, a major constituent of the normal microflora on healthy human skin, acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already present opportunistic pathogens. Our resident commensal microbes produce their own AMPs, act to enhance the normal production of AMPs by keratinocytes, and are beneficial to maintaining inflammatory homeostasis by suppressing excess cytokine release after minor epidermal injury. These observations indicate that the normal human skin microflora protects skin by various modes of action, a conclusion supported by many lines of evidence associating diseases such as acne, atopic dermatitis, psoriasis, and rosacea with an imbalance of the microflora even in the absence of classical infection. This review highlights recent observations on the importance of innate immune systems and the relationship with the normal skin microflora to maintain healthy skin.

  12. A proteomics perspective on viral DNA sensors in host defense and viral immune evasion mechanisms.

    PubMed

    Crow, Marni S; Javitt, Aaron; Cristea, Ileana M

    2015-06-01

    The sensing of viral DNA is an essential step of cellular immune response to infections with DNA viruses. These human pathogens are spread worldwide, triggering a wide range of virus-induced diseases, and are associated with high levels of morbidity and mortality. Despite similarities between DNA molecules, mammalian cells have the remarkable ability to distinguish viral DNA from their own DNA. This detection is carried out by specialized antiviral proteins, called DNA sensors. These sensors bind to foreign DNA to activate downstream immune signaling pathways and alert neighboring cells by eliciting the expression of antiviral cytokines. The sensing of viral DNA was shown to occur both in the cytoplasm and in the nucleus of infected cells, disproving the notion that sensing occurred by simple spatial separation of viral and host DNA. A number of omic approaches, in particular, mass-spectrometry-based proteomic methods, have significantly contributed to the constantly evolving field of viral DNA sensing. Here, we review the impact of omic methods on the identification of viral DNA sensors, as well as on the characterization of mechanisms involved in host defense or viral immune evasion.

  13. Role of Adaptive Immunity in Alcoholic Liver Disease

    PubMed Central

    Albano, Emanuele

    2012-01-01

    Stimulation of innate immunity is increasingly recognized to play an important role in the pathogenesis of alcoholic liver disease (ALD), while the contribution of adaptive immunity has received less attention. Clinical and experimental data show the involvement of Th-1 and Th-17 T-lymphocytes in alcoholic hepatitis. Nonetheless, the mechanisms by which alcohol triggers adaptive immunity are still incompletely characterized. Patients with advanced ALD have circulating IgG and T-lymphocytes recognizing epitopes derived from protein modification by hydroxyethyl free radicals and end products of lipid-peroxidation. High titers of IgG against lipid peroxidation-derived antigens are associated with an increased hepatic production of proinflammatory cytokines/chemokines. Moreover, the same antigens favor the breaking of self-tolerance towards liver constituents. In particular, autoantibodies against cytochrome P4502E1 (CYP2E1) are evident in a subset of ALD patients. Altogether these results suggest that allo- and autoimmune reactions triggered by oxidative stress might contribute to hepatic inflammation during the progression of ALD. PMID:22229098

  14. Adaptation of inducible defense in Euplotes daidaleos (Ciliophora) to predation risks by various predators.

    PubMed

    Kusch, J

    1995-07-01

    The extent of induced morphological defense in Euplotes daidaleos correlates to this ciliate's predation risk from the defense-inducing predator species. Euplotes daidaleos responded by morphological transformation only to organisms that are able to feed on typically formed Euplotes cells (63 ± 5 μm cell width in E. daidaleos). Three of those potential predator species caused defensive changes to various degrees (Student's t-test, P < 0.1 to P < 0.0001): Lembadion bullinum (Ciliata) induced 82 ± 6 μm cell width in E. daidaleos; Chaetogaster diastrophus (Oligochaeta) induced 85 = 6 μm width; and Stenostomum sphagnetorum (Turbellaria) induced 89 ± 8 μm width (at a density of 10 predators per milliliter, respectively). At higher predator densities (50 or 100 organisms per milliliter), Euplotes developed a correspondingly larger width (to a maximum of 103 ± 10 μm in the presence of S. sphagnetorum). Euplotes did not respond to organisms (e.g., Blepharisma japonicum, Colpidium campylum, Didinium nasutum, Paramecium caudatum, Spirostomum ambiguum, Stentor coeruleus) that cannot feed on this ciliate species. Daphnia longispina and Bursaria truncatella predators, which can feed on large prey of ≥125, or ≥200 μm in diameter, respectively, also had no effect on the morphology of Euplotes. The extent of defense in Euplotes that was induced by 10 predators per milliliter during 24 h decreased the predation risk from those predators to 67% in the presence of S. sphagnetorum, to 50% with L. bullinum, and to 15% with C. diastrophus, compared to the typical form of Euplotes. In a natural population, the defensive form of E. daidaleos was found with average cell widths of 88 ± 8 μm. The results indicate that predator-induced defense in natural Euplotes populations is beneficial to this prey and that it is adapted to the predation abilities of Euplotes predators, whereby energetical costs related to defensive changes may be saved. PMID:24185414

  15. NOD2, an Intracellular Innate Immune Sensor Involved in Host Defense and Crohn's Disease

    PubMed Central

    Strober, Warren; Watanabe, Tomohiro

    2013-01-01

    Nucleotide binding oligomerization domain 2 (NOD2) is an intracellular sensor for small peptides derived from the bacterial cell wall component, peptidoglycan. Recent studies have uncovered unexpected functions of NOD2 in innate immune responses such as induction of type I IFN and facilitation of autophagy; moreover, they have disclosed extensive cross-talk between NOD2 and Toll-like receptors which plays an indispensable role both in host defense against microbial infection and in the development of autoimmunity. Of particular interest, polymorphisms of CARD15 encoding NOD2 are associated with Crohn's disease and other autoimmune states such as graft versus host disease. In this review, we summarize recent findings regarding normal functions of NOD2 and discuss the mechanisms by which NOD2 polymorphisms associated with Crohn's disease lead to intestinal inflammation. PMID:21750585

  16. IL-36γ Augments Host Defense and Immune Responses in Human Female Reproductive Tract Epithelial Cells.

    PubMed

    Winkle, Sean M; Throop, Andrea L; Herbst-Kralovetz, Melissa M

    2016-01-01

    IL-36γ is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36γ in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36γ and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36γ in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36γ treatment resulted in self-amplification of IL-36γ and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36γ are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36γ is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT. PMID:27379082

  17. IL-36γ Augments Host Defense and Immune Responses in Human Female Reproductive Tract Epithelial Cells

    PubMed Central

    Winkle, Sean M.; Throop, Andrea L.; Herbst-Kralovetz, Melissa M.

    2016-01-01

    IL-36γ is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36γ in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36γ and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36γ in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36γ treatment resulted in self-amplification of IL-36γ and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36γ are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36γ is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT. PMID:27379082

  18. Agent-based modeling approach of immune defense against spores of opportunistic human pathogenic fungi.

    PubMed

    Tokarski, Christian; Hummert, Sabine; Mech, Franziska; Figge, Marc Thilo; Germerodt, Sebastian; Schroeter, Anja; Schuster, Stefan

    2012-01-01

    Opportunistic human pathogenic fungi like the ubiquitous fungus Aspergillus fumigatus are a major threat to immunocompromised patients. An impaired immune system renders the body vulnerable to invasive mycoses that often lead to the death of the patient. While the number of immunocompromised patients is rising with medical progress, the process, and dynamics of defense against invaded and ready to germinate fungal conidia are still insufficiently understood. Besides macrophages, neutrophil granulocytes form an important line of defense in that they clear conidia. Live imaging shows the interaction of those phagocytes and conidia as a dynamic process of touching, dragging, and phagocytosis. To unravel strategies of phagocytes on the hunt for conidia an agent-based modeling approach is used, implemented in NetLogo. Different modes of movement of phagocytes are tested regarding their clearing efficiency: random walk, short-term persistence in their recent direction, chemotaxis of chemokines excreted by conidia, and communication between phagocytes. While the short-term persistence hunting strategy turned out to be superior to the simple random walk, following a gradient of chemokines released by conidial agents is even better. The advantage of communication between neutrophilic agents showed a strong dependency on the spatial scale of the focused area and the distribution of the pathogens.

  19. Innate Immunity Holding the Flanks until Reinforced by Adaptive Immunity against Mycobacterium tuberculosis Infection

    PubMed Central

    Khan, Nargis; Vidyarthi, Aurobind; Javed, Shifa; Agrewala, Javed N.

    2016-01-01

    T cells play a cardinal role in imparting protection against Mycobacterium tuberculosis (Mtb). However, ample time is required before T-cells are able to evoke efficient effector responses in the lung, where the mycobacterium inflicts disease. This delay in T cells priming, which is termed as lag phase, provides sufficient time for Mtb to replicate and establish itself within the host. In contrast, innate immunity efficiently curb the growth of Mtb during initial phase of infection through several mechanisms. Pathogen recognition by innate cells rapidly triggers a cascade of events, such as apoptosis, autophagy, inflammasome formation and nitric oxide production to kill intracellular pathogens. Furthermore, bactericidal mechanisms such as autophagy and apoptosis, augment the antigen processing and presentation, thereby contributing substantially to the induction of adaptive immunity. This manuscript highlights the role of innate immune mechanisms in restricting the survival of Mtb during lag phase. Finally, this article provides new insight for designing immuno-therapies by targeting innate immune mechanisms to achieve optimum immune response to cure TB. PMID:27014247

  20. Turning inducible defenses on and off: adaptive responses of Daphnia to a gape-limited predator.

    PubMed

    Riessen, Howard P; Trevett-Smith, Julie B

    2009-12-01

    The use of inducible defenses is a common strategy to reduce predation while minimizing associated costs for prey. The most effective use of these defenses, however, may involve turning them on and off at different stages of ontogenetic development, with the timing dependent on prey body size and the nature of the predation environment. We develop a model based on the strike efficiency of a size-selective predator that examines the interaction between induced morphological defenses and prey body size, including the consequences of this interaction for the optimal development of the defenses during the prey's ontogeny. We then examine this model with respect to a model system of inducible defenses: neck spine induction in the water flea Daphnia in response to predatory larvae of the phantom midge Chaoborus. In accordance with predictions of the model, the body size and timing of neck spine acquisition during Daphnia development are related to the relative sizes of the Daphnia and Chaoborus species interacting in a pond or lake. The Daphnia species examined first acquire neck spines in either the first, second, or third juvenile instar, at body lengths that range from 0.58 to 0.83 mm. Neck spine formation is initiated at larger Daphnia body sizes when these prey are subject to predation by a larger Chaoborus species (C. trivittatus) and at smaller sizes when exposed only to a smaller predator (C. americanus). Induction of these morphological defenses in Daphnia occurs later in juvenile development in the smaller of the two species we examined (D. minnehaha) than in the larger (D. pulex). Delayed acquisition of neck spines also occurs when Daphnia are exposed to predation by larger Chaoborus. The close match between model predictions and the patterns observed in nature suggests that these patterns are adaptive developmental responses to different predator environments.

  1. A Role for Host Activation-Induced Cytidine Deaminase in Innate Immune Defense against KSHV

    PubMed Central

    Bekerman, Elena; Jeon, Diana; Ardolino, Michele; Coscoy, Laurent

    2013-01-01

    Activation-induced cytidine deaminase (AID) is specifically induced in germinal center B cells to carry out somatic hypermutation and class-switch recombination, two processes responsible for antibody diversification. Because of its mutagenic potential, AID expression and activity are tightly regulated to minimize unwanted DNA damage. Surprisingly, AID expression has been observed ectopically during pathogenic infections. However, the function of AID outside of the germinal centers remains largely uncharacterized. In this study, we demonstrate that infection of human primary naïve B cells with Kaposi's sarcoma-associated herpesvirus (KSHV) rapidly induces AID expression in a cell intrinsic manner. We find that infected cells are marked for elimination by Natural Killer cells through upregulation of NKG2D ligands via the DNA damage pathway, a pathway triggered by AID. Moreover, without having a measurable effect on KSHV latency, AID impinges directly on the viral fitness by inhibiting lytic reactivation and reducing infectivity of KSHV virions. Importantly, we uncover two KSHV-encoded microRNAs that directly regulate AID abundance, further reinforcing the role for AID in the antiviral response. Together our findings reveal additional functions for AID in innate immune defense against KSHV with implications for a broader involvement in innate immunity to other pathogens. PMID:24244169

  2. Human Macrophage SCN5A Activates an Innate Immune Signaling Pathway for Antiviral Host Defense*

    PubMed Central

    Jones, Alexis; Kainz, Danielle; Khan, Faatima; Lee, Cara; Carrithers, Michael D.

    2014-01-01

    Pattern recognition receptors contain a binding domain for pathogen-associated molecular patterns coupled to a signaling domain that regulates transcription of host immune response genes. Here, a novel mechanism that links pathogen recognition to channel activation and downstream signaling is proposed. We demonstrate that an intracellular sodium channel variant, human macrophage SCN5A, initiates signaling and transcription through a calcium-dependent isoform of adenylate cyclase, ADCY8, and the transcription factor, ATF2. Pharmacological stimulation with a channel agonist or treatment with cytoplasmic poly(I:C), a mimic of viral dsRNA, activates this pathway to regulate expression of SP100-related genes and interferon β. Electrophysiological analysis reveals that the SCN5A variant mediates nonselective outward currents and a small, but detectable, inward current. Intracellular poly(I:C) markedly augments an inward voltage-sensitive sodium current and inhibits the outward nonselective current. These results suggest human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense. It is postulated that SCN5A is a novel pathogen sensor and that this pathway represents a channel activation-dependent mechanism of transcriptional regulation. PMID:25368329

  3. Innate and Adaptive Immune Response to Fungal Products and Allergens.

    PubMed

    Williams, P Brock; Barnes, Charles S; Portnoy, Jay M

    2016-01-01

    Exposure to fungi and their products is practically ubiquitous, yet most of this is of little consequence to most healthy individuals. This is because there are a number of elaborate mechanisms to deal with these exposures. Most of these mechanisms are designed to recognize and neutralize such exposures. However, in understanding these mechanisms it has become clear that many of them overlap with our ability to respond to disruptions in tissue function caused by trauma or deterioration. These responses involve the innate and adaptive immune systems usually through the activation of nuclear factor kappa B and the production of cytokines that are considered inflammatory accompanied by other factors that can moderate these reactivities. Depending on different genetic backgrounds and the extent of activation of these mechanisms, various pathologies with resulting symptoms can ensue. Complicating this is the fact that these mechanisms can bias toward type 2 innate and adaptive immune responses. Thus, to understand what we refer to as allergens from fungal sources, we must first understand how they influence these innate mechanisms. In doing so it has become clear that many of the proteins that are described as fungal allergens are essentially homologues of our own proteins that signal or cause tissue disruptions.

  4. Autophagy suppresses host adaptive immune responses toward Borrelia burgdorferi.

    PubMed

    Buffen, Kathrin; Oosting, Marije; Li, Yang; Kanneganti, Thirumala-Devi; Netea, Mihai G; Joosten, Leo A B

    2016-09-01

    We have previously demonstrated that inhibition of autophagy increased the Borrelia burgdorferi induced innate cytokine production in vitro, but little is known regarding the effect of autophagy on in vivo models of Borrelia infection. Here, we showed that ATG7-deficient mice that were intra-articular injected with Borrelia spirochetes displayed increased joint swelling, cell influx, and enhanced interleukin-1β and interleukin-6 production by inflamed synovial tissue. Because both interleukin-1β and interleukin-6 are linked to the development of adaptive immune responses, we examine the function of autophagy on Borrelia induced adaptive immunity. Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increase in interleukin-17, interleukin-22, and interferon-γ production in response to exposure to Borrelia burgdorferi. Increased IL-17 production was dependent on IL-1β release but, interestingly, not on interleukin-23 production. In addition, cytokine quantitative trait loci in ATG9B modulate the Borrelia induced interleukin-17 production. Because high levels of IL-17 have been found in patients with confirmed, severe, chronic borreliosis, we propose that the modulation of autophagy may be a potential target for anti-inflammatory therapy in patients with persistent Lyme disease. PMID:27101991

  5. How a well-adapted immune system is organized

    PubMed Central

    Mayer, Andreas; Balasubramanian, Vijay; Mora, Thierry; Walczak, Aleksandra M.

    2015-01-01

    The repertoire of lymphocyte receptors in the adaptive immune system protects organisms from diverse pathogens. A well-adapted repertoire should be tuned to the pathogenic environment to reduce the cost of infections. We develop a general framework for predicting the optimal repertoire that minimizes the cost of infections contracted from a given distribution of pathogens. The theory predicts that the immune system will have more receptors for rare antigens than expected from the frequency of encounters; individuals exposed to the same infections will have sparse repertoires that are largely different, but nevertheless exploit cross-reactivity to provide the same coverage of antigens; and the optimal repertoires can be reached via the dynamics of competitive binding of antigens by receptors and selective amplification of stimulated receptors. Our results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. Our predictions can be tested in high-throughput surveys of receptor and pathogen diversity. PMID:25918407

  6. [Adaptive immune response and associated trigger factors in atopic dermatitis].

    PubMed

    Heratizadeh, A; Werfel, T; Rösner, L M

    2015-02-01

    Due to a broad variety of extrinsic trigger factors, patients with atopic dermatitis (AD) are characterized by complex response mechanisms of the adaptive immune system. Notably, skin colonization with Staphylococcus aureus seems to be of particular interest since not only exotoxins, but also other proteins of S. aureus can induce specific humoral and cellular immune responses which partially also correlate with the severity of AD. In a subgroup of AD patients Malassezia species induce specific IgE- and T cell-responses which has been demonstrated by atopy patch tests. Moreover, Mala s 13 is characterized by high cross-reactivity to the human corresponding protein (thioredoxin). Induction of a potential autoallergy due to molecular mimicry seems therefore to be relevant for Malassezia-sensitized AD patients. In addition, sensitization mechanisms to autoallergens aside from cross-reactivity are under current investigation. Regarding inhalant allergens, research projects are in progress with the aim to elucidate allergen-specific immune response mechanisms in more depth. For grass-pollen allergens a flare-up of AD following controlled exposure has been observed while for house dust mite-allergens a polarization towards Th2 and Th2/Th17 T cell phenotypes can be observed. These and further findings might finally contribute to the development of specific and effective treatments for aeroallergen-sensitized AD patients. PMID:25532900

  7. Immune defense reduces respiratory fitness in Callinectes sapidus, the Atlantic blue crab.

    PubMed

    Burnett, Louis E; Holman, Jeremy D; Jorgensen, Darwin D; Ikerd, Jennifer L; Burnett, Karen G

    2006-08-01

    Crustacean gills function in gas exchange, ion transport, and immune defense against microbial pathogens. Hemocyte aggregates that form in response to microbial pathogens become trapped in the fine vasculature of the gill, leading to the suggestion by others that respiration and ion regulation might by impaired during the course of an immune response. In the present study, injection of the pathogenic bacterium Vibrio campbellii into Callinectes sapidus, the Atlantic blue crab, caused a dramatic decline in oxygen uptake from 4.53 to 2.56 micromol g-1 h-1. This decline in oxygen uptake is associated with a large decrease in postbranchial PO2, from 16.2 (+/-0.46 SEM, n=7) to 13.1 kPa (+/-0.77 SEM, n=9), while prebranchial PO2 remains unchanged. In addition, injection of Vibrio results in the disappearance of a pH change across the gills, an indication of reduced CO2 excretion. The hemolymph hydrostatic pressure change across the gill circulation increases nearly 2-fold in Vibrio-injected crabs compared with a negligible change in pressure across the gill circulation in saline-injected, control crabs. This change, in combination with stability of heart rate and branchial chamber pressure, is indicative of a significant increase in vascular resistance across the gills that is induced by hemocyte nodule formation. A healthy, active blue crab can eliminate most invading bacteria, but the respiratory function of the gills is impaired. Thus, when blue crabs are engaged in the immune response, they are less equipped to engage in oxygen-fueled activities such as predator avoidance, prey capture, and migration. Furthermore, crabs are less fit to invade environments that are hypoxic.

  8. Adaptive evolution of defense ability leads to diversification of prey species.

    PubMed

    Zu, Jian; Wang, Jinliang; Du, Jianqiang

    2014-06-01

    In this paper, by using the adaptive dynamics approach, we investigate how the adaptive evolution of defense ability promotes the diversity of prey species in an initial one-prey-two-predator community. We assume that the prey species can evolve to a safer strategy such that it can reduce the predation risk, but a prey with a high defense ability for one predator may have a low defense ability for the other and vice versa. First, by using the method of critical function analysis, we find that if the trade-off is convex in the vicinity of the evolutionarily singular strategy, then this singular strategy is a continuously stable strategy. However, if the trade-off is weakly concave near the singular strategy and the competition between the two predators is relatively weak, then the singular strategy may be an evolutionary branching point. Second, we find that after the branching has occurred in the prey strategy, if the trade-off curve is globally concave, then the prey species might eventually evolve into two specialists, each caught by only one predator species. However, if the trade-off curve is convex-concave-convex, the prey species might eventually branch into two partial specialists, each being caught by both of the two predators and they can stably coexist on the much longer evolutionary timescale.

  9. The innate and adaptive immune response to avian influenza virus infections and vaccines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Protective immunity against viruses is mediated by the early innate immune responses and later on by the adaptive immune responses. The early innate immunity is designed to contain and limit virus replication in the host, primarily through cytokine and interferon production. Most all cells are cap...

  10. The role of the adaptive immune system in regulation of gut microbiota.

    PubMed

    Kato, Lucia M; Kawamoto, Shimpei; Maruya, Mikako; Fagarasan, Sidonia

    2014-07-01

    The gut nourishes rich bacterial communities that affect profoundly the functions of the immune system. The relationship between gut microbiota and the immune system is one of reciprocity. The microbiota contributes to nutrient processing and the development, maturation, and function of the immune system. Conversely, the immune system, particularly the adaptive immune system, plays a key role in shaping the repertoire of gut microbiota. The fitness of host immune system is reflected in the gut microbiota, and deficiencies in either innate or adaptive immunity impact on diversity and structures of bacterial communities in the gut. Here, we discuss the mechanisms that underlie this reciprocity and emphasize how the adaptive immune system via immunoglobulins (i.e. IgA) contributes to diversification and balance of gut microbiota required for immune homeostasis.

  11. Th17 cells at the cross roads of innate and adaptive immunity against infectious diseases at the mucosa

    PubMed Central

    Khader, Shabaana A.; Gaffen, Sarah L.; Kolls, Jay K.

    2010-01-01

    T helper type 17 (Th17) cells are a distinct lineage of T cells that produce the effector molecules IL-17, IL-17F, IL-21 and IL-22. Although the role of Th17 cells in autoimmunity is well documented, there is growing evidence that the Th17 lineage and other IL-17 producing cells are critical for host defense against bacterial, fungal and viral infections at mucosal surfaces. Here we summarize recent progress in our understanding of the function of IL-17 producing cells as a bridge between innate and adaptive immunity against infectious diseases at the mucosa. PMID:19587639

  12. Mast cells in allergy and autoimmunity: implications for adaptive immunity.

    PubMed

    Gregory, Gregory D; Brown, Melissa A

    2006-01-01

    As in the fashion industry, trends in a particular area of scientific investigation often are fleeting but then return with renewed and enthusiastic interest. Studies of mast cell biology are good examples of this. Although dogma once relegated mast cells almost exclusively to roles in pathological inflammation associated with allergic disease, these cells are emerging as important players in a number of other physiological processes. Consequently, they are quickly becoming the newest "trendy" cell, both within and outside the field of immunology. As sources of a large array of pro- and anti-inflammatory mediators, mast cells also express cell surface molecules with defined functions in lymphocyte activation and trafficking. Here, we provide an overview of the traditional and newly appreciated contributions of mast cells to both innate and adaptive immune responses.

  13. An inflammatory CC chemokine of Cynoglossus semilaevis is involved in immune defense against bacterial infection.

    PubMed

    Li, Yong-xin; Sun, Jin-sheng; Sun, Li

    2011-09-01

    Chemokines are a family of small cytokines that regulate leukocyte migration. Based on the arrangement of the first two cysteine residues, chemokines are classified into four groups called CXC(α), CC(β), C, and CX(3)C. In this study, we identified a CC chemokine, CsCCK1, from half-smooth tongue sole (Cynoglossus semilaevis) and analyzed its biological activity. The deduced amino acid sequence of CsCCK1 contains 111 amino acid residues and is phylogenetically belonging to the CCL19/21/25 group of CC chemokines. CsCCK1 possesses a DCCL motif that is highly conserved among CC chemokines. Quantitative real time RT-PCR analysis showed that the expression of CsCCK1 was relatively abundant in immune organs under normal physiological conditions and was upregulated by experimental infection of a bacterial pathogen. Purified recombinant CsCCK1 (rCsCCK1) induced chemotaxis in peripheral blood leukocytes (PBL) of both tongue sole and turbot (Scophthalmus maximus) in a dose-dependent manner. Mutation of the CC residues in the DCCL motif by serine substitution completely abolished the biological activity of rCsCCK1. When rCsCCK1, but not the mutant protein, was added to the cell culture of PBL, it enhanced cellular resistance against intracellular bacterial infection. Taken together, these results indicate that CsCCK1 is a functional CC chemokine whose biological activity depends on the DCCL motif and that CsCCK1 plays a role in host immune defense against bacterial infection.

  14. GATA-3 function in innate and adaptive immunity.

    PubMed

    Tindemans, Irma; Serafini, Nicolas; Di Santo, James P; Hendriks, Rudi W

    2014-08-21

    The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor.

  15. Dynamics of adaptive immunity against phage in bacterial populations

    NASA Astrophysics Data System (ADS)

    Bradde, Serena; Vucelja, Marija; Tesileanu, Tiberiu; Balasubramanian, Vijay

    The CRISPR (clustered regularly interspaced short palindromic repeats) mechanism allows bacteria to adaptively defend against phages by acquiring short genomic sequences (spacers) that target specific sequences in the viral genome. We propose a population dynamical model where immunity can be both acquired and lost. The model predicts regimes where bacterial and phage populations can co-exist, others where the populations oscillate, and still others where one population is driven to extinction. Our model considers two key parameters: (1) ease of acquisition and (2) spacer effectiveness in conferring immunity. Analytical calculations and numerical simulations show that if spacers differ mainly in ease of acquisition, or if the probability of acquiring them is sufficiently high, bacteria develop a diverse population of spacers. On the other hand, if spacers differ mainly in their effectiveness, their final distribution will be highly peaked, akin to a ``winner-take-all'' scenario, leading to a specialized spacer distribution. Bacteria can interpolate between these limiting behaviors by actively tuning their overall acquisition rate.

  16. Adaptive Immunity Restricts Replication of Novel Murine Astroviruses

    PubMed Central

    Yokoyama, Christine C.; Loh, Joy; Zhao, Guoyan; Stappenbeck, Thaddeus S.; Wang, David; Huang, Henry V.

    2012-01-01

    The mechanisms of astrovirus pathogenesis are largely unknown, in part due to a lack of a small-animal model of disease. Using shotgun sequencing and a custom analysis pipeline, we identified two novel astroviruses capable of infecting research mice, murine astrovirus (MuAstV) STL1 and STL2. Subsequent analysis revealed the presence of at least two additional viruses (MuAstV STL3 and STL4), suggestive of a diverse population of murine astroviruses in research mice. Complete genomic characterization and subsequent phylogenetic analysis showed that MuAstV STL1 to STL4 are members of the mamastrovirus genus and are likely members of a new mamastrovirus genogroup. Using Rag1−/− mice deficient in B and T cells, we demonstrate that adaptive immunity is required to control MuAstV infection. Furthermore, using Stat1−/− mice deficient in innate signaling, we demonstrate a role for the innate immune response in the control of MuAstV replication. Our results demonstrate that MuAstV STL permits the study of the mechanisms of astrovirus infection and host-pathogen interactions in a genetically manipulable small-animal model. Finally, we detected MuAstV in commercially available mice, suggesting that these viruses may be present in academic and commercial research mouse facilities, with possible implications for interpretation of data generated in current mouse models of disease. PMID:22951832

  17. Adapting to Health Impacts of Climate Change in the Department of Defense.

    PubMed

    Chrétien, Jean-Paul

    2016-01-01

    The Department of Defense (DoD) recognizes climate change as a threat to its mission and recently issued policy to implement climate change adaptation measures. However, the DoD has not conducted a comprehensive assessment of health-related climate change effects. To catalyze the needed assessment--a first step toward a comprehensive DoD climate change adaptation plan for health--this article discusses the DoD relevance of 3 selected climate change impacts: heat injuries, vector-borne diseases, and extreme weather that could lead to natural disasters. The author uses these examples to propose a comprehensive approach to planning for health-related climate change impacts in the DoD. PMID:27081888

  18. The full-of-bacteria gene is required for phagosome maturation during immune defense in Drosophila

    PubMed Central

    Akbar, Mohammed Ali; Tracy, Charles; Kahr, Walter H.A.

    2011-01-01

    Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a fatal recessive disorder caused by mutations in the VPS33B or VPS16B genes. Both encode homologues of the Vps33p and Vps16p subunits of the HOPS complex necessary for fusions of vacuoles in yeast. Here, we describe a mutation in the full-of-bacteria (fob) gene, which encodes Drosophila Vps16B. Flies null for fob are homozygous viable and fertile. They exhibit, however, a defect in their immune defense that renders them hypersensitive to infections with nonpathogenic bacteria. fob hemocytes (fly macrophages) engulf bacteria but fail to digest them. Phagosomes undergo early steps of maturation and transition to a Rab7-positive stage, but do not mature to fully acidified phagolysosomes. This reflects a specific requirement of fob in the fusion of phagosomes with late endosomes/lysosomes. In contrast, cargo of autophagosomes as well as endosomes exhibit normal lysosomal delivery in fob cells. These findings suggest that defects in phagosome maturation may contribute to symptoms of ARC patients including recurring infections. PMID:21282466

  19. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin.

    PubMed

    Harder, Jurgen; Schroder, Jens-Michael

    2002-11-29

    We analyzed healthy human skin for the presence of endogenous antimicrobial proteins that might explain the unusually high resistance of human skin against infections. A novel 14.5-kDa antimicrobial ribonuclease, termed RNase 7, was isolated from skin-derived stratum corneum. RNase 7 exhibited potent ribonuclease activity and thus may contribute to the well known ribonuclease activity of human skin. RNase 7 revealed broad spectrum antimicrobial activity against many pathogenic microorganisms and remarkably potent activity (lethal dose of 90% < 30 nm) against a vancomycin-resistant Enterococcus faecium. Molecular cloning from skin-derived primary keratinocytes and purification of RNase 7 from supernatants of cultured primary keratinocytes indicate that keratinocytes represent the major cellular source in skin and that RNase 7 is secreted. RNase 7 mRNA expression was detected in various epithelial tissues including skin, respiratory tract, genitourinary tract, and at a low level, in the gut. In addition to a constitutive expression, RNase 7 mRNA was induced in cultured primary keratinocytes by interleukin-1beta, interferon-gamma, and bacterial challenge. This is the first report demonstrating RNases as a novel class of epithelial inducible antimicrobial proteins, which may play an important role in the innate immune defense system of human epithelia.

  20. Attenuated innate immune defenses in very premature neonates during the neonatal period

    PubMed Central

    Marchant, Elizabeth A.; Kan, Bernard; Sharma, Ashish A.; van Zanten, Alice; Kollmann, Tobias R.; Brant, Rollin; Lavoie, Pascal M.

    2016-01-01

    Background Anti-microbial responses have been shown to be profoundly attenuated in very preterm neonates when examined on cord blood. However, we lack data on these responses at the time these neonates are most vulnerable to infections. Methods Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: LPS (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 weeks of gestation (n=50) during the first 28 days of age using whole blood and single-cell multi-parameter flow cytometry assays. Results were compared to term neonates (n=30) and adult controls (n=25). Results In preterm neonates, LPS and R848 responses remained attenuated in both cord blood and in the first 28 days of age. These responses showed significant maturation over time after adjusting for gestational age and were confirmed in blood monocytes and dendritic cells on a per-cell basis. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode of delivery to the maturation of cytokine responses. Conclusion Innate immune anti-microbial defenses are profoundly attenuated developmentally in very preterm neonates during the neonatal period, suggesting that exogenous factors drive the sustained systemic inflammation that has been linked to increased morbidities in these infants. PMID:26186294

  1. Molecular properties and immune defense of two ferritin subunits from freshwater pearl mussel, Hyriopsis schlegelii.

    PubMed

    He, Shuhao; Peng, Kou; Hong, Yijiang; Wang, Junhua; Sheng, Junqing; Gu, Qing

    2013-03-01

    Ferritin is a conserved iron-binding protein involved in cellular iron metabolism and host defense. In the present study, two distinct cDNAs for ferritins in the freshwater pearl mussel Hyriopsis schlegelii were identified (designated as HsFer-1 and HsFer-2) by SMART RACE approach and expressed sequence tag (EST) analysis. The full-length cDNAs of HsFer-1 and HsFer-2 were of 760 and 877 bp, respectively. Both of the two cDNAs contained an open reading frame (ORF) of 522 bp encoding for 174 amino acid residues. Sequence characterization and homology alignment indicated that HsFer-1 and HsFer-2 had higher similarity to H-type subunit of vertebrate ferritins than L-type subunit. Analysis of the HsFer-1 and HsFer-2 untranslated regions (UTR) showed that both of them had an iron response element (IRE) in the 5'-UTR, which was considered to be the binding site for iron regulatory protein (IRP). Quantitative real-time PCR (qPCR) assays were employed to examine the mRNA expression profiles. Under normal physiological conditions, the expression level of both HsFer-1 and HsFer-2 mRNA were the highest in hepatopancreas, moderate in gonad, axe foot, intestine, kidney, heart, gill, adductor muscle and mantle, the lowest in hemocytes. After stimulation with bacteria Aeromonas hydrophila, HsFer-1 mRNA experienced a different degree of increase in the tissues of hepatopancreas, gonad and hemocytes, the peak level was 2.47-fold, 9.59-fold and 1.37-fold, respectively. Comparatively, HsFer-2 showed up-regulation in gonad but down-regulation in hepatopancreas and hemocytes. Varying expression patterns indicate that two types of ferritins in H. schlegelii might play different roles in response to bacterial challenge. Further bacteriostatic analysis showed that both the purified recombinant ferritins inhibited the growth of A. hydrophila to a certain degree. Collectively, our results suggest that HsFer-1 and HsFer-2 are likely to be functional proteins involved in immune defense

  2. Stimulatory effects of chitinase on growth and immune defense of orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Yanhong; Feng, Shaozhen; Chen, Jun; Qin, Chaobin; Lin, Haoran; Li, Wensheng

    2012-05-01

    Chitinase, belonging to either family 18 or family 19 of the glycosylhydrolases, hydrolyze chitin into oligosaccharides. In the present study, the cDNA fragment encoding orange-spotted grouper (Epinephelus coioides) chitinase1 was subcloned into pPIC3.5K vector and expressed in Pichia pastoris GS115. The results showed that a band with the size of about 53 kDa could be detected by SDS-PAGE and Western blot. The recombinant protein of grouper chitinase1 (rgChi1) was added into the fish diet containing shrimp shell chitin for feeding experiment lasting 8 weeks. The weight of orange-spotted grouper, fed with diets containing rgChi1 at 0, 5, 10 and 20 μg/g was calculated on the 2nd, 4th, 6th and 8th weeks, and difference in growth rates was first observed in the 6th week of the feeding period and it kept until the end of the feeding experiment. At the end of 8 weeks feeding trial, the percent weight gain (PWG), growth rate (GR) and specific growth rate (SGR) of fish fed with 10 and 20 μg rgChi1/g feed were significantly higher compared to the control group. The neuropeptide Y (NPY), growth-hormone-releasing hormone (GHRH), growth-hormone (GH), interleukin-1beta (IL-1β), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD) (Cu/Zn) and SOD (Mn) mRNA expression of fish fed with diet containing 10 μg/g or/and 20 μg/g rgChi1 were obviously higher than the control group. The lysozyme (LZM) and total SOD activity of fish fed with diet containing rgChi1 at 10 and 20 μg/g were significantly higher than that of the control. The aspartate aminotransferase (AST)/glutamic oxalacetic transaminases (GOT) activity in 20 μg/g group decreased compared to the control group. These results indicated that the grouper chitinase1 was successfully produced using the P. pastoris expression system and the recombinant protein had obvious effects on growth and immune defense. The mRNA expression and protein secretion of grouper chitinase1 and chitinase2 were significantly stimulated in

  3. Stimulatory effects of chitinase on growth and immune defense of orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Yanhong; Feng, Shaozhen; Chen, Jun; Qin, Chaobin; Lin, Haoran; Li, Wensheng

    2012-05-01

    Chitinase, belonging to either family 18 or family 19 of the glycosylhydrolases, hydrolyze chitin into oligosaccharides. In the present study, the cDNA fragment encoding orange-spotted grouper (Epinephelus coioides) chitinase1 was subcloned into pPIC3.5K vector and expressed in Pichia pastoris GS115. The results showed that a band with the size of about 53 kDa could be detected by SDS-PAGE and Western blot. The recombinant protein of grouper chitinase1 (rgChi1) was added into the fish diet containing shrimp shell chitin for feeding experiment lasting 8 weeks. The weight of orange-spotted grouper, fed with diets containing rgChi1 at 0, 5, 10 and 20 μg/g was calculated on the 2nd, 4th, 6th and 8th weeks, and difference in growth rates was first observed in the 6th week of the feeding period and it kept until the end of the feeding experiment. At the end of 8 weeks feeding trial, the percent weight gain (PWG), growth rate (GR) and specific growth rate (SGR) of fish fed with 10 and 20 μg rgChi1/g feed were significantly higher compared to the control group. The neuropeptide Y (NPY), growth-hormone-releasing hormone (GHRH), growth-hormone (GH), interleukin-1beta (IL-1β), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD) (Cu/Zn) and SOD (Mn) mRNA expression of fish fed with diet containing 10 μg/g or/and 20 μg/g rgChi1 were obviously higher than the control group. The lysozyme (LZM) and total SOD activity of fish fed with diet containing rgChi1 at 10 and 20 μg/g were significantly higher than that of the control. The aspartate aminotransferase (AST)/glutamic oxalacetic transaminases (GOT) activity in 20 μg/g group decreased compared to the control group. These results indicated that the grouper chitinase1 was successfully produced using the P. pastoris expression system and the recombinant protein had obvious effects on growth and immune defense. The mRNA expression and protein secretion of grouper chitinase1 and chitinase2 were significantly stimulated in

  4. Adaptive immunity increases the pace and predictability of evolutionary change in commensal gut bacteria

    PubMed Central

    Barroso-Batista, João; Demengeot, Jocelyne; Gordo, Isabel

    2015-01-01

    Co-evolution between the mammalian immune system and the gut microbiota is believed to have shaped the microbiota's astonishing diversity. Here we test the corollary hypothesis that the adaptive immune system, directly or indirectly, influences the evolution of commensal species. We compare the evolution of Escherichia coli upon colonization of the gut of wild-type and Rag2−/− mice, which lack lymphocytes. We show that bacterial adaptation is slower in immune-compromised animals, a phenomenon explained by differences in the action of natural selection within each host. Emerging mutations exhibit strong beneficial effects in healthy hosts but substantial antagonistic pleiotropy in immune-deficient mice. This feature is due to changes in the composition of the gut microbiota, which differs according to the immune status of the host. Our results indicate that the adaptive immune system influences the tempo and predictability of E. coli adaptation to the mouse gut. PMID:26615893

  5. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense.

    PubMed

    Garaude, Johan; Acín-Pérez, Rebeca; Martínez-Cano, Sarai; Enamorado, Michel; Ugolini, Matteo; Nistal-Villán, Estanislao; Hervás-Stubbs, Sandra; Pelegrín, Pablo; Sander, Leif E; Enríquez, José A; Sancho, David

    2016-09-01

    Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.

  6. Toll-like receptors are part of the innate immune defense system of sponges (demospongiae: Porifera).

    PubMed

    Wiens, Matthias; Korzhev, Michael; Perovic-Ottstadt, Sanja; Luthringer, Bérengère; Brandt, David; Klein, Stefanie; Müller, Werner E G

    2007-03-01

    During evolution and with the emergence of multicellular animals, the need arose to ward off foreign organisms that threaten the integrity of the animal body. Among many different receptors that participate in the recognition of microbial invaders, toll-like receptors (TLRs) play an essential role in mediating the innate immune response. After binding distinct microbial components, TLRs activate intracellular signaling cascades that result in an induced expression of diverse antimicrobial molecules. Because sponges (phylum Porifera) are filter feeders, they are abundantly exposed to microorganisms that represent a potential threat. Here, we describe the identification, cloning, and deduced protein sequence from 3 major elements of the poriferan innate response (to bacterial lipopeptides): the TLR, the IL-1 receptor-associated kinase-4-like protein (IRAK-4l), and a novel effector caspase from the demosponge Suberites domuncula. Each molecule shares significant sequence similarity with its homologues in higher Metazoa. Sequence homologies were found in particular within the family-specific domains toll/interleukin-1 receptor/resistance (TLR family), Ser/Thr/Tyr kinase domain (IRAK family), and CASc (caspase family). In addition, in situ hybridization and immunohistological analyses revealed an abundance of SDTLR (TLR) transcripts in epithelial layers of the sponge surface (exopinacoderm and endopinacoderm). Furthermore, it is shown that both SDTLR and SDIRAK-4 like (IRAK) are expressed constitutively, regardless of treatment with synthetic triacyl lipopeptide Pam(3)Cys-Ser-(Lys)(4). In contrast, SDCASL (caspase) expression is highly Pam(3)Cys-Ser-(Lys)(4) inducible. However, blocking of the lipopeptide with recombinant TLR prior to its application completely prevented the induced expression of this poriferan caspase. These results underscore that the phylogenetically oldest extant metazoan phylum is provided already with the signaling pathways of the antimicrobial

  7. Interplay between innate and adaptive immunity in the development of non infectious uveitis

    PubMed Central

    Willermain, François; Rosenbaum, James T; Bodaghi, Bahram; Rosenzweig, Holly L; Childers, Sarah; Behrend, Travis; Wildner, Gerhild; Dick, Andrew D

    2012-01-01

    In vertebrates, the innate and adaptive immune systems have evolved seamlessly to protect the host by rapidly responding to danger signals, eliminating pathogens and creating immunological memory as well as immunological tolerance to self. The innate immune system harnesses receptors that recognize conserved pathogen patterns and alongside the more specific recognition systems and memory of adaptive immunity, their interplay is evidenced by respective roles during generation and regulation of immune responses. The hallmark of adaptive immunity which requires engagement of innate immunity is an ability to discriminate between self and non-self (and eventually between pathogen and symbiont) as well as peripheral control mechanisms maintaining immunological health and appropriate responses. Loss of control mechanisms and/or regulation of either the adaptive or the innate immune system lead to autoimmunity and autoinflammation respectively. Although autoimmune pathways have been largely studied to date in the context of development of non-infectious intraocular inflammation, the recruitment and activation of innate immunity is required for full expression of the varied phenotypes of non-infectious uveitis. Since autoimmunity and autoinflammation implicate different molecular pathways, even though some convergence occurs, increasing our understanding of their respective roles in the development of uveitis will highlight treatment targets and influence our understanding of immune mechanisms operative in other retinal diseases. Herein, we extrapolate from the basic mechanisms of activation and control of innate and adaptive immunity to how autoinflammatory and autoimmune pathways contribute to disease development in non-infectious uveitis patients. PMID:22120610

  8. Foreign DNA capture during CRISPR–Cas adaptive immunity

    PubMed Central

    Nuñez, James K.; Harrington, Lucas B.; Kranzusch, Philip J.; Engelman, Alan N.; Doudna, Jennifer A.

    2015-01-01

    Bacteria and archaea generate adaptive immunity against phages and plasmids by integrating foreign DNA of specific 30–40 base pair (bp) lengths into clustered regularly interspaced short palindromic repeats (CRISPR) loci as spacer segments1–6. The universally conserved Cas1–Cas2 integrase complex catalyzes spacer acquisition using a direct nucleophilic integration mechanism similar to retroviral integrases and transposases7–13. How the Cas1–Cas2 complex selects foreign DNA substrates for integration remains unknown. Here we present X-ray crystal structures of the Escherichia coli Cas1–Cas2 complex bound to cognate 33 nucleotide (nt) protospacer DNA substrates. The protein complex creates a curved binding surface spanning the length of the DNA and splays the ends of the protospacer to allow each terminal nucleophilic 3′–OH to enter a channel leading into the Cas1 active sites. Phosphodiester backbone interactions between the protospacer and the proteins explain the sequence-nonspecific substrate selection observed in vivo2–4. Our results uncover the structural basis for foreign DNA capture and the mechanism by which Cas1–Cas2 functions as a molecular ruler to dictate the sequence architecture of CRISPR loci. PMID:26503043

  9. Foreign DNA capture during CRISPR-Cas adaptive immunity.

    PubMed

    Nuñez, James K; Harrington, Lucas B; Kranzusch, Philip J; Engelman, Alan N; Doudna, Jennifer A

    2015-11-26

    Bacteria and archaea generate adaptive immunity against phages and plasmids by integrating foreign DNA of specific 30-40-base-pair lengths into clustered regularly interspaced short palindromic repeat (CRISPR) loci as spacer segments. The universally conserved Cas1-Cas2 integrase complex catalyses spacer acquisition using a direct nucleophilic integration mechanism similar to retroviral integrases and transposases. How the Cas1-Cas2 complex selects foreign DNA substrates for integration remains unknown. Here we present X-ray crystal structures of the Escherichia coli Cas1-Cas2 complex bound to cognate 33-nucleotide protospacer DNA substrates. The protein complex creates a curved binding surface spanning the length of the DNA and splays the ends of the protospacer to allow each terminal nucleophilic 3'-OH to enter a channel leading into the Cas1 active sites. Phosphodiester backbone interactions between the protospacer and the proteins explain the sequence-nonspecific substrate selection observed in vivo. Our results uncover the structural basis for foreign DNA capture and the mechanism by which Cas1-Cas2 functions as a molecular ruler to dictate the sequence architecture of CRISPR loci.

  10. Adaptive evolution of threonine deaminase in plant defense against insect herbivores

    SciTech Connect

    Gonzales-Vigil, Eliana; Bianchetti, Christopher M.; Phillips, Jr., George N.; Howe, Gregg A.

    2011-11-07

    Gene duplication is a major source of plant chemical diversity that mediates plant-herbivore interactions. There is little direct evidence, however, that novel chemical traits arising from gene duplication reduce herbivory. Higher plants use threonine deaminase (TD) to catalyze the dehydration of threonine (Thr) to {alpha}-ketobutyrate and ammonia as the committed step in the biosynthesis of isoleucine (Ile). Cultivated tomato and related Solanum species contain a duplicated TD paralog (TD2) that is coexpressed with a suite of genes involved in herbivore resistance. Analysis of TD2-deficient tomato lines showed that TD2 has a defensive function related to Thr catabolism in the gut of lepidopteran herbivores. During herbivory, the regulatory domain of TD2 is removed by proteolysis to generate a truncated protein (pTD2) that efficiently degrades Thr without being inhibited by Ile. We show that this proteolytic activation step occurs in the gut of lepidopteran but not coleopteran herbivores, and is catalyzed by a chymotrypsin-like protease of insect origin. Analysis of purified recombinant enzymes showed that TD2 is remarkably more resistant to proteolysis and high temperature than the ancestral TD1 isoform. The crystal structure of pTD2 provided evidence that electrostatic interactions constitute a stabilizing feature associated with adaptation of TD2 to the extreme environment of the lepidopteran gut. These findings demonstrate a role for gene duplication in the evolution of a plant defense that targets and co-opts herbivore digestive physiology.

  11. Modulation of host immune defenses by Aeromonas and Yersinia species: convergence on toxins secreted by various secretion systems

    PubMed Central

    Rosenzweig, Jason A.; Chopra, Ashok K.

    2013-01-01

    Like other pathogenic bacteria, Yersinia and Aeromonas species have been continuously co-evolving with their respective hosts. Although the former is a bonafide human pathogen, the latter has gained notararity as an emerging disease-causing agent. In response to immune cell challenges, bacterial pathogens have developed diverse mechanism(s) enabling their survival, and, at times, dominance over various host immune defense systems. The bacterial type three secretion system (T3SS) is evolutionarily derived from flagellar subunits and serves as a vehicle by which microbes can directly inject/translocate anti-host factors/effector proteins into targeted host immune cells. A large number of Gram-negative bacterial pathogens possess a T3SS empowering them to disrupt host cell signaling, actin cytoskeleton re-arrangements, and even to induce host-cell apoptotic and pyroptotic pathways. All pathogenic yersiniae and most Aeromonas species possess a T3SS, but they also possess T2- and T6-secreted toxins/effector proteins. This review will focus on the mechanisms by which the T3SS effectors Yersinia outer membrane protein J (YopJ) and an Aeromonas hydrophila AexU protein, isolated from the diarrheal isolate SSU, mollify host immune system defenses. Additionally, the mechanisms that are associated with host cell apoptosis/pyroptosis by Aeromonas T2SS secreted Act, a cytotoxic enterotoxin, and Hemolysin co-regulated protein (Hcp), an A. hydrophila T6SS effector, will also be discussed. PMID:24199174

  12. Selection for increased mass-independent maximal metabolic rate suppresses innate but not adaptive immune function

    PubMed Central

    Downs, Cynthia J.; Brown, Jessi L.; Wone, Bernard; Donovan, Edward R.; Hunter, Kenneth; Hayes, Jack P.

    2013-01-01

    Both appropriate metabolic rates and sufficient immune function are essential for survival. Consequently, eco-immunologists have hypothesized that animals may experience trade-offs between metabolic rates and immune function. Previous work has focused on how basal metabolic rate (BMR) may trade-off with immune function, but maximal metabolic rate (MMR), the upper limit to aerobic activity, might also trade-off with immune function. We used mice artificially selected for high mass-independent MMR to test for trade-offs with immune function. We assessed (i) innate immune function by quantifying cytokine production in response to injection with lipopolysaccharide and (ii) adaptive immune function by measuring antibody production in response to injection with keyhole limpet haemocyanin. Selection for high mass-independent MMR suppressed innate immune function, but not adaptive immune function. However, analyses at the individual level also indicate a negative correlation between MMR and adaptive immune function. By contrast BMR did not affect immune function. Evolutionarily, natural selection may favour increasing MMR to enhance aerobic performance and endurance, but the benefits of high MMR may be offset by impaired immune function. This result could be important in understanding the selective factors acting on the evolution of metabolic rates. PMID:23303541

  13. The Role of Innate Immunity in Osteoarthritis: When Our First Line of Defense Goes on the Offensive

    PubMed Central

    Orlowsky, Eric W.; Kraus, Virginia Byers

    2015-01-01

    Although mankind has been suffering from osteoarthritis (OA) dating to the dawn of humankind, its pathogenesis remains poorly understood. OA is no longer considered a “wear and tear” condition but rather one driven by proteases where chronic low-grade inflammation may play a role in perpetuating proteolytic activity. While multiple factors are likely active in this process, recent evidence has implicated the importance of the innate immune system, the older or more primitive part of our body’s immune defense mechanisms. The role of some of the components of the innate immune system have been tested in OA models in vivo including the role of synovial macrophages and the complement system. This review is a selective overview of a large and evolving field. Insights into these mechanisms might inform our ability to phenotype patient subsets and give hope for the advent of novel OA therapies. PMID:25593231

  14. Interactions of innate and adaptive immunity in brain development and function

    PubMed Central

    Filiano, Anthony J.; Gadani, Sachin P.; Kipnis, Jonathan

    2014-01-01

    It has been known for decades that the immune system has a tremendous impact on behavior. Most work has described the negative role of immune cells on the central nervous system. However, we and others have demonstrated over the last decade that a well-regulated immune system is needed for proper brain function. Here we discuss several neuro-immune interactions, using examples from brain homeostasis and disease states. We will highlight our understanding of the consequences of malfunctioning immunity on neurodevelopment and will discuss the roles of the innate and adaptive immune system in neurodevelopment and how T cells maintain a proper innate immune balance in the brain surroundings and within its parenchyma. Also, we describe how immune imbalance impairs higher order brain functioning, possibly leading to behavioral and cognitive impairment. Lastly, we propose our hypothesis that some behavioral deficits in neurodevelopmental disorders, such as in autism spectrum disorder, are the consequence of malfunctioning immunity. PMID:25110235

  15. The nuclear immune receptor RPS4 is required for RRS1SLH1-dependent constitutive defense activation in Arabidopsis thaliana.

    PubMed

    Sohn, Kee Hoon; Segonzac, Cécile; Rallapalli, Ghanasyam; Sarris, Panagiotis F; Woo, Joo Yong; Williams, Simon J; Newman, Toby E; Paek, Kyung Hee; Kobe, Bostjan; Jones, Jonathan D G

    2014-10-01

    Plant nucleotide-binding leucine-rich repeat (NB-LRR) disease resistance (R) proteins recognize specific "avirulent" pathogen effectors and activate immune responses. NB-LRR proteins structurally and functionally resemble mammalian Nod-like receptors (NLRs). How NB-LRR and NLR proteins activate defense is poorly understood. The divergently transcribed Arabidopsis R genes, RPS4 (resistance to Pseudomonas syringae 4) and RRS1 (resistance to Ralstonia solanacearum 1), function together to confer recognition of Pseudomonas AvrRps4 and Ralstonia PopP2. RRS1 is the only known recessive NB-LRR R gene and encodes a WRKY DNA binding domain, prompting suggestions that it acts downstream of RPS4 for transcriptional activation of defense genes. We define here the early RRS1-dependent transcriptional changes upon delivery of PopP2 via Pseudomonas type III secretion. The Arabidopsis slh1 (sensitive to low humidity 1) mutant encodes an RRS1 allele (RRS1SLH1) with a single amino acid (leucine) insertion in the WRKY DNA-binding domain. Its poor growth due to constitutive defense activation is rescued at higher temperature. Transcription profiling data indicate that RRS1SLH1-mediated defense activation overlaps substantially with AvrRps4- and PopP2-regulated responses. To better understand the genetic basis of RPS4/RRS1-dependent immunity, we performed a genetic screen to identify suppressor of slh1 immunity (sushi) mutants. We show that many sushi mutants carry mutations in RPS4, suggesting that RPS4 acts downstream or in a complex with RRS1. Interestingly, several mutations were identified in a domain C-terminal to the RPS4 LRR domain. Using an Agrobacterium-mediated transient assay system, we demonstrate that the P-loop motif of RPS4 but not of RRS1SLH1 is required for RRS1SLH1 function. We also recapitulate the dominant suppression of RRS1SLH1 defense activation by wild type RRS1 and show this suppression requires an intact RRS1 P-loop. These analyses of RRS1SLH1 shed new light

  16. Multi-user cognitive radio network resource allocation based on the adaptive niche immune genetic algorithm

    NASA Astrophysics Data System (ADS)

    Zu, Yun-Xiao; Zhou, Jie

    2012-01-01

    Multi-user cognitive radio network resource allocation based on the adaptive niche immune genetic algorithm is proposed, and a fitness function is provided. Simulations are conducted using the adaptive niche immune genetic algorithm, the simulated annealing algorithm, the quantum genetic algorithm and the simple genetic algorithm, respectively. The results show that the adaptive niche immune genetic algorithm performs better than the other three algorithms in terms of the multi-user cognitive radio network resource allocation, and has quick convergence speed and strong global searching capability, which effectively reduces the system power consumption and bit error rate.

  17. Adaptive immune response of Vγ2Vδ2 T cells: a new paradigm

    PubMed Central

    Chen, Zheng W.; Letvin, Norman L.

    2010-01-01

    The role of γδ T cells in adaptive immunity remains uncertain. Recent studies have demonstrated that a unique subset of γδ T cells in primates can mount adaptive immune responses during mycobacterial infections. This Review discusses notable similarities and differences in adaptive immune responses between non-peptide-specific γδ T cells and peptide-specific αβ T cells, and discusses both the molecular basis for γδ T-cell responses and potential functions of these enigmatic cells. PMID:12697454

  18. Coordinate actions of innate immune responses oppose those of the adaptive immune system during Salmonella infection of mice.

    PubMed

    Hotson, Andrew N; Gopinath, Smita; Nicolau, Monica; Khasanova, Anna; Finck, Rachel; Monack, Denise; Nolan, Garry P

    2016-01-12

    The immune system enacts a coordinated response when faced with complex environmental and pathogenic perturbations. We used the heterogeneous responses of mice to persistent Salmonella infection to model system-wide coordination of the immune response to bacterial burden. We hypothesized that the variability in outcomes of bacterial growth and immune response across genetically identical mice could be used to identify immune elements that serve as integrators enabling co-regulation and interconnectedness of the innate and adaptive immune systems. Correlation analysis of immune response variation to Salmonella infection linked bacterial load with at least four discrete, interacting functional immune response "cassettes." One of these, the innate cassette, in the chronically infected mice included features of the innate immune system, systemic neutrophilia, and high serum concentrations of the proinflammatory cytokine interleukin-6. Compared with mice with a moderate bacterial load, mice with the highest bacterial burden exhibited high activity of this innate cassette, which was associated with a dampened activity of the adaptive T cell cassette-with fewer plasma cells and CD4(+) T helper 1 cells and increased numbers of regulatory T cells-and with a dampened activity of the cytokine signaling cassette. System-wide manipulation of neutrophil numbers revealed that neutrophils regulated signal transducer and activator of transcription (STAT) signaling in B cells during infection. Thus, a network-level approach demonstrated unappreciated interconnections that balanced innate and adaptive immune responses during the dynamic course of disease and identified signals associated with pathogen transmission status, as well as a regulatory role for neutrophils in cytokine signaling.

  19. Evolutionary implication of B-1 lineage cells from innate to adaptive immunity.

    PubMed

    Zhu, Lv-yun; Shao, Tong; Nie, Li; Zhu, Ling-yun; Xiang, Li-xin; Shao, Jian-zhong

    2016-01-01

    The paradigm that B cells mainly play a central role in adaptive immunity may have to be reevaluated because B-1 lineage cells have been found to exhibit innate-like functions, such as phagocytic and bactericidal activities. Therefore, the evolutionary connection of B-1 lineage cells between innate and adaptive immunities have received much attention. In this review, we summarized various innate-like characteristics of B-1 lineage cells, such as natural antibody production, antigen-presenting function in primary adaptive immunity, and T cell-independent immune responses. These characteristics seem highly conserved between fish B cells and mammalian B-1 cells during vertebrate evolution. We proposed an evolutionary outline of B cells by comparing biological features, including morphology, phenotype, ontogeny, and functional activity between B-1 lineage cells and macrophages or B-2 cells. The B-1 lineage may be a transitional cell type between phagocytic cells (e.g., macrophages) and B-2 cells that functionally connects innate and adaptive immunities. Our discussion would contribute to the understanding on the origination of B cells specialized in adaptive immunity from innate immunity. The results might provide further insight into the evolution of the immune system as a whole.

  20. Chemical Tools To Monitor and Manipulate Adaptive Immune Responses.

    PubMed

    Doran, Todd M; Sarkar, Mohosin; Kodadek, Thomas

    2016-05-18

    Methods to monitor and manipulate the immune system are of enormous clinical interest. For example, the development of vaccines represents one of the earliest and greatest accomplishments of the biomedical research enterprise. More recently, drugs capable of "reawakening" the immune system to cancer have generated enormous excitement. But, much remains to be done. All drugs available today that manipulate the immune system cannot distinguish between "good" and "bad" immune responses and thus drive general and systemic immune suppression or activation. Indeed, with the notable exception of vaccines, our ability to monitor and manipulate antigen-specific immune responses is in its infancy. Achieving this finer level of control would be highly desirable. For example, it might allow the pharmacological editing of pathogenic immune responses without restricting the ability of the immune system to defend against infection. On the diagnostic side, a method to comprehensively monitor the circulating, antigen-specific antibody population could provide a treasure trove of clinically useful biomarkers, since many diseases expose the immune system to characteristic molecules that are deemed foreign and elicit the production of antibodies against them. This Perspective will discuss the state-of-the-art of this area with a focus on what we consider seminal opportunities for the chemistry community to contribute to this important field.

  1. Transcriptomic insight into the immune defenses in the ghost moth, Hepialus xiaojinensis, during an Ophiocordyceps sinensis fungal infection.

    PubMed

    Meng, Qian; Yu, Hai-Ying; Zhang, Huan; Zhu, Wei; Wang, Meng-Long; Zhang, Ji-Hong; Zhou, Gui-Ling; Li, Xuan; Qin, Qi-Lian; Hu, Song-Nian; Zou, Zhen

    2015-09-01

    Hepialus xiaojinensis is an economically important species of Lepidopteran insect. The fungus Ophiocordyceps sinensis can infect its larvae, which leads to mummification after 5-12 months, providing a valuable system with which to study interactions between the insect hosts and pathogenic fungi. However, little sequence information is available for this insect. A time-course analysis of the fat body transcriptome was performed to explore the host immune response to O. sinensis infection. In total, 50,164 unigenes were obtained by assembling the reads from two high-throughput approaches: 454 pyrosequencing and Illumina Hiseq2000. Hierarchical clustering and functional examination revealed four major gene clusters. Clusters 1-3 included transcripts markedly induced by the fungal infection within 72 h. Cluster 4, with a lower number of transcripts, was suppressed during the early phase of infection but returned to normal expression levels sometime before 1 year. Based on sequence similarity to orthologs known to participate in immune defenses, 258 candidate immunity-related transcripts were identified, and their functions were hypothesized. The genes were more primitive than those in other Lepidopteran insects. In addition, lineage-specific family expansion of the clip-domain serine proteases and C-type lectins were apparent and likely caused by selection pressures. Global expression profiles of immunity-related genes indicated that H. xiaojinensis was capable of a rapid response to an O. sinensis challenge; however, the larvae developed tolerance to the fungus after prolonged infection, probably due to immune suppression. Specifically, antimicrobial peptide mRNAs could not be detected after chronic infection, because key components of the Toll pathway (MyD88, Pelle and Cactus) were downregulated. Taken together, this study provides insights into the defense system of H. xiaojinensis, and a basis for understanding the molecular aspects of the interaction between the

  2. Production and Release of Antimicrobial and Immune Defense Proteins by Mammary Epithelial Cells following Streptococcus uberis Infection of Sheep

    PubMed Central

    Pisanu, Salvatore; Marogna, Gavino; Cubeddu, Tiziana; Pagnozzi, Daniela; Cacciotto, Carla; Campesi, Franca; Schianchi, Giuseppe; Rocca, Stefano

    2013-01-01

    Investigating the innate immune response mediators released in milk has manifold implications, spanning from elucidation of the role played by mammary epithelial cells (MECs) in fighting microbial infections to the discovery of novel diagnostic markers for monitoring udder health in dairy animals. Here, we investigated the mammary gland response following a two-step experimental infection of lactating sheep with the mastitis-associated bacterium Streptococcus uberis. The establishment of infection was confirmed both clinically and by molecular methods, including PCR and fluorescent in situ hybridization of mammary tissues. Proteomic investigation of the milk fat globule (MFG), a complex vesicle released by lactating MECs, enabled detection of enrichment of several proteins involved in inflammation, chemotaxis of immune cells, and antimicrobial defense, including cathelicidins and calprotectin (S100A8/S100A9), in infected animals, suggesting the consistent involvement of MECs in the innate immune response to pathogens. The ability of MECs to produce and release antimicrobial and immune defense proteins was then demonstrated by immunohistochemistry and confocal immunomicroscopy of cathelicidin and the calprotectin subunit S100A9 on mammary tissues. The time course of their release in milk was also assessed by Western immunoblotting along the course of the experimental infection, revealing the rapid increase of these proteins in the MFG fraction in response to the presence of bacteria. Our results support an active role of MECs in the innate immune response of the mammary gland and provide new potential for the development of novel and more sensitive tools for monitoring mastitis in dairy animals. PMID:23774600

  3. Immune response of mice to non-adapted avian influenza A virus.

    PubMed

    Stropkovská, A; Mikušková, T; Bobišová, Z; Košík, I; Mucha, V; Kostolanský, F; Varečková, E

    2015-12-01

    immune sera after the second dose of virus and a slight increase of mRNA expression of immune mediators tumor necrosis factor alpha (TNF-α) and IP10 has been observed in lungs of these mice 48 hr after the infection. These observations correspond to the limited replication ability of the virus in mice and provided an important information about its ability to induce virus-specific antibodies, including those neutralizing virus, even without the previous virus adaptation to the new mammalian host. Such antibodies could consequently influence the immune potential of exposed individuals and their defensive capability against the newly emerged, even more virulent IAV.

  4. Immune response of mice to non-adapted avian influenza A virus.

    PubMed

    Stropkovská, A; Mikušková, T; Bobišová, Z; Košík, I; Mucha, V; Kostolanský, F; Varečková, E

    2015-12-01

    immune sera after the second dose of virus and a slight increase of mRNA expression of immune mediators tumor necrosis factor alpha (TNF-α) and IP10 has been observed in lungs of these mice 48 hr after the infection. These observations correspond to the limited replication ability of the virus in mice and provided an important information about its ability to induce virus-specific antibodies, including those neutralizing virus, even without the previous virus adaptation to the new mammalian host. Such antibodies could consequently influence the immune potential of exposed individuals and their defensive capability against the newly emerged, even more virulent IAV. PMID:26666183

  5. Inter-organ defense networking: Leaf whitefly sucking elicits plant immunity to crown gall disease caused by Agrobacterium tumefaciens.

    PubMed

    Park, Yong-Soon; Ryu, Choong-Min

    2015-01-01

    Plants have elaborate defensive machinery to protect against numerous pathogens and insects. Plant hormones function as modulators of defensive mechanisms to maintain plant resistance to natural enemies. Our recent study suggests that salicylic acid (SA) is the primary phytohormone regulating plant responses to Agrobacterium tumefaciens infection. Tobacco (Nicotiana benthamiana Domin.) immune responses against Agrobacterium-mediated crown gall disease were activated by exposure to the sucking insect whitefly, which stimulated SA biosynthesis in aerial tissues; in turn, SA synthesized in aboveground tissues systemically modulated SA secretion in root tissues. Further investigation revealed that endogenous SA biosynthesis negatively modulated Agrobacterium-mediated plant genetic transformation. Our study provides novel evidence that activation of the SA-signaling pathway mediated by a sucking insect infestation has a pivotal role in subsequently attenuating Agrobacterium infection. These results demonstrate new insights into interspecies cross-talking among insects, plants, and soil bacteria. PMID:26357873

  6. Inter-organ defense networking: Leaf whitefly sucking elicits plant immunity to crown gall disease caused by Agrobacterium tumefaciens

    PubMed Central

    Park, Yong-Soon; Ryu, Choong-Min

    2015-01-01

    Plants have elaborate defensive machinery to protect against numerous pathogens and insects. Plant hormones function as modulators of defensive mechanisms to maintain plant resistance to natural enemies. Our recent study suggests that salicylic acid (SA) is the primary phytohormone regulating plant responses to Agrobacterium tumefaciens infection. Tobacco (Nicotiana benthamiana Domin.) immune responses against Agrobacterium-mediated crown gall disease were activated by exposure to the sucking insect whitefly, which stimulated SA biosynthesis in aerial tissues; in turn, SA synthesized in aboveground tissues systemically modulated SA secretion in root tissues. Further investigation revealed that endogenous SA biosynthesis negatively modulated Agrobacterium-mediated plant genetic transformation. Our study provides novel evidence that activation of the SA-signaling pathway mediated by a sucking insect infestation has a pivotal role in subsequently attenuating Agrobacterium infection. These results demonstrate new insights into interspecies cross-talking among insects, plants, and soil bacteria. PMID:26357873

  7. Highly Dynamic Exon Shuffling in Candidate Pathogen Receptors … What if Brown Algae Were Capable of Adaptive Immunity?

    PubMed Central

    Zambounis, Antonios; Elias, Marek; Sterck, Lieven; Maumus, Florian; Gachon, Claire M.M.

    2012-01-01

    Pathogen recognition is the first step of immune reactions. In animals and plants, direct or indirect pathogen recognition is often mediated by a wealth of fast-evolving receptors, many of which contain ligand-binding and signal transduction domains, such as leucine-rich or tetratricopeptide repeat (LRR/TPR) and NB-ARC domains, respectively. In order to identify candidates potentially involved in algal defense, we mined the genome of the brown alga Ectocarpus siliculosus for homologues of these genes and assessed the evolutionary pressures acting upon them. We thus annotated all Ectocarpus LRR-containing genes, in particular an original group of LRR-containing GTPases of the ROCO family, and 24 NB-ARC–TPR proteins. They exhibit high birth and death rates, while a diversifying selection is acting on their LRR (respectively TPR) domain, probably affecting the ligand-binding specificities. Remarkably, each repeat is encoded by an exon, and the intense exon shuffling underpins the variability of LRR and TPR domains. We conclude that the Ectocarpus ROCO and NB-ARC–TPR families are excellent candidates for being involved in recognition/transduction events linked to immunity. We further hypothesize that brown algae may generate their immune repertoire via controlled somatic recombination, so far only known from the vertebrate adaptive immune systems. PMID:22144640

  8. Tolerance of fungal infection in European water frogs exposed to Batrachochytrium dendrobatidis after experimental reduction of innate immune defenses

    PubMed Central

    2012-01-01

    Background While emerging diseases are affecting many populations of amphibians, some populations are resistant. Determining the relative contributions of factors influencing disease resistance is critical for effective conservation management. Innate immune defenses in amphibian skin are vital host factors against a number of emerging pathogens such as ranaviruses and the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). Adult water frogs from Switzerland (Pelophylax esculentus and P. lessonae) collected in the field with their natural microbiota intact were exposed to Bd after experimental reduction of microbiota, skin peptides, both, or neither to determine the relative contributions of these defenses. Results Naturally-acquired Bd infections were detected in 10/51 P. lessonae and 4/19 P. esculentus, but no disease outbreaks or population declines have been detected at this site. Thus, this population was immunologically primed, and disease resistant. No mortality occurred during the 64 day experiment. Forty percent of initially uninfected frogs became sub-clinically infected upon experimental exposure to Bd. Reduction of both skin peptide and microbiota immune defenses caused frogs to gain less mass when exposed to Bd than frogs in other treatments. Microbiota-reduced frogs increased peptide production upon Bd infection. Ranavirus was undetectable in all but two frogs that appeared healthy in the field, but died within a week under laboratory conditions. Virus was detectable in both toe-clips and internal organs. Conclusion Intact skin microbiota reduced immune activation and can minimize subclinical costs of infection. Tolerance of Bd or ranavirus infection may differ with ecological conditions. PMID:23088169

  9. Standard of hygiene and immune adaptation in newborn infants.

    PubMed

    Kallionpää, Henna; Laajala, Essi; Öling, Viveka; Härkönen, Taina; Tillmann, Vallo; Dorshakova, Natalya V; Ilonen, Jorma; Lähdesmäki, Harri; Knip, Mikael; Lahesmaa, Riitta

    2014-11-01

    The prevalence of immune-mediated diseases, such as allergies and type 1 diabetes, is on the rise in the developed world. In order to explore differences in the gene expression patterns induced in utero in infants born in contrasting standards of living and hygiene, we collected umbilical cord blood RNA samples from infants born in Finland (modern society), Estonia (rapidly developing society) and the Republic of Karelia, Russia (poor economic conditions). The whole blood transcriptome of Finnish and Estonian neonates differed from their Karelian counterparts, suggesting exposure to toll-like receptor (TLR) ligands and a more matured immune response in infants born in Karelia. These results further support the concept of a conspicuous plasticity in the developing immune system: the environmental factors that play a role in the susceptibility/protection towards immune-mediated diseases begin to shape the neonatal immunity already in utero and direct the maturation in accordance with the surrounding microbial milieu. PMID:25245264

  10. Saliva-Induced Clotting Captures Streptococci: Novel Roles for Coagulation and Fibrinolysis in Host Defense and Immune Evasion

    PubMed Central

    Mohanty, Tirthankar; Karlsson, Christofer; Mörgelin, Matthias; Frick, Inga-Maria; Malmström, Johan; Björck, Lars

    2016-01-01

    Streptococcal pharyngitis is among the most common bacterial infections, but the molecular mechanisms involved remain poorly understood. Here we investigate the interactions among three major players in streptococcal pharyngitis: streptococci, plasma, and saliva. We find that saliva activates the plasma coagulation system through both the extrinsic and the intrinsic pathways, entrapping the bacteria in fibrin clots. The bacteria escape the clots by activating host plasminogen. Our results identify a potential function for the intrinsic pathway of coagulation in host defense and a corresponding role for fibrinolysis in streptococcal immune evasion. PMID:27456827

  11. Saliva-Induced Clotting Captures Streptococci: Novel Roles for Coagulation and Fibrinolysis in Host Defense and Immune Evasion.

    PubMed

    Wollein Waldetoft, Kristofer; Mohanty, Tirthankar; Karlsson, Christofer; Mörgelin, Matthias; Frick, Inga-Maria; Malmström, Johan; Björck, Lars

    2016-10-01

    Streptococcal pharyngitis is among the most common bacterial infections, but the molecular mechanisms involved remain poorly understood. Here we investigate the interactions among three major players in streptococcal pharyngitis: streptococci, plasma, and saliva. We find that saliva activates the plasma coagulation system through both the extrinsic and the intrinsic pathways, entrapping the bacteria in fibrin clots. The bacteria escape the clots by activating host plasminogen. Our results identify a potential function for the intrinsic pathway of coagulation in host defense and a corresponding role for fibrinolysis in streptococcal immune evasion. PMID:27456827

  12. Isonitrosoacetophenone Drives Transcriptional Reprogramming in Nicotiana tabacum Cells in Support of Innate Immunity and Defense

    PubMed Central

    Djami-Tchatchou, Arnaud T.; Maake, Mmapula P.; Piater, Lizelle A.; Dubery, Ian A.

    2015-01-01

    Plants respond to various stress stimuli by activating broad-spectrum defense responses both locally as well as systemically. As such, identification of expressed genes represents an important step towards understanding inducible defense responses and assists in designing appropriate intervention strategies for disease management. Genes differentially expressed in tobacco cell suspensions following elicitation with isonitrosoacetophenone (INAP) were identified using mRNA differential display and pyro-sequencing. Sequencing data produced 14579 reads, which resulted in 198 contigs and 1758 singletons. Following BLAST analyses, several inducible plant defense genes of interest were identified and classified into functional categories including signal transduction, transcription activation, transcription and protein synthesis, protein degradation and ubiquitination, stress-responsive, defense-related, metabolism and energy, regulation, transportation, cytoskeleton and cell wall-related. Quantitative PCR was used to investigate the expression of 17 selected target genes within these categories. Results indicate that INAP has a sensitising or priming effect through activation of salicylic acid-, jasmonic acid- and ethylene pathways that result in an altered transcriptome, with the expression of genes involved in perception of pathogens and associated cellular re-programming in support of defense. Furthermore, infection assays with the pathogen Pseudomonas syringae pv. tabaci confirmed the establishment of a functional anti-microbial environment in planta. PMID:25658943

  13. T Cell Adaptive Immunity Proceeds through Environment-Induced Adaptation from the Exposure of Cryptic Genetic Variation

    PubMed Central

    Whitacre, James M.; Lin, Joseph; Harding, Angus

    2011-01-01

    Evolution is often characterized as a process involving incremental genetic changes that are slowly discovered and fixed in a population through genetic drift and selection. However, a growing body of evidence is finding that changes in the environment frequently induce adaptations that are much too rapid to occur by an incremental genetic search process. Rapid evolution is hypothesized to be facilitated by mutations present within the population that are silent or “cryptic” within the first environment but are co-opted or “exapted” to the new environment, providing a selective advantage once revealed. Although cryptic mutations have recently been shown to facilitate evolution in RNA enzymes, their role in the evolution of complex phenotypes has not been proven. In support of this wider role, this paper describes an unambiguous relationship between cryptic genetic variation and complex phenotypic responses within the immune system. By reviewing the biology of the adaptive immune system through the lens of evolution, we show that T cell adaptive immunity constitutes an exemplary model system where cryptic alleles drive rapid adaptation of complex traits. In naive T cells, normally cryptic differences in T cell receptor reveal diversity in activation responses when the cellular population is presented with a novel environment during infection. We summarize how the adaptive immune response presents a well studied and appropriate experimental system that can be used to confirm and expand upon theoretical evolutionary models describing how seemingly small and innocuous mutations can drive rapid cellular evolution. PMID:22363338

  14. Pseudechis australis venomics: adaptation for a defense against microbial pathogens and recruitment of body transferrin.

    PubMed

    Georgieva, Dessislava; Seifert, Jana; Öhler, Michaela; von Bergen, Martin; Spencer, Patrick; Arni, Raghuvir K; Genov, Nicolay; Betzel, Christian

    2011-05-01

    The venom composition of Pseudechis australis, a widely distributed in Australia reptile, was analyzed by 2-DE and mass spectrometric analysis. In total, 102 protein spots were identified as venom toxins. The gel is dominated by horizontal trains of spots with identical or very similar molecular masses but differing in the pI values. This suggests possible post-translational modifications of toxins, changing their electrostatic charge. The results demonstrate a highly specialized biosynthesis of toxins destroying the hemostasis (P-III metalloproteases, SVMPs), antimicrobial proteins (L-amino acid oxidases, LAAOs, and transferrin-like proteins, TFLPs), and myotoxins (phospholipase A(2)s, PLA(2)s). The three transferrin isoforms of the Australian P. australis (Elapidae snake) venom are highly homologous to the body transferrin of the African Lamprophis fuliginosus (Colubridae), an indication for the recruitment of body transferrin. The venomic composition suggests an adaptation for a defense against microbial pathogens from the prey. Transferrins have not previously been reported as components of elapid or other snake venoms. Ecto-5'-nucleotidases (5'-NTDs), nerve growth factors (VNGFs), and a serine proteinase inhibitor (SPI) were also identified. The venom composition and enzymatic activities explain the clinical manifestation of the king brown snakebite. The results can be used for medical, scientific, and biotechnological purposes. PMID:21417486

  15. Pseudechis australis venomics: adaptation for a defense against microbial pathogens and recruitment of body transferrin.

    PubMed

    Georgieva, Dessislava; Seifert, Jana; Öhler, Michaela; von Bergen, Martin; Spencer, Patrick; Arni, Raghuvir K; Genov, Nicolay; Betzel, Christian

    2011-05-01

    The venom composition of Pseudechis australis, a widely distributed in Australia reptile, was analyzed by 2-DE and mass spectrometric analysis. In total, 102 protein spots were identified as venom toxins. The gel is dominated by horizontal trains of spots with identical or very similar molecular masses but differing in the pI values. This suggests possible post-translational modifications of toxins, changing their electrostatic charge. The results demonstrate a highly specialized biosynthesis of toxins destroying the hemostasis (P-III metalloproteases, SVMPs), antimicrobial proteins (L-amino acid oxidases, LAAOs, and transferrin-like proteins, TFLPs), and myotoxins (phospholipase A(2)s, PLA(2)s). The three transferrin isoforms of the Australian P. australis (Elapidae snake) venom are highly homologous to the body transferrin of the African Lamprophis fuliginosus (Colubridae), an indication for the recruitment of body transferrin. The venomic composition suggests an adaptation for a defense against microbial pathogens from the prey. Transferrins have not previously been reported as components of elapid or other snake venoms. Ecto-5'-nucleotidases (5'-NTDs), nerve growth factors (VNGFs), and a serine proteinase inhibitor (SPI) were also identified. The venom composition and enzymatic activities explain the clinical manifestation of the king brown snakebite. The results can be used for medical, scientific, and biotechnological purposes.

  16. Biochemical defense strategies in sterilized seedlings of Nymphoides peltatum adapted to lead stress.

    PubMed

    Qiao, Xuqiang; Shi, Guoxin; Yang, Xiaoke; Zheng, Zhenzhen; Xu, Xiaoying; Yang, Haiyan

    2014-01-01

    In order to study potential antioxidant defense mechanisms, the effects of increasing concentrations of lead (Pb) on polyamines (PAs), various thiols, vitamins C and E, and proline contents in sterilized seedlings of Nymphoides peltata (S.G. mel.) Kuntze were investigated after 5 days of exposure. The levels of total putrescine (Put), spermidine (Spd), and spermine (Spm) decreased significantly, while the ratio of (Spd + Spm)/Put first increased but then declined as the concentration of Pb increased. The trends for free, perchloric acid soluble-conjugated (PS-conjugated), and perchloric acid insoluble-bound (PIS-bound) PAs were similar to the trend seen for total PAs. Moreover, reduced glutathione (GSH), nonprotein thiols (NP-SH), phytochelatins (PCs), and vitamin C were induced at high Pb concentrations. No significant change was observed in vitamin E. An initial decline in proline content was followed by an increase as the Pb concentration rose. The reduced level of Put and elevated contents of GSH, NP-SH, PCs, vitamin C, and proline were found to be associated with antioxidant efficiency, which supports the hypothesis that they could play a significant role in the adaptation mechanisms of N. peltatum under Pb stress.

  17. Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus ▿

    PubMed Central

    Miao, Hongyu; Hollenbaugh, Joseph A.; Zand, Martin S.; Holden-Wiltse, Jeanne; Mosmann, Tim R.; Perelson, Alan S.; Wu, Hulin; Topham, David J.

    2010-01-01

    Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ∼1.2 days, and the half-life of free infectious IAV is ∼4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ∼0.5 days, and the average half-life of free infectious virus is ∼1.8 min. During the adaptive phase, model fitting confirms that CD8+ CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity. PMID:20410284

  18. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function.

    PubMed

    Marsh, Samuel E; Abud, Edsel M; Lakatos, Anita; Karimzadeh, Alborz; Yeung, Stephen T; Davtyan, Hayk; Fote, Gianna M; Lau, Lydia; Weinger, Jason G; Lane, Thomas E; Inlay, Matthew A; Poon, Wayne W; Blurton-Jones, Mathew

    2016-03-01

    The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression. PMID:26884167

  19. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function.

    PubMed

    Marsh, Samuel E; Abud, Edsel M; Lakatos, Anita; Karimzadeh, Alborz; Yeung, Stephen T; Davtyan, Hayk; Fote, Gianna M; Lau, Lydia; Weinger, Jason G; Lane, Thomas E; Inlay, Matthew A; Poon, Wayne W; Blurton-Jones, Mathew

    2016-03-01

    The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.

  20. Adaptive immunity maintains occult cancer in an equilibrium state.

    PubMed

    Koebel, Catherine M; Vermi, William; Swann, Jeremy B; Zerafa, Nadeen; Rodig, Scott J; Old, Lloyd J; Smyth, Mark J; Schreiber, Robert D

    2007-12-01

    The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes that function either independently or in sequence: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods.

  1. Prophylactic and Therapeutic Modulation of Innate and Adaptive Immunity Against Mucosal Infection of Herpes Simplex Virus

    PubMed Central

    Uyangaa, Erdenebileg; Patil, Ajit Mahadev

    2014-01-01

    Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the most common cause of genital ulceration in humans worldwide. Typically, HSV-1 and 2 infections via mucosal route result in a lifelong latent infection after peripheral replication in mucosal tissues, thereby providing potential transmission to neighbor hosts in response to reactivation. To break the transmission cycle, immunoprophylactics and therapeutic strategies must be focused on prevention of infection or reduction of infectivity at mucosal sites. Currently, our understanding of the immune responses against mucosal infection of HSV remains intricate and involves a balance between innate signaling pathways and the adaptive immune responses. Numerous studies have demonstrated that HSV mucosal infection induces type I interferons (IFN) via recognition of Toll-like receptors (TLRs) and activates multiple immune cell populations, including NK cells, conventional dendritic cells (DCs), and plasmacytoid DCs. This innate immune response is required not only for the early control of viral replication at mucosal sites, but also for establishing adaptive immune responses against HSV antigens. Although the contribution of humoral immune response is controversial, CD4+ Th1 T cells producing IFN-γ are believed to play an important role in eradicating virus from the hosts. In addition, the recent experimental successes of immunoprophylactic and therapeutic compounds that enhance resistance and/or reduce viral burden at mucosal sites have accumulated. This review focuses on attempts to modulate innate and adaptive immunity against HSV mucosal infection for the development of prophylactic and therapeutic strategies. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses. Thus, we summarized the current evidence of various immune mediators in response to mucosal HSV infection, focusing on the importance of innate immune responses. PMID:25177251

  2. Genes of the adaptive immune system are expressed early in zebrafish larval development following lipopolysaccharide stimulation

    NASA Astrophysics Data System (ADS)

    Li, Fengling; Zhang, Shicui; Wang, Zhiping; Li, Hongyan

    2011-03-01

    Information regarding immunocompetence of the adaptive immune system (AIS) in zebrafish Danio rerio remains limited. Here, we stimulated an immune response in fish embryos, larvae and adults using lipopolysaccharide (LPS) and measured the upregulation of a number of AIS-related genes ( Rag2, AID, TCRAC, IgLC-1, mIg, sIg, IgZ and DAB) 3 and 18 h later. We found that all of the genes evaluated were strongly induced following LPS stimulation, with most of them responding at 8 d post fertilization. This confirms that a functional adaptive immune response is present in D. rerio larvae, and provides a window for further functional analyses.

  3. Interferon-γ Is a Crucial Activator of Early Host Immune Defense against Mycobacterium ulcerans Infection in Mice

    PubMed Central

    Bieri, Raphael; Bolz, Miriam; Ruf, Marie-Thérèse; Pluschke, Gerd

    2016-01-01

    Buruli ulcer (BU), caused by infection with Mycobacterium ulcerans, is a chronic necrotizing human skin disease associated with the production of the cytotoxic macrolide exotoxin mycolactone. Despite extensive research, the type of immune responses elicited against this pathogen and the effector functions conferring protection against BU are not yet fully understood. While histopathological analyses of advanced BU lesions have demonstrated a mainly extracellular localization of the toxin producing acid fast bacilli, there is growing evidence for an early intra-macrophage growth phase of M. ulcerans. This has led us to investigate whether interferon-γ might play an important role in containing M. ulcerans infections. In an experimental Buruli ulcer mouse model we found that interferon-γ is indeed a critical regulator of early host immune defense against M. ulcerans infections. Interferon-γ knockout mice displayed a faster progression of the infection compared to wild-type mice. This accelerated progression was reflected in faster and more extensive tissue necrosis and oedema formation, as well as in a significantly higher bacterial burden after five weeks of infection, indicating that mice lacking interferon-γ have a reduced capacity to kill intracellular bacilli during the early intra-macrophage growth phase of M. ulcerans. This data demonstrates a prominent role of interferon-γ in early defense against M. ulcerans infection and supports the view that concepts for vaccine development against tuberculosis may also be valid for BU. PMID:26863011

  4. Nuclear accumulation of the Arabidopsis immune receptor RPS4 is necessary for triggering EDS1-dependent defense.

    PubMed

    Wirthmueller, Lennart; Zhang, Yan; Jones, Jonathan D G; Parker, Jane E

    2007-12-01

    Recognition of specific pathogen molecules inside the cell by nucleotide-binding domain and leucine-rich repeat (NB-LRR) receptors constitutes an important layer of innate immunity in plants. Receptor activation triggers host cellular reprogramming involving transcriptional potentiation of basal defenses and localized programmed cell death. The sites and modes of action of NB-LRR receptors are, however, poorly understood. Arabidopsis Toll/Interleukin-1 (TIR) type NB-LRR receptor RPS4 recognizes the bacterial type III effector AvrRps4. We show that epitope-tagged RPS4 expressed under its native regulatory sequences distributes between endomembranes and nuclei in healthy and AvrRps4-triggered tissues. RPS4 accumulation in the nucleus, mediated by a bipartite nuclear localization sequence (NLS) at its C terminus, is necessary for triggering immunity through authentic activation by AvrRps4 in Arabidopsis or as an effector-independent "deregulated" receptor in tobacco. A strikingly conserved feature of TIR-NB-LRR receptors is their recruitment of the nucleocytoplasmic basal-defense regulator EDS1 in resistance to diverse pathogens. We find that EDS1 is an indispensable component of RPS4 signaling and that it functions downstream of RPS4 activation but upstream of RPS4-mediated transcriptional reprogramming in the nucleus.

  5. Interferon-γ Is a Crucial Activator of Early Host Immune Defense against Mycobacterium ulcerans Infection in Mice.

    PubMed

    Bieri, Raphael; Bolz, Miriam; Ruf, Marie-Thérèse; Pluschke, Gerd

    2016-02-01

    Buruli ulcer (BU), caused by infection with Mycobacterium ulcerans, is a chronic necrotizing human skin disease associated with the production of the cytotoxic macrolide exotoxin mycolactone. Despite extensive research, the type of immune responses elicited against this pathogen and the effector functions conferring protection against BU are not yet fully understood. While histopathological analyses of advanced BU lesions have demonstrated a mainly extracellular localization of the toxin producing acid fast bacilli, there is growing evidence for an early intra-macrophage growth phase of M. ulcerans. This has led us to investigate whether interferon-γ might play an important role in containing M. ulcerans infections. In an experimental Buruli ulcer mouse model we found that interferon-γ is indeed a critical regulator of early host immune defense against M. ulcerans infections. Interferon-γ knockout mice displayed a faster progression of the infection compared to wild-type mice. This accelerated progression was reflected in faster and more extensive tissue necrosis and oedema formation, as well as in a significantly higher bacterial burden after five weeks of infection, indicating that mice lacking interferon-γ have a reduced capacity to kill intracellular bacilli during the early intra-macrophage growth phase of M. ulcerans. This data demonstrates a prominent role of interferon-γ in early defense against M. ulcerans infection and supports the view that concepts for vaccine development against tuberculosis may also be valid for BU.

  6. From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.

    PubMed

    Fulop, T; Dupuis, G; Baehl, S; Le Page, A; Bourgade, K; Frost, E; Witkowski, J M; Pawelec, G; Larbi, A; Cunnane, S

    2016-02-01

    Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases. PMID:26472173

  7. Epithelial cells, the “switchboard” of respiratory immune defense responses: effects of air pollutants

    PubMed Central

    Müller, Loretta; Jaspers, Ilona

    2015-01-01

    Summary “Epimmunome”, a term introduced recently by Swamy and colleagues, describes all molecules and pathways used by epithelial cells (ECs) to instruct immune cells. Today, we know that ECs are among the first sites within the human body to be exposed to pathogens (such as influenza viruses) and that the release of chemokine and cytokines by ECs is influenced by inhaled agents. The role of the ECs as a switchboard to initiate and regulate immune responses is altered through air pollutant exposure, such as ozone, tobacco smoke and diesel exhaust emissions. The details of the interplay between ECs and immune cells are not yet fully understood and need to be investigated further. Co-culture models, cell specific genetically-modified mice and the analysis of human biopsies provide great tools to gain knowledge about potential mechanisms. Increasing our understanding about the role of ECs in respiratory immunity may yield novel therapeutic targets to modulate downstream diseases. PMID:22851042

  8. Host Defenses in Murine Malaria: Immunological Characteristics of a Protracted State of Immunity to Plasmodium yoelii

    PubMed Central

    Murphy, James R.

    1980-01-01

    Random-bred ICR mice recovered from infection with avirulent Plasmodium yoelii were challenged at various later times with virulent P. yoelii or with another species of Plasmodium, P. berghei, to characterize the immunological nature of the long-term state of immunity generated in response to the avirulent infection. It was found that recovered mice resisted lethal challenge with virulent P. yoelii through at least 416 days after primary infection. However, the quality of this immunity changed as the time after avirulent infection increased. Mice challenged early after recovery were able to prevent the development of patent parasitemia. Later, these immune animals lost this capacity and after challenge infections progressed to patency at the same rate as did nonimmune controls. However, after the establishment of parasitemia, those animals which had encountered the homologous parasite a long time before controlled, and then eliminated, blood infection and survived. The “early” state of immunity was expressed by animals which may have harbored small numbers of viable avirulent parasites and possessed a protective humoral factor which could passively transfer anti-P. yoelii activity to naive recipients. In contrast, animals with “late” immunity showed evidence of neither persisting avirulent parasites nor serum anti-P. yoelii activity. The results support the proposition that immunity to this parasite exists as two distinct but interrelated states of immunological reactivity: an early “active” immunity and a later state which has characteristics suggestive of a state of immunological memory wherewith the animals were capable of anamnestically responding to P. yoelii challenge. Little evidence of heterologous immunity to P. berghei was observed for animals recovered from P. yoelii. PMID:6987179

  9. Innate and Adaptive Immunity Synergize to Trigger Inflammation in the Mammary Gland.

    PubMed

    Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B

    2016-01-01

    The mammary gland is able to detect and react to bacterial intrusion through innate immunity mechanisms, but mammary inflammation can also result from antigen-specific adaptive immunity. We postulated that innate and adaptive immune responses could synergize to trigger inflammation in the mammary gland. To test this hypothesis, we immunized cows with the model antigen ovalbumin and challenged the sensitized animals with either Escherichia coli lipopolysaccharide (LPS) as innate immunity agonist, ovalbumin as adaptive immunity agonist, or both agonists in three different udder quarters of lactating cows. There was a significant amplification of the initial milk leukocytosis in the quarters challenged with the two agonists compared to leukocytosis in quarters challenged with LPS or ovalbumin alone. This synergistic response occurred only with the cows that developed the ovalbumin-specific inflammatory response, and there were significant correlations between milk leukocytosis and production of IL-17A and IFN-γ in a whole-blood ovalbumin stimulation assay. The antigen-specific response induced substantial concentrations of IL-17A and IFN-γ in milk contrary to the response to LPS. Such a synergy at the onset of the reaction of the mammary gland suggests that induction of antigen-specific immune response with bacterial antigens could improve the initial immune response to infection, hence reducing the bacterial load and contributing to protection. PMID:27100324

  10. Innate and Adaptive Immunity Synergize to Trigger Inflammation in the Mammary Gland

    PubMed Central

    Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B.

    2016-01-01

    The mammary gland is able to detect and react to bacterial intrusion through innate immunity mechanisms, but mammary inflammation can also result from antigen-specific adaptive immunity. We postulated that innate and adaptive immune responses could synergize to trigger inflammation in the mammary gland. To test this hypothesis, we immunized cows with the model antigen ovalbumin and challenged the sensitized animals with either Escherichia coli lipopolysaccharide (LPS) as innate immunity agonist, ovalbumin as adaptive immunity agonist, or both agonists in three different udder quarters of lactating cows. There was a significant amplification of the initial milk leukocytosis in the quarters challenged with the two agonists compared to leukocytosis in quarters challenged with LPS or ovalbumin alone. This synergistic response occurred only with the cows that developed the ovalbumin-specific inflammatory response, and there were significant correlations between milk leukocytosis and production of IL-17A and IFN-γ in a whole-blood ovalbumin stimulation assay. The antigen-specific response induced substantial concentrations of IL-17A and IFN-γ in milk contrary to the response to LPS. Such a synergy at the onset of the reaction of the mammary gland suggests that induction of antigen-specific immune response with bacterial antigens could improve the initial immune response to infection, hence reducing the bacterial load and contributing to protection. PMID:27100324

  11. Immune Defense Varies within an Instar in the Tobacco Hornworm, Manduca sexta.

    PubMed

    Booth, Kimberly; Cambron, Lizzette; Fisher, Nathan; Greenlee, Kendra J

    2015-01-01

    Research on how insect immunity changes with age as insects develop within an instar, or larval developmental stage, is limited and contradictory. Insects within an instar are preparing for the next developmental stage, which may involve changes in morphology or habitat. Immunity may also vary accordingly. To determine how immunity varies in the fifth instar, we tested humoral immune responses, antimicrobial peptide activity, and phenoloxidase activity using the tobacco hornworm, Manduca sexta. We determined that while M. sexta have more robust antimicrobial peptide and phenoloxidase responses at the beginning of their fifth instar, this did not translate into better survival of bacterial infection or lower bacterial load in the hemolymph. We also determined that M. sexta injected with bacteria early in the fifth instar experience lower growth rates and longer development times than caterpillars of the same age injected with sham. This could indicate a shift in energy allocation from growth and development to metabolically costly immune responses. Because of the importance of insects as pests and pollinators, understanding how immunity varies throughout development is critical. PMID:25730277

  12. Evasion of Influenza A Viruses from Innate and Adaptive Immune Responses

    PubMed Central

    van de Sandt, Carolien E.; Kreijtz, Joost H. C. M.; Rimmelzwaan, Guus F.

    2012-01-01

    The influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses and recognition by components of the humoral and cellular immune response, which consequently may result in reduced clearing of the virus and virus-infected cells. Finally, we discuss how the current knowledge about immune evasion can be used to improve influenza A vaccination strategies. PMID:23170167

  13. The microbiota in adaptive immune homeostasis and disease.

    PubMed

    Honda, Kenya; Littman, Dan R

    2016-07-06

    In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota-host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy.

  14. Modulation of host adaptive immunity by hRSV proteins

    PubMed Central

    Espinoza, Janyra A; Bohmwald, Karen; Céspedes, Pablo F; Riedel, Claudia A; Bueno, Susan M; Kalergis, Alexis M

    2014-01-01

    Globally, the human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infections (LRTIs) in infants and children younger than 2 years old. Furthermore, the number of hospitalizations due to LRTIs has shown a sustained increase every year due to the lack of effective vaccines against hRSV. Thus, this virus remains as a major public health and economic burden worldwide. The lung pathology developed in hRSV-infected humans is characterized by an exacerbated inflammatory and Th2 immune response. In order to rationally design new vaccines and therapies against this virus, several studies have focused in elucidating the interactions between hRSV virulence factors and the host immune system. Here, we discuss the main features of hRSV biology, the processes involved in virus recognition by the immune system and the most relevant mechanisms used by this pathogen to avoid the antiviral host response. PMID:25513775

  15. Genetic and phenotypic relationships between immune defense, melanism and life-history traits at different temperatures and sexes in Tenebrio molitor.

    PubMed

    Prokkola, J; Roff, D; Kärkkäinen, T; Krams, I; Rantala, M J

    2013-08-01

    Insect cuticle melanism is linked to a number of life-history traits, and a positive relationship is hypothesized between melanism and the strength of immune defense. In this study, the phenotypic and genetic relationships between cuticular melanization, innate immune defense, individual development time and body size were studied in the mealworm beetle (Tenebrio molitor) using three different temperatures with a half-sib breeding design. Both innate immune defense and cuticle darkness were higher in females than males, and a positive correlation between the traits was found at the lowest temperature. The effect of temperature on all the measured traits was strong, with encapsulation ability and development time decreasing and cuticle darkness increasing with a rise in temperature, and body size showing a curved response. The analysis showed a highly integrated system sensitive to environmental change involving physiological, morphological and life-history traits. PMID:23572120

  16. Genetic and phenotypic relationships between immune defense, melanism and life-history traits at different temperatures and sexes in Tenebrio molitor

    PubMed Central

    Prokkola, J; Roff, D; Kärkkäinen, T; Krams, I; Rantala, M J

    2013-01-01

    Insect cuticle melanism is linked to a number of life-history traits, and a positive relationship is hypothesized between melanism and the strength of immune defense. In this study, the phenotypic and genetic relationships between cuticular melanization, innate immune defense, individual development time and body size were studied in the mealworm beetle (Tenebrio molitor) using three different temperatures with a half-sib breeding design. Both innate immune defense and cuticle darkness were higher in females than males, and a positive correlation between the traits was found at the lowest temperature. The effect of temperature on all the measured traits was strong, with encapsulation ability and development time decreasing and cuticle darkness increasing with a rise in temperature, and body size showing a curved response. The analysis showed a highly integrated system sensitive to environmental change involving physiological, morphological and life-history traits. PMID:23572120

  17. Genetic and phenotypic relationships between immune defense, melanism and life-history traits at different temperatures and sexes in Tenebrio molitor.

    PubMed

    Prokkola, J; Roff, D; Kärkkäinen, T; Krams, I; Rantala, M J

    2013-08-01

    Insect cuticle melanism is linked to a number of life-history traits, and a positive relationship is hypothesized between melanism and the strength of immune defense. In this study, the phenotypic and genetic relationships between cuticular melanization, innate immune defense, individual development time and body size were studied in the mealworm beetle (Tenebrio molitor) using three different temperatures with a half-sib breeding design. Both innate immune defense and cuticle darkness were higher in females than males, and a positive correlation between the traits was found at the lowest temperature. The effect of temperature on all the measured traits was strong, with encapsulation ability and development time decreasing and cuticle darkness increasing with a rise in temperature, and body size showing a curved response. The analysis showed a highly integrated system sensitive to environmental change involving physiological, morphological and life-history traits.

  18. Immune-related transcriptome of Coptotermes formosanus Shiraki workers: the defense mechanism.

    PubMed

    Hussain, Abid; Li, Yi-Feng; Cheng, Yu; Liu, Yang; Chen, Chuan-Cheng; Wen, Shuo-Yang

    2013-01-01

    Formosan subterranean termites, Coptotermes formosanus Shiraki, live socially in microbial-rich habitats. To understand the molecular mechanism by which termites combat pathogenic microbes, a full-length normalized cDNA library and four Suppression Subtractive Hybridization (SSH) libraries were constructed from termite workers infected with entomopathogenic fungi (Metarhizium anisopliae and Beauveria bassiana), Gram-positive Bacillus thuringiensis and Gram-negative Escherichia coli, and the libraries were analyzed. From the high quality normalized cDNA library, 439 immune-related sequences were identified. These sequences were categorized as pattern recognition receptors (47 sequences), signal modulators (52 sequences), signal transducers (137 sequences), effectors (39 sequences) and others (164 sequences). From the SSH libraries, 27, 17, 22 and 15 immune-related genes were identified from each SSH library treated with M. anisopliae, B. bassiana, B. thuringiensis and E. coli, respectively. When the normalized cDNA library was compared with the SSH libraries, 37 immune-related clusters were found in common; 56 clusters were identified in the SSH libraries, and 259 were identified in the normalized cDNA library. The immune-related gene expression pattern was further investigated using quantitative real time PCR (qPCR). Important immune-related genes were characterized, and their potential functions were discussed based on the integrated analysis of the results. We suggest that normalized cDNA and SSH libraries enable us to discover functional genes transcriptome. The results remarkably expand our knowledge about immune-inducible genes in C. formosanus Shiraki and enable the future development of novel control strategies for the management of Formosan subterranean termites.

  19. Immune-Related Transcriptome of Coptotermes formosanus Shiraki Workers: The Defense Mechanism

    PubMed Central

    Hussain, Abid; Li, Yi-Feng; Cheng, Yu; Liu, Yang; Chen, Chuan-Cheng; Wen, Shuo-Yang

    2013-01-01

    Formosan subterranean termites, Coptotermes formosanus Shiraki, live socially in microbial-rich habitats. To understand the molecular mechanism by which termites combat pathogenic microbes, a full-length normalized cDNA library and four Suppression Subtractive Hybridization (SSH) libraries were constructed from termite workers infected with entomopathogenic fungi (Metarhizium anisopliae and Beauveria bassiana), Gram-positive Bacillus thuringiensis and Gram-negative Escherichia coli, and the libraries were analyzed. From the high quality normalized cDNA library, 439 immune-related sequences were identified. These sequences were categorized as pattern recognition receptors (47 sequences), signal modulators (52 sequences), signal transducers (137 sequences), effectors (39 sequences) and others (164 sequences). From the SSH libraries, 27, 17, 22 and 15 immune-related genes were identified from each SSH library treated with M. anisopliae, B. bassiana, B. thuringiensis and E. coli, respectively. When the normalized cDNA library was compared with the SSH libraries, 37 immune-related clusters were found in common; 56 clusters were identified in the SSH libraries, and 259 were identified in the normalized cDNA library. The immune-related gene expression pattern was further investigated using quantitative real time PCR (qPCR). Important immune-related genes were characterized, and their potential functions were discussed based on the integrated analysis of the results. We suggest that normalized cDNA and SSH libraries enable us to discover functional genes transcriptome. The results remarkably expand our knowledge about immune-inducible genes in C. formosanus Shiraki and enable the future development of novel control strategies for the management of Formosan subterranean termites. PMID:23874972

  20. The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens*

    PubMed Central

    Djoko, Karrera Y.; Ong, Cheryl-lynn Y.; Walker, Mark J.; McEwan, Alastair G.

    2015-01-01

    Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function. PMID:26055706

  1. H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection

    PubMed Central

    2011-01-01

    Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed. PMID:22044597

  2. Innate and adaptive immunity in bacteria: mechanisms of programmed genetic variation to fight bacteriophages.

    PubMed

    Bikard, David; Marraffini, Luciano A

    2012-02-01

    Bacteria are constantly challenged by bacteriophages (viruses that infect bacteria), the most abundant microorganism on earth. Bacteria have evolved a variety of immunity mechanisms to resist bacteriophage infection. In response, bacteriophages can evolve counter-resistance mechanisms and launch a 'virus versus host' evolutionary arms race. In this context, rapid evolution is fundamental for the survival of the bacterial cell. Programmed genetic variation mechanisms at loci involved in immunity against bacteriophages generate diversity at a much faster rate than random point mutation and enable bacteria to quickly adapt and repel infection. Diversity-generating retroelements (DGRs) and phase variation mechanisms enhance the generic (innate) immune response against bacteriophages. On the other hand, the integration of small bacteriophage sequences in CRISPR loci provide bacteria with a virus-specific and sequence-specific adaptive immune response. Therefore, although using different molecular mechanisms, both prokaryotes and higher organisms rely on programmed genetic variation to increase genetic diversity and fight rapidly evolving infectious agents.

  3. Toward a molecular understanding of adaptive immunity: a chronology, part I

    PubMed Central

    Smith, Kendall A.

    2012-01-01

    The adaptive immune system has been the core of immunology for the past century, as immunologists have been primarily focused on understanding the basis for adaptive immunity for the better part of this time. Immunological thought has undergone an evolution with regard to our understanding as the complexity of the cells and the molecules of the system became elucidated. The original immunologists performed their experiments with whole animals (or humans), and for the most part they were focused on observing what happens when a foreign substance is introduced into the body. However, since Burnet formulated his clonal selection theory we have witnessed reductionist science focused first on cell populations, then individual cells and finally on molecules, in our quests to learn how the system works. This review is the first part of a chronology of our evolution toward a molecular understanding of adaptive immunity. PMID:23230443

  4. Rafts and the battleships of defense: the multifaceted microdomains for positive and negative signals in immune cells.

    PubMed

    Szöor, Arpád; Szöllosi, János; Vereb, György

    2010-05-01

    Recognition of the heterogeneity of the cell membrane was one of the most important scientific achievements in the last decades. Since coining the term "lipid rafts", continuous development of advanced microscopic and spectroscopic techniques has vastly expanded our view on these cell membrane microdomains that appear to have almost as many faces as researchers that look at them; they are variable in stability, size and composition that can change in a highly dynamic manner both by recruiting and expelling components as well as by coalescing and breaking up into smaller units. They have, however, one common feature: all eukaryotic cells present some variation of lipid rafts. Cells of the immune system are not exception to this, regardless of their lymphoid or myeloid origin their membranes show a domain structure and these domains serve to condense or reject particular transmembrane, GPI-linked and intracellularly membrane-anchored proteins as function requires. Here we provide a concise overview about the various weapons and shields that immune cells concentrate into their rafts, which have come into sight during the past years. The positive and negative regulatory roles of these microdomains are essential both in the functions of innate immunity and processes concatenated in the adaptive immune response. PMID:20026358

  5. A temporal analysis of the relationships between social stress, humoral immune response and glutathione-related antioxidant defenses.

    PubMed

    Gonçalves, Luciane; Dafre, Alcir Luiz; Carobrez, Sonia Gonçalves; Gasparotto, Odival Cezar

    2008-10-10

    The exposure to different kinds of stress impacts on the reactive oxygen species production with potential risk to the integrity of the tissues. Psychological or biological stress is responsible for a significant increase in the oxidative stress markers and also for activation of the antioxidant defense system. In this study, we analyzed the relationships between social stress, humoral immune response and glutathione-related antioxidant defenses. Groups of male Swiss mice were subjected to different lengths of social stress exposure (social confrontation) which varied from 1 up to 13 days. As a biological stressor, 10(9) sheep red blood cells (SRBC)/mL were injected by intraperitoneal route. As controls, animals not subjected to social stress and/or injected with vehicle solution were used. The serum samples and the cerebral cortex were collected at 4 h, 3, 5, 7, 9, 11, and 13 days after the end of social confrontation. The results indicated that the antioxidant enzymes activities were affected by psychological as well as by biological stressor. These alterations were dependent on the timing of stress exposure which resulted in a positive or in a negative correlation between the antibody titres to SRBC and antioxidant enzymes. We also discuss the possible role of SRBC injection in the modulation of the effects of psychosocial stress on antioxidant metabolism.

  6. Racing against host's immunity defenses: a likely strategy for passive evasion of encapsulation in Asobara tabida parasitoids.

    PubMed

    Eslin; Prévost

    2000-08-01

    The hymenopteran Asobara tabida Nees (Braconidae, Alysiinae) develops as a solitary endophagous parasite in larvae of several Drosophila species. Most A. tabida eggs possess a sticky chorion which attaches to the tissue of the host organs within a few hours following oviposition. A. tabida sticky eggs usually avoid encapsulation, though the probability of survival decreases in hosts carrying a larger number of circulating hemocytes. Here, we hypothesized that the elicitation of the encapsulation reaction may result from a race between two phenomena: the host's hemocytic reaction and the embedment of the parasitic egg within the host tissues. In order to test this hypothesis, we measured the speed of capsule formation in D. melanogaster larvae of different ages, knowing that the number of circulating hemocytes increases with the age of the larvae. Using a non-virulent A. tabida strain, the eggs of which do not attach to the host tissue, we found that the speed of capsule formation increased correlatively with the age of the D. melanogaster larva. Therefore, the hypothesis of a physiological race between host's immunity defenses and parasite's avoidance of host's defenses is strongly supported by our results. Also, A. tabida eggs which attach to the host's tissue before the attack by the hemocytes has taken place may be considered as a strategy of passive evasion from encapsulation.

  7. TLR7 is required for optimal immune defense against bacterial infection in tongue sole (Cynoglossus semilaevis).

    PubMed

    Li, Xue-peng; Sun, Li

    2015-11-01

    In mammals as well as in teleost, toll-like receptor 7 (TLR7) is known to be involved in antiviral immunity by recognizing viral RNA. However, the antibacterial potential of fish TLR7 is unclear. In this study, we analyzed the TLR7 of tongue sole (Cynoglossus semilaevis), CsTLR7, and examined its potential involvement in antibacterial immunity. CsTLR7 is composed of 1052 amino acid residues and shares 64.0%-75.9% overall sequence identities with known teleost TLR7. CsTLR7 possesses a toll/interleukin-1 receptor domain and six leucine-rich repeats. Constitutive expression of CsTLR7 occurred in relatively high levels in kidney, spleen and liver. Bacterial infection upregulated CsTLR7 expression, whereas viral infection downregulated CsTLR7 expression. Knockdown of CsTLR7 significantly enhanced bacterial dissemination in the tissues of tongue sole. Treatment of tongue sole with the imidazoquinoline compound R848 (TLR7 activator) and the endosomal acidification inhibitor chloroquine (TLR7 inhibitor) caused enhanced and reduced resistance against bacterial infection respectively. These results indicate that CsTLR7 plays an essential role in the antibacterial immunity of tongue sole. PMID:26327112

  8. Infection of goats with goatpox virus triggers host antiviral defense through activation of innate immune signaling.

    PubMed

    Zeng, Xiancheng; Wang, Song; Chi, Xiaojuan; Chen, Shi-long; Huang, Shile; Lin, Qunqun; Xie, Baogui; Chen, Ji-Long

    2016-02-01

    Goatpox, caused by goatpox virus (GTPV), is one of the most serious infectious diseases associated with high morbidity and mortality in goats. However, little is known about involvement of host innate immunity during the GTPV infection. For this, goats were experimentally infected with GTPV. The results showed that GTPV infection significantly induced mRNA expression of type I interferon (IFN)-α and IFN-β in peripheral blood lymphocytes, spleen and lung. In addition, GTPV infection enhanced expression of several inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18; and tumor necrosis factor-α (TNF-α). Strikingly, infection with GTPV activated signal transducers and activators of transcription 3 (STAT3), a critical cytokine signaling molecule. Interestingly, the virus infection induced expression of suppressor of cytokine signaling (SOCS)-1. Importantly, the infection resulted in an increased expression of some critical interferon-stimulated genes, such as interferon-induced transmembrane protein (IFITM) 1, IFITM3, interferon stimulated gene (ISG) 15 and ISG20. Furthermore, we found that infection with GTPV up-regulated expression of Toll-like receptor (TLR) 2 and TLR9. These results revealed that GTPV infection activated host innate immune signaling and thereby triggered antiviral innate immunity. The findings provide novel insights into complex mechanisms underlying GTPV-host interaction and pathogenesis of GTPV. PMID:26850535

  9. Modulatory Effects of Antidepressant Classes on the Innate and Adaptive Immune System in Depression.

    PubMed

    Eyre, H A; Lavretsky, H; Kartika, J; Qassim, A; Baune, B T

    2016-05-01

    Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies - in clinical and pre-clinical populations. PMID:26951496

  10. Modulatory Effects of Antidepressant Classes on the Innate and Adaptive Immune System in Depression.

    PubMed

    Eyre, H A; Lavretsky, H; Kartika, J; Qassim, A; Baune, B T

    2016-05-01

    Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies - in clinical and pre-clinical populations.

  11. Neutrophil-Mediated Regulation of Innate and Adaptive Immunity: The Role of Myeloperoxidase

    PubMed Central

    Odobasic, Dragana; Kitching, A. Richard; Holdsworth, Stephen R.

    2016-01-01

    Neutrophils are no longer seen as leukocytes with a sole function of being the essential first responders in the removal of pathogens at sites of infection. Being armed with numerous pro- and anti-inflammatory mediators, these phagocytes can also contribute to the development of various autoimmune diseases and can positively or negatively regulate the generation of adaptive immune responses. In this review, we will discuss how myeloperoxidase, the most abundant neutrophil granule protein, plays a key role in the various functions of neutrophils in innate and adaptive immunity. PMID:26904693

  12. No Compensatory Relationship between the Innate and Adaptive Immune System in Wild-Living European Badgers

    PubMed Central

    Sin, Yung Wa; Newman, Chris; Dugdale, Hannah L.; Buesching, Christina; Mannarelli, Maria-Elena; Annavi, Geetha; Burke, Terry; Macdonald, David W.

    2016-01-01

    The innate immune system provides the primary vertebrate defence system against pathogen invasion, but it is energetically costly and can have immune pathological effects. A previous study in sticklebacks found that intermediate major histocompatibility complex (MHC) diversity correlated with a lower leukocyte coping capacity (LCC), compared to individuals with fewer, or many, MHC alleles. The organization of the MHC genes in mammals, however, differs to the highly duplicated MHC genes in sticklebacks by having far fewer loci. Using European badgers (Meles meles), we therefore investigated whether innate immune activity, estimated functionally as the ability of an individual’s leukocytes to produce a respiratory burst, was influenced by MHC diversity. We also investigated whether LCC was influenced by factors such as age-class, sex, body condition, season, year, neutrophil and lymphocyte counts, and intensity of infection with five different pathogens. We found that LCC was not associated with specific MHC haplotypes, MHC alleles, or MHC diversity, indicating that the innate immune system did not compensate for the adaptive immune system even when there were susceptible MHC alleles/haplotypes, or when the MHC diversity was low. We also identified a seasonal and annual variation of LCC. This temporal variation of innate immunity was potentially due to physiological trade-offs or temporal variation in pathogen infections. The innate immunity, estimated as LCC, does not compensate for MHC diversity suggests that the immune system may function differently between vertebrates with different MHC organizations, with implications for the evolution of immune systems in different taxa. PMID:27695089

  13. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity.

    PubMed

    Winning, Sandra; Fandrey, Joachim

    2016-01-01

    Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

  14. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

    PubMed Central

    Winning, Sandra; Fandrey, Joachim

    2016-01-01

    Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity. PMID:26966693

  15. The interplay between the microbiome and the adaptive immune response in cancer development

    PubMed Central

    Russo, Edda; Taddei, Antonio; Ringressi, Maria Novella; Ricci, Federica; Amedei, Amedeo

    2016-01-01

    The data from different studies suggest a bacterial role in cancer genesis/progression, often modulating the local immune response. This is particularly so at the mucosal level where the bacterial presence is strong and the immune system is highly reactive. The epithelial surfaces of the body, such as the skin and mucosa, are colonized by a vast number of microorganisms, which represent the so-called normal microbiome. Normally the microbiome does not cause a proinflammatory response because the immune system has developed different strategies for the tolerance of commensal bacteria, but when these mechanisms are impaired or new pathogenic bacteria are introduced into this balanced system, the immune system reacts to the microbiome and can trigger tumor growth in the intestine. In this review, we discuss the potential role of the bacterial microbiome in carcinogenesis, focusing on the direct and indirect immune adaptive mechanisms, that the bacteria can modulate in different ways. PMID:27366226

  16. Plant Innate Immunity Multicomponent Model.

    PubMed

    Andolfo, Giuseppe; Ercolano, Maria R

    2015-01-01

    Our understanding of plant-pathogen interactions is making rapid advances in order to address issues of global importance such as improving agricultural productivity and sustainable food security. Innate immunity has evolved in plants, resulting in a wide diversity of defense mechanisms adapted to specific threats. The postulated PTI/ETI model describes two perception layers of plant innate immune system, which belong to a first immunity component of defense response activation. To better describe the sophisticated defense system of plants, we propose a new model of plant immunity. This model considers the plant's ability to distinguish the feeding behavior of their many foes, such as a second component that modulates innate immunity. This hypothesis provides a new viewpoint highlighting the relevance of hormone crosstalk and primary metabolism in regulating plant defense against the different behaviors of pathogens with the intention to stimulate further interest in this research area. PMID:26617626

  17. Plant Innate Immunity Multicomponent Model.

    PubMed

    Andolfo, Giuseppe; Ercolano, Maria R

    2015-01-01

    Our understanding of plant-pathogen interactions is making rapid advances in order to address issues of global importance such as improving agricultural productivity and sustainable food security. Innate immunity has evolved in plants, resulting in a wide diversity of defense mechanisms adapted to specific threats. The postulated PTI/ETI model describes two perception layers of plant innate immune system, which belong to a first immunity component of defense response activation. To better describe the sophisticated defense system of plants, we propose a new model of plant immunity. This model considers the plant's ability to distinguish the feeding behavior of their many foes, such as a second component that modulates innate immunity. This hypothesis provides a new viewpoint highlighting the relevance of hormone crosstalk and primary metabolism in regulating plant defense against the different behaviors of pathogens with the intention to stimulate further interest in this research area.

  18. Participation of blood vessel cells in human adaptive immune responses.

    PubMed

    Pober, Jordan S; Tellides, George

    2012-01-01

    Circulating T cells contact blood vessels either when they extravasate across the walls of microvessels into inflamed tissues or when they enter into the walls of larger vessels in inflammatory diseases such as atherosclerosis. The blood vessel wall is largely composed of three cell types: endothelial cells lining the entire vascular tree; pericytes supporting the endothelium of microvessels; and smooth muscle cells forming the bulk of large vessel walls. Each of these cell types interacts with and alters the behavior of infiltrating T cells in different ways, making these cells active participants in the processes of immune-mediated inflammation. In this review, we compare and contrast what is known about the nature of these interactions in humans. PMID:22030237

  19. Polyreactive antibodies in adaptive immune responses to viruses.

    PubMed

    Mouquet, Hugo; Nussenzweig, Michel C

    2012-05-01

    B cells express immunoglobulins on their surface where they serve as antigen receptors. When secreted as antibodies, the same molecules are key elements of the humoral immune response against pathogens such as viruses. Although most antibodies are restricted to binding a specific antigen, some are polyreactive and have the ability to bind to several different ligands, usually with low affinity. Highly polyreactive antibodies are removed from the repertoire during B-cell development by physiologic tolerance mechanisms including deletion and receptor editing. However, a low level of antibody polyreactivity is tolerated and can confer additional binding properties to pathogen-specific antibodies. For example, high-affinity human antibodies to HIV are frequently polyreactive. Here we review the evidence suggesting that in the case of some pathogens like HIV, polyreactivity may confer a selective advantage to pathogen-specific antibodies.

  20. Delayed adaptive immunity is related to higher MMR vaccine-induced antibody titers in children.

    PubMed

    Strömbeck, Anna; Lundell, Anna-Carin; Nordström, Inger; Andersson, Kerstin; Adlerberth, Ingegerd; Wold, Agnes E; Rudin, Anna

    2016-04-01

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles-mumps-rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-induced antibody titers were measured in plasma samples obtained at 36 months of age. Infants' blood samples obtained at birth, 3-5 days and at 4 and 18 months of age were analyzed for T- and B-cell numbers, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells. Multivariate factor analyses show that higher anti-MMR antibody titers were associated with a lower degree of adaptive immune maturation, that is, lower proportions of memory T cells and a lower capacity of mononuclear cells to produce cytokines, but with higher proportions of putative regulatory T cells. Further, children born by cesarean section (CS) had significantly higher anti-measles titers than vaginally-born children; and CS was found to be associated with delayed adaptive immunity. Also, girls presented with significantly higher anti-mumps and anti-rubella antibody levels than boys at 36 months of age. These results indicate that delayed adaptive immune maturation before and in close proximity to immunization seems to be advantageous for the ability of children to respond with higher anti-MMR antibody levels after vaccination.

  1. Delayed adaptive immunity is related to higher MMR vaccine-induced antibody titers in children.

    PubMed

    Strömbeck, Anna; Lundell, Anna-Carin; Nordström, Inger; Andersson, Kerstin; Adlerberth, Ingegerd; Wold, Agnes E; Rudin, Anna

    2016-04-01

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles-mumps-rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-induced antibody titers were measured in plasma samples obtained at 36 months of age. Infants' blood samples obtained at birth, 3-5 days and at 4 and 18 months of age were analyzed for T- and B-cell numbers, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells. Multivariate factor analyses show that higher anti-MMR antibody titers were associated with a lower degree of adaptive immune maturation, that is, lower proportions of memory T cells and a lower capacity of mononuclear cells to produce cytokines, but with higher proportions of putative regulatory T cells. Further, children born by cesarean section (CS) had significantly higher anti-measles titers than vaginally-born children; and CS was found to be associated with delayed adaptive immunity. Also, girls presented with significantly higher anti-mumps and anti-rubella antibody levels than boys at 36 months of age. These results indicate that delayed adaptive immune maturation before and in close proximity to immunization seems to be advantageous for the ability of children to respond with higher anti-MMR antibody levels after vaccination. PMID:27195118

  2. Short Toxin-like Proteins Attack the Defense Line of Innate Immunity

    PubMed Central

    Tirosh, Yitshak; Ofer, Dan; Eliyahu, Tsiona; Linial, Michal

    2013-01-01

    ClanTox (classifier of animal toxins) was developed for identifying toxin-like candidates from complete proteomes. Searching mammalian proteomes for short toxin-like proteins (coined TOLIPs) revealed a number of overlooked secreted short proteins with an abundance of cysteines throughout their sequences. We applied bioinformatics and data-mining methods to infer the function of several top predicted candidates. We focused on cysteine-rich peptides that adopt the fold of the three-finger proteins (TFPs). We identified a cluster of duplicated genes that share a structural similarity with elapid neurotoxins, such as α-bungarotoxin. In the murine proteome, there are about 60 such proteins that belong to the Ly6/uPAR family. These proteins are secreted or anchored to the cell membrane. Ly6/uPAR proteins are associated with a rich repertoire of functions, including binding to receptors and adhesion. Ly6/uPAR proteins modulate cell signaling in the context of brain functions and cells of the innate immune system. We postulate that TOLIPs, as modulators of cell signaling, may be associated with pathologies and cellular imbalance. We show that proteins of the Ly6/uPAR family are associated with cancer diagnosis and malfunction of the immune system. PMID:23881252

  3. Identification of a serine proteinase homolog (Sp-SPH) involved in immune defense in the mud crab Scylla paramamosain.

    PubMed

    Zhang, Qiu-xia; Liu, Hai-peng; Chen, Rong-yuan; Shen, Kai-li; Wang, Ke-jian

    2013-01-01

    Clip domain serine proteinase homologs are involved in many biological processes including immune response. To identify the immune function of a serine proteinase homolog (Sp-SPH), originally isolated from hemocytes of the mud crab, Scylla paramamosain, the Sp-SPH was expressed recombinantly and purified for further studies. It was found that the Sp-SPH protein could bind to a number of bacteria (including Aeromonas hydrophila, Escherichia coli, Staphylococcus aureus, Vibrio fluvialis, Vibrio harveyi and Vibrio parahemolyticus), bacterial cell wall components such as lipopolysaccharide or peptidoglycan (PGN), and β-1, 3-glucan of fungus. But no direct antibacterial activity of Sp-SPH protein was shown by using minimum inhibitory concentration or minimum bactericidal concentration assays. Nevertheless, the Sp-SPH protein was found to significantly enhance the crab hemocyte adhesion activity (paired t-test, P<0.05), and increase phenoloxidase activity if triggered by PGN in vitro (paired t-test, P<0.05). Importantly, the Sp-SPH protein was demonstrated to promote the survival rate of the animals after challenge with A. hydrophila or V. parahemolyticus which were both recognized by Sp-SPH protein, if pre-incubated with Sp-SPH protein, respectively. Whereas, the crabs died much faster when challenged with Vibrio alginolyiicus, a pathogenic bacterium not recognized by Sp-SPH protein, compared to those of crabs challenged with A. hydrophila or V. parahemolyticus when pre-coated with Sp-SPH protein. Taken together, these data suggested that Sp-SPH molecule might play an important role in immune defense against bacterial infection in the mud crab S. paramamosain.

  4. Effects of dietary L-glutamine supplementation on specific and general defense responses in mice immunized with inactivated Pasteurella multocida vaccine.

    PubMed

    Chen, Shuai; Liu, Shuping; Zhang, Fengmei; Ren, Wenkai; Li, Nengzhang; Yin, Jie; Duan, Jielin; Peng, Yuanyi; Liu, Gang; Yin, Yulong; Wu, Guoyao

    2014-10-01

    Little is known about effects of dietary glutamine supplementation on specific and general defense responses in a vaccine-immunized animal model. Thus, this study determined roles for dietary glutamine supplementation in specific and general defense responses in mice immunized with inactivated Pasteurella multocida vaccine. The measured variables included: (1) the production of pathogen-specific antibodies; (2) mRNA levels for pro-inflammatory cytokines, toll-like receptors and anti-oxidative factors; and (3) the distribution of P. multocida in tissues and the expression of its major virulence factors in vivo. Dietary supplementation with 0.5 % glutamine had a better protective role than 1 or 2 % glutamine against P. multocida infection in vaccine-immunized mice, at least partly resulting from its effects in modulation of general defense responses. Dietary glutamine supplementation had little effects on the production of P. multocida-specific antibodies. Compared to the non-supplemented group, dietary supplementation with 0.5 % glutamine had no effect on bacterial burden in vivo but decreased the expression of major virulence factors in the spleen. Collectively, supplementing 0.5 % glutamine to a conventional diet provides benefits in vaccine-immunized mice by enhancing general defense responses and decreasing expression of specific virulence factors.

  5. Innate and adaptive immune responses to in utero infection with bovine viral diarrhea virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infection of pregnant cows with noncytopathic (ncp) BVDV induces rapid innate and adaptive immune responses resulting in clearance of the virus in less than 3 weeks. Seven to 14 days after inoculation of the cow, ncpBVDV crosses the placenta and induces a fetal viremia. Establishment of persistent ...

  6. IL-17A in Human Respiratory Diseases: Innate or Adaptive Immunity? Clinical Implications

    PubMed Central

    Bullens, Dominique M. A.; Decraene, Ann; Seys, Sven; Dupont, Lieven J.

    2013-01-01

    Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A), called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases. PMID:23401702

  7. Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205

    PubMed Central

    D'Apice, Luciana; Costa, Valerio; Sartorius, Rossella; Trovato, Maria; Aprile, Marianna; De Berardinis, Piergiuseppe

    2015-01-01

    The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response. PMID:26380324

  8. Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205.

    PubMed

    D'Apice, Luciana; Costa, Valerio; Sartorius, Rossella; Trovato, Maria; Aprile, Marianna; De Berardinis, Piergiuseppe

    2015-01-01

    The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response.

  9. Regulation of Adaptive Immunity in Health and Disease by Cholesterol Metabolism

    PubMed Central

    Fessler, Michael B.

    2015-01-01

    Four decades ago, it was observed that stimulation of T cells induces rapid changes in cellular cholesterol that are required before proliferation can commence. Investigators returning to this phenomenon have finally revealed its molecular underpinnings. Cholesterol trafficking and its dysregulation are now also recognized to strongly influence dendritic cell function, T cell polarization, and antibody responses. In this review, the state of the literature is reviewed on how cholesterol and its trafficking regulate the cells of the adaptive immune response and in vivo disease phenotypes of dysregulated adaptive immunity, including allergy, asthma, and autoimmune disease. Emerging evidence supporting a potential role for statins and other lipid-targeted therapies in the treatment of these diseases is presented. Just as vascular biologists have embraced immunity in the pathogenesis and treatment of atherosclerosis, so should basic and clinical immunologists in allergy, pulmonology, and other disciplines seek to encompass a basic understanding of lipid science. PMID:26149587

  10. Regulation of the Adaptive Immune Response by the IκB Family Protein Bcl-3

    PubMed Central

    Herrington, Felicity D.; Nibbs, Robert J. B.

    2016-01-01

    Bcl-3 is a member of the IκB family of proteins and an important regulator of Nuclear Factor (NF)-κB activity. The ability of Bcl-3 to bind and regulate specific NF-κB dimers has been studied in great depth, but its physiological roles in vivo are still not fully understood. It is, however, becoming clear that Bcl-3 is essential for the proper development, survival and activity of adaptive immune cells. Bcl-3 dysregulation can be observed in a number of autoimmune pathologies, and Bcl3-deficient animals are more susceptible to bacterial and parasitic infection. This review will describe our current understanding of the roles played by Bcl-3 in the development and regulation of the adaptive immune response, including lymphoid organogenesis, immune tolerance, lymphocyte function and dendritic cell biology. PMID:27023613

  11. Genome adaptations of a tripartite motif protein for retroviral defense in cattle and sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tripartite motif (TRIM) genes encode proteins composed of RING, B-box, and coiled coil motif domains. Primate TRIM5' has been shown to be a primary determinant of retroviral host cell range restriction in primates. TRIM5 restriction was originally thought to be a primate-specific defense mechanism...

  12. [The CRISPR case, « ready-made » mutations and Lamarckian evolution of an adaptive immunity system].

    PubMed

    Casane, Didier; Laurenti, Patrick

    2016-01-01

    Since genetics has shown that mutation predates selection, biology has developed within the Darwinian paradigm framework. However, a mechanism that produces favorable mutations preferentially in response to adaptive constraints has been recently identified. This mechanism, the CRISPR-Cas adaptive immunity system, is considered as a bona fide example of Lamarckian evolution, even if it only reflects loosely Lamarck's ideas. This unusual evolutionary process is made possible by two prokaryotic properties: i) somatic and germinal cells are not distinct sets of cells; ii) Archae and Bacteria very frequently integrate DNA fragments from the environment, and they therefore have access to a source of "ready-made" useful genetic information. The CRISPR-Cas is a defense system against viruses and plasmids that is based on the integration of genomic fragments of these infectious agents into the host genome, and that protects the host against subsequent infections. Therefore, this mechanism does produce advantageous mutations by integrating DNA from the environment and allowing its transmission to descendants. In conclusion, most of the time evolution relies on purely Darwinian processes, i.e. mutations occurring at random, but in a small minority of cases the occurrence of mutations is more or less biased, and is therefore more or less Lamarckian. Although they are rare, such processes are nevertheless important to our understanding of the plurality of modes of evolution. PMID:27406776

  13. Recognition of Extracellular Bacteria by NLRs and Its Role in the Development of Adaptive Immunity

    PubMed Central

    Ferrand, Jonathan; Ferrero, Richard Louis

    2013-01-01

    Innate immune recognition of bacteria is the first requirement for mounting an effective immune response able to control infection. Over the previous decade, the general paradigm was that extracellular bacteria were only sensed by cell surface-expressed Toll-like receptors (TLRs), whereas cytoplasmic sensors, including members of the Nod-like receptor (NLR) family, were specific to pathogens capable of breaching the host cell membrane. It has become apparent, however, that intracellular innate immune molecules, such as the NLRs, play key roles in the sensing of not only intracellular, but also extracellular bacterial pathogens or their components. In this review, we will discuss the various mechanisms used by bacteria to activate NLR signaling in host cells. These mechanisms include bacterial secretion systems, pore-forming toxins, and outer membrane vesicles. We will then focus on the influence of NLR activation on the development of adaptive immune responses in different cell types. PMID:24155747

  14. [Demographic aspects of adaptive changes of human immune system in the North].

    PubMed

    Gelfgat, E L; Lozovoĭ, V P; Konenkov, V I

    1993-01-01

    The dynamics of an immunotypological structure in migrants in Magadan was studied in relation to the duration of residence in the North. The changes were assessed by the integrated immune heterogeneity index, the atypic immune status index, frequencies of some immune phenotypes, the prevalence of clinical immunopathological signs and HLA Class 1 antigen distribution in the groups of the examinees. The dynamics of the immunotypological structure of migrants to the North was shown to have regular features depending upon the duration of "life in the North", some certain time-dependent, qualitative and quantitative characteristics. The mechanisms of some changes in the population immune structure and their role in the adaptation of northern newcomers to extreme ecological conditions are discussed.

  15. Beyond TLR Signaling—The Role of SARM in Antiviral Immune Defense, Apoptosis & Development.

    PubMed

    Panneerselvam, Porkodi; Ding, Jeak Ling

    2015-01-01

    SARM (Sterile alpha and armadillo motif-containing protein) is the recently identified TIR domain-containing cytosolic protein. Classified as a member of the TLR adaptor family, the multiple locations and functions of SARM (sometimes playing opposing roles), provoke an enigma on its biology. Although originally assumed to be a member of the TLR adaptor family (functioning as a negative regulator of TLR signaling pathway), latest findings indicate that SARM regulates signaling differently from other TLR adaptor proteins. Recent studies have highlighted the significant functional role of SARM in mediating apoptosis and antiviral innate immune response. In this review, we provide an update on the evolutionary conservation, spatial distribution, and regulated expression of SARM to highlight its diverse functional roles. The review will summarize findings on the known interacting partners of SARM and provide analogy on how they add new dimensions to the current understanding on the multifaceted roles of SARM in antiviral activities and apoptotic functions. In addition, we provide a future perspective on the roles of SARM in differentiation and development, with substantial emphasis on the molecular insights to its mechanisms of action. PMID:26268046

  16. Lipocalin-2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response

    PubMed Central

    Nairz, Manfred; Schroll, Andrea; Haschka, David; Dichtl, Stefanie; Sonnweber, Thomas; Theurl, Igor; Theurl, Milan; Lindner, Ewald; Demetz, Egon; Aβhoff, Malte; Bellmann-Weiler, Rosa; Müller, Raphael; Gerner, Romana R.; Moschen, Alexander R.; Baumgartner, Nadja; Moser, Patrizia L.; Talasz, Heribert; Tilg, Herbert; Fang, Ferric C.; Weiss, Günter

    2015-01-01

    Lipocalin-2 (Lcn2) is an innate immune peptide with pleiotropic effects. Lcn2 binds iron-laden bacterial siderophores, chemo-attracts neutrophils and has immunomodulatory and apoptosis-regulating effects. In this study we show that upon infection with Salmonella enterica serovar Typhimurium, Lcn2 promotes iron export from Salmonella-infected macrophages, which reduces cellular iron content and enhances the generation of pro-inflammatory cytokines. Lcn2 represses IL-10 production while augmenting Nos2, TNF-α and IL-6 expression. Lcn2-/- macrophages have elevated IL-10 levels as a consequence of increased iron content. The crucial role of Lcn-2/IL-10 interactions was further demonstrated by the greater ability of Lcn2-/- IL-10-/- macrophages and mice to control intracellular Salmonella proliferation in comparison to Lcn2-/- counterparts. Over-expression of the iron exporter ferroportin-1 in Lcn2-/- macrophages represses IL-10 and restores TNF-α and IL-6 production to the levels found in wild-type macrophages, so that killing and clearance of intracellular Salmonella is promoted. Our observations suggest that Lcn2 promotes host resistance to Salmonella Typhimurium infection by binding bacterial siderophores and suppressing IL-10 production, and that both functions are linked to its ability to shuttle iron from macrophages. PMID:26332507

  17. HDAC2 deregulation in tumorigenesis is causally connected to repression of immune modulation and defense escape.

    PubMed

    Conte, Mariarosaria; Dell'Aversana, Carmela; Benedetti, Rosaria; Petraglia, Francesca; Carissimo, Annamaria; Petrizzi, Valeria Belsito; D'Arco, Alfonso Maria; Abbondanza, Ciro; Nebbioso, Angela; Altucci, Lucia

    2015-01-20

    Histone deacetylase 2 (HDAC2) is overexpressed or mutated in several disorders such as hematological cancers, and plays a critical role in transcriptional regulation, cell cycle progression and developmental processes. Here, we performed comparative transcriptome analyses in acute myeloid leukemia to investigate the biological implications of HDAC2 silencing versus its enzymatic inhibition using epigenetic-based drug(s). By gene expression analysis of HDAC2-silenced vs wild-type cells, we found that HDAC2 has a specific role in leukemogenesis. Gene expression profiling of U937 cell line with or without treatment of the well-known HDAC inhibitor vorinostat (SAHA) identifies and characterizes several gene clusters where inhibition of HDAC2 'mimics' its silencing, as well as those where HDAC2 is selectively and exclusively regulated by HDAC2 protein expression levels. These findings may represent an important tool for better understanding the mechanisms underpinning immune regulation, particularly in the study of major histocompatibility complex class II genes. PMID:25473896

  18. Graphene Oxides Decorated with Carnosine as an Adjuvant To Modulate Innate Immune and Improve Adaptive Immunity in Vivo.

    PubMed

    Meng, Chunchun; Zhi, Xiao; Li, Chao; Li, Chuanfeng; Chen, Zongyan; Qiu, Xusheng; Ding, Chan; Ma, Lijun; Lu, Hongmin; Chen, Di; Liu, Guangqing; Cui, Daxiang

    2016-02-23

    Current studies have revealed the immune effects of graphene oxide (GO) and have utilized them as vaccine carriers and adjuvants. However, GO easily induces strong oxidative stress and inflammatory reaction at the site of injection. It is very necessary to develop an alternative adjuvant based on graphene oxide derivatives for improving immune responses and decreasing side effects. Carnosine (Car) is an outstanding and safe antioxidant. Herein, the feasibility and efficiency of ultrasmall graphene oxide decorated with carnosine as an alternative immune adjuvant were explored. OVA@GO-Car was prepared by simply mixing ovalbumin (OVA, a model antigen) with ultrasmall GO covalently modified with carnosine (GO-Car). We investigated the immunological properties of the GO-Car adjuvant in model mice. Results show that OVA@GO-Car can promote robust and durable OVA-specific antibody response, increase lymphocyte proliferation efficiency, and enhance CD4(+) T and CD8(+) T cell activation. The presence of Car in GO also probably contributes to enhancing the antigen-specific adaptive immune response through modulating the expression of some cytokines, including IL-6, CXCL1, CCL2, and CSF3. In addition, the safety of GO-Car as an adjuvant was evaluated comprehensively. No symptoms such as allergic response, inflammatory redness swelling, raised surface temperatures, physiological anomalies of blood, and remarkable weight changes were observed. Besides, after modification with carnosine, histological damages caused by GO-Car in lung, muscle, kidney, and spleen became weaken significantly. This study sufficiently suggest that GO-Car as a safe adjuvant can effectively enhance humoral and innate immune responses against antigens in vivo.

  19. The 3 major types of innate and adaptive cell-mediated effector immunity.

    PubMed

    Annunziato, Francesco; Romagnani, Chiara; Romagnani, Sergio

    2015-03-01

    The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet(+) IFN-γ-producing group 1 ILCs (ILC1 and natural killer cells), CD8(+) cytotoxic T cells (TC1), and CD4(+) TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3(+) ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid-related orphan receptor γt(+) ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases.

  20. Sublingual Vaccination Induces Mucosal and Systemic Adaptive Immunity for Protection against Lung Tumor Challenge

    PubMed Central

    Singh, Shailbala; Yang, Guojun; Schluns, Kimberly S.; Anthony, Scott M.; Sastry, K. Jagannadha

    2014-01-01

    Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA) metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer) for harnessing the adjuvant potential of natural killer T (NKT) cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases. PMID:24599269

  1. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium.

    PubMed

    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-08-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4(+) T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses.

  2. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium

    PubMed Central

    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-01-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4+ T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses. PMID:21631497

  3. Tissue-specific defense and thermo-adaptive mechanisms of soybean seedlings under heat stress revealed by proteomic approach.

    PubMed

    Ahsan, Nagib; Donnart, Tifenn; Nouri, Mohammad-Zaman; Komatsu, Setsuko

    2010-08-01

    A comparative proteomic approach was employed to explore tissue-specific protein expression patterns in soybean seedlings under heat stress. The changes in the protein expression profiles of soybean seedling leaves, stems, and roots were analyzed after exposure to high temperatures. A total of 54, 35, and 61 differentially expressed proteins were identified from heat-treated leaves, stems, and roots, respectively. Differentially expressed heat shock proteins (HSPs) and proteins involved in antioxidant defense were mostly up-regulated, whereas proteins associated with photosynthesis, secondary metabolism, and amino acid and protein biosynthesis were down-regulated in response to heat stress. A group of proteins, specifically low molecular weight HSPs and HSP70, were up-regulated and expressed in a similar manner in all tissues. Proteomic analysis indicated that the responses of HSP70, CPN-60 beta, and ChsHSP were tissue specific, and this observation was validated by immunoblot analysis. The heat-responsive sHSPs were not induced by other stresses such as cold and hydrogen peroxide. Taken together, these results suggest that to cope with heat stress soybean seedlings operate tissue-specific defenses and adaptive mechanisms, whereas a common defense mechanism associated with the induction of several HSPs was employed in all three tissues. In addition, tissue-specific proteins may play a crucial role in defending each type of tissues against thermal stress.

  4. A novel ortholog of serum response factor (SRF) with immune defense function identified in Crassostrea hongkongensis.

    PubMed

    Xiang, Zhiming; Qu, Fufa; Qi, Lin; Zhang, Yang; Xiao, Shu; Yu, Ziniu

    2014-01-01

    Serum response factor (SRF) function is essential for transcriptional regulation of numerous growth-factor-inducible genes and triggers proliferation, differentiation and apoptosis of the cells. In this report, the first mollusk serum response factor like homolog gene (designated ChSRF) was identified and characterized from the Hong Kong oyster, Crassostrea hongkongensis. The full-length cDNA of ChSRF was 1716 bp in length and encodes a putative protein of 434 amino acids respectively, and shares the MADS domain at the N-terminal. ChSRF is ubiquitously expressed in various tissues, with the highest expression level observed in muscle. Temporal expression of ChSRF following microbe infection shows that the expression of ChSRF in hemocytes increases from 3 to 24 h post-challenge. As a target gene of SRF, β-actin demonstrates a similar gene expression mode in constitutive tissue and pathogen infection. Furthermore, some protein profiles of ChSRF was revealed, fluorescence microscopy results show that ChSRF located in the nuclei of HeLa cells and over-expression of ChSRF activated the transcriptional activities of MAPK signal pathway in HEK293T cells. These results indicate that ChSRF maybe play an important role in signal transduction in the immunity and development response of oysters. Furthermore, we found that ChSRF could regulate the expression of β-actin gene, which indicate that ChSRF is a muscle differentiation regulator in the oyster and it will help us to improve aquaculture production.

  5. The identification of the first molluscan Akirin2 with immune defense function in the Hong Kong oyster Crassostrea hongkongensis.

    PubMed

    Qu, Fufa; Xiang, Zhiming; Zhang, Yang; Li, Jun; Zhang, Yuehuan; Yu, Ziniu

    2014-12-01

    The Akirin protein is a nuclear factor in the innate immune system that is highly conserved from insects to mammals and plays key roles in diverse biological processes, including immunity, myogenesis, development and the cellular stress response. However, the function of Akirins in mollusk, the second most diverse group of animals, is still poorly understood. In this study, we report the discovery of an Akirin2 gene homolog (ChAkirin2) and its biological functions in the Hong Kong oyster Crassostrea hongkongensis. ChAkirin2 is 189 amino acids in length and shares significant homology with invertebrate homologs. Phylogenetic analysis results revealed that ChAkirin2 is clustered with invertebrate Akirin2s. A sequence analysis of the 5' flanking regions of ChAkirin2 indicated that it harbors several potential PAMP-activated transcription factor binding sites (TFB), including sites for NF-κB, C/EBPα, AP-1, SRF, Oct-1 and GATA-1. An RT-PCR analysis showed that ChAkirin2 mRNA was ubiquitously expressed in various tissues and at different embryonic and larval stages. Additionally, upon infection by pathogens (Vibrio alginolyticus, Staphylococcus haemolyticus and Saccharomyces cerevisiae) and pathogen-associated molecular patterns (PAMPs: LPS, PGN and polyI:C), the expression of ChAkirin2 was significantly up-regulated. Moreover, fluorescence microscopy observations show that ChAkirin2 is located in the nuclei of HeLa cells, and the overexpression of ChAkirin2 activated the transcriptional activities of the NF-κB reporter gene in HEK293T cells. Altogether, this report provided the first experimental demonstration that mollusks possess a functional Akirin2 that is involved in the innate defense and embryogenesis processes of the oyster.

  6. CsCCL17, a CC chemokine of Cynoglossus semilaevis, induces leukocyte trafficking and promotes immune defense against viral infection.

    PubMed

    Hu, Yong-Hua; Zhang, Jian

    2015-08-01

    CC chemokines are the largest subfamily of chemokines, which are important components of the innate immune system. To date, sequences of several CC chemokines have been identified in half-smooth tongue sole (Cynoglossus semilaevis); however, the activities and functions of these putative chemokines remain unknown. Herein, we characterized a CC chemokine, CsCCL17, from tongue sole, and examined its activity. CsCCL17 contains a 303 bp open reading frame, which encodes a polypeptide of 100 amino acids with a molecular mass of 12 kDa CsCCL17 is phylogenetically related to the CCL17/22 group of CC chemokines and possesses the typical arrangement of four cysteines and an SCCR motif found in known CC chemokines. Under normal physiological conditions, CsCCL17 expression was detected in spleen, liver, heart, gill, head kidney, muscle, brain, and intestine. When the fish were infected by bacterial and viral pathogens, CsCCL17 expression was significantly up-regulated in a time-dependent manner. Chemotactic analysis showed that recombinant CsCCL17 (rCsCCL17) induced migration of peripheral blood leukocytes. A mutagenesis study showed that when the two cysteine residues in the SCCR motif were replaced by serine, no apparent chemotactic activity was observed in the mutant protein rCsCCL17M. rCsCCL17 enhanced the resistance of tongue sole against viral infection, but rCsCCL17M lacked this antiviral effect. Taken together, these findings indicate that CsCCL17 is a functional CC chemokine with the ability to recruit leukocytes and enhance host immune defense in a manner that requires the conserved SCCR motif.

  7. A thymosin beta-4 is involved in production of hemocytes and immune defense of Hong Kong oyster, Crassostrea hongkongensis.

    PubMed

    Li, Jun; Zhang, Yuehuan; Liu, Ying; Zhang, Yang; Xiang, Zhiming; Qu, Fufa; Yu, Ziniu

    2016-04-01

    Thymosin beta-4 (Tβ4) is a ubiquitous protein with multiple and diverse intracellular and extracellular functions in vertebrates. In this study, the full-length cDNA of Tβ4 was cloned and identified in Crassostrea hongkongensis, designated as ChTβ4. The full-length cDNA of ChTβ4 consists of 530 bp with an open reading frame of 126 bp encoding a 41 amino acid polypeptide. SMART analysis indicated that there is one thymosin domain and a highly conserved actin-binding motif (18LKKTET23) in ChTβ4. In vivo injection of recombinant ChTβ4 protein could significantly increase total hemocytes count in oysters, and knockdown of the expression of ChTβ4 resulted in a significant decrease in the circulating hemocytes. Tissue distribution analysis revealed a ubiquitous presence of ChTβ4, with the highest expression in hemocytes. The upregulated transcripts of ChTβ4 in response to bacterial challenge and tissue injury suggest that ChTβ4 is involved in both innate immunity against pathogen infection and wound healing. Moreover, bacteria-clearance experiment showed ChTβ4 could facilitate the clearance of injected bacteria in oysters. In vivo injection with ChTβ4 resulted in reduction of the intracellular ROS in hemocytes, which was associated with increased expression of antioxidant enzymes Cu/Zn superoxide dismutase (SOD), Catalase, and Glutathione Peroxidase (GPX) by pre-treatment with ChTβ4. These results suggest that ChTβ4 is a thymosin beta-4 homolog and plays a vital role in the immune defense of C. hongkongensis.

  8. Plasmatocyte-spreading peptide (PSP) plays a central role in insect cellular immune defenses against bacterial infection.

    PubMed

    Eleftherianos, I; Xu, M; Yadi, H; Ffrench-Constant, R H; Reynolds, S E

    2009-06-01

    Insect hemocytes (blood cells) are a central part of the insect's cellular response to bacterial pathogens, and these specialist cells can both recognize and engulf bacteria. During this process, hemocytes undergo poorly characterized changes in adhesiveness. Previously, a peptide termed plasmatocyte-spreading peptide (PSP), which induces the adhesion and spreading of plasmatocytes on foreign surfaces, has been identified in lepidopteran insects. Here, we investigate the function of this peptide in the moth Manduca sexta using RNA interference (RNAi) to prevent expression of the precursor protein proPSP. We show that infection with the insect-specific bacterial pathogen Photorhabdus luminescens and non-pathogenic Escherichia coli induces proPSP mRNA transcription in the insect fat body but not in hemocytes; subsequently, proPSP protein can be detected in cell-free hemolymph. We used RNAi to silence this upregulation of proPSP and found that the knock-down insects succumbed faster to infection with P. luminescens, but not E. coli. RNAi-treated insects infected with E. coli showed a reduction in the number of circulating hemocytes and higher bacterial growth in hemolymph as well as a reduction in overall cellular immune function compared with infected controls. Interestingly, RNAi-mediated depletion of proPSP adversely affected the formation of melanotic nodules but had no additional effect on other cellular responses when insects were infected with P. luminescens, indicating that this pathogen employs mechanisms that suppress key cellular immune functions in M. sexta. Our results provide evidence for the central role of PSP in M. sexta cellular defenses against bacterial infections. PMID:19483002

  9. Unconscious Vigilance: Worldview Defense Without Adaptations for Terror, Coalition, or Uncertainty Management

    PubMed Central

    Holbrook, Colin; Sousa, Paulo; Hahn-Holbrook, Jennifer

    2012-01-01

    Individuals subtly reminded of death, coalitional challenges, or feelings of uncertainty display exaggerated preferences for affirmations and against criticisms of their cultural in-groups. Terror management, coalitional psychology, and uncertainty management theories postulate this “worldview defense” effect as the output of mechanisms evolved either to allay the fear of death, foster social support, or reduce anxiety by increasing adherence to cultural values. In 4 studies, we report evidence for an alternative perspective. We argue that worldview defense owes to unconscious vigilance, a state of accentuated reactivity to affective targets (which need not relate to cultural worldviews) that follows detection of subtle alarm cues (which need not pertain to death, coalitional challenges, or uncertainty). In Studies 1 and 2, death-primed participants produced exaggerated ratings of worldview-neutral affective targets. In Studies 3 and 4, subliminal threat manipulations unrelated to death, coalitional challenges, or uncertainty evoked worldview defense. These results are discussed as they inform evolutionary interpretations of worldview defense and future investigations of the influence of unconscious alarm on judgment. PMID:21644809

  10. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

    PubMed

    Koyama, Shohei; Akbay, Esra A; Li, Yvonne Y; Herter-Sprie, Grit S; Buczkowski, Kevin A; Richards, William G; Gandhi, Leena; Redig, Amanda J; Rodig, Scott J; Asahina, Hajime; Jones, Robert E; Kulkarni, Meghana M; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E; Johnson, Bruce E; Janne, Pasi A; Engelman, Jeffrey A; Gangadharan, Sidharta P; Costa, Daniel B; Freeman, Gordon J; Bueno, Raphael; Hodi, F Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S

    2016-01-01

    Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade. PMID:26883990

  11. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

    PubMed Central

    Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Richards, William G.; Gandhi, Leena; Redig, Amanda J.; Rodig, Scott J.; Asahina, Hajime; Jones, Robert E.; Kulkarni, Meghana M.; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E.; Johnson, Bruce E.; Janne, Pasi A.; Engelman, Jeffrey A.; Gangadharan, Sidharta P.; Costa, Daniel B.; Freeman, Gordon J.; Bueno, Raphael; Hodi, F. Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S.

    2016-01-01

    Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade. PMID:26883990

  12. Transcriptional Analysis of The Adaptive Digestive System of The Migratory Locust in Response to Plant Defensive Protease Inhibitors

    PubMed Central

    Spit, Jornt; Holtof, Michiel; Badisco, Liesbet; Vergauwen, Lucia; Vogel, Elise; Knapen, Dries; Vanden Broeck, Jozef

    2016-01-01

    Herbivorous insects evolved adaptive mechanisms to compensate for the presence of plant defensive protease inhibitors (PI) in their food. The underlying regulatory mechanisms of these compensatory responses remain largely elusive. In the current study, we investigated the initiation of this adaptive response in the migratory locust, Locusta migratoria, via microarray analysis of gut tissues. Four hours after dietary uptake of PIs, 114 and 150 transcripts were respectively found up- or downregulated. The results suggest a quick trade-off between compensating for potential loss of digestive activity on the one hand, and stress tolerance, defense, and structural integrity of the gut on the other hand. We additionally addressed the role of a group of related upregulated hexamerin-like proteins in the PI-induced response. Simultaneous knockdown of corresponding transcripts by means of RNA interference resulted in a reduced capacity of the locust nymphs to cope with the effects of PI. Moreover, since insect hexamerins have been shown to bind Juvenile Hormone (JH), we also investigated the effect of JH on the proteolytic digestion in L. migratoria. Our results indicate that JH has a stimulatory effect on the expression of three homologous chymotrypsin genes, while knocking down the JH receptor (methoprene tolerant) led to opposite effects. PMID:27581362

  13. Transcriptional Analysis of The Adaptive Digestive System of The Migratory Locust in Response to Plant Defensive Protease Inhibitors

    NASA Astrophysics Data System (ADS)

    Spit, Jornt; Holtof, Michiel; Badisco, Liesbet; Vergauwen, Lucia; Vogel, Elise; Knapen, Dries; vanden Broeck, Jozef

    2016-09-01

    Herbivorous insects evolved adaptive mechanisms to compensate for the presence of plant defensive protease inhibitors (PI) in their food. The underlying regulatory mechanisms of these compensatory responses remain largely elusive. In the current study, we investigated the initiation of this adaptive response in the migratory locust, Locusta migratoria, via microarray analysis of gut tissues. Four hours after dietary uptake of PIs, 114 and 150 transcripts were respectively found up- or downregulated. The results suggest a quick trade-off between compensating for potential loss of digestive activity on the one hand, and stress tolerance, defense, and structural integrity of the gut on the other hand. We additionally addressed the role of a group of related upregulated hexamerin-like proteins in the PI-induced response. Simultaneous knockdown of corresponding transcripts by means of RNA interference resulted in a reduced capacity of the locust nymphs to cope with the effects of PI. Moreover, since insect hexamerins have been shown to bind Juvenile Hormone (JH), we also investigated the effect of JH on the proteolytic digestion in L. migratoria. Our results indicate that JH has a stimulatory effect on the expression of three homologous chymotrypsin genes, while knocking down the JH receptor (methoprene tolerant) led to opposite effects.

  14. Transcriptional Analysis of The Adaptive Digestive System of The Migratory Locust in Response to Plant Defensive Protease Inhibitors.

    PubMed

    Spit, Jornt; Holtof, Michiel; Badisco, Liesbet; Vergauwen, Lucia; Vogel, Elise; Knapen, Dries; Vanden Broeck, Jozef

    2016-01-01

    Herbivorous insects evolved adaptive mechanisms to compensate for the presence of plant defensive protease inhibitors (PI) in their food. The underlying regulatory mechanisms of these compensatory responses remain largely elusive. In the current study, we investigated the initiation of this adaptive response in the migratory locust, Locusta migratoria, via microarray analysis of gut tissues. Four hours after dietary uptake of PIs, 114 and 150 transcripts were respectively found up- or downregulated. The results suggest a quick trade-off between compensating for potential loss of digestive activity on the one hand, and stress tolerance, defense, and structural integrity of the gut on the other hand. We additionally addressed the role of a group of related upregulated hexamerin-like proteins in the PI-induced response. Simultaneous knockdown of corresponding transcripts by means of RNA interference resulted in a reduced capacity of the locust nymphs to cope with the effects of PI. Moreover, since insect hexamerins have been shown to bind Juvenile Hormone (JH), we also investigated the effect of JH on the proteolytic digestion in L. migratoria. Our results indicate that JH has a stimulatory effect on the expression of three homologous chymotrypsin genes, while knocking down the JH receptor (methoprene tolerant) led to opposite effects. PMID:27581362

  15. Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment.

    PubMed

    Debnath, Monojit

    2015-12-01

    Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.

  16. Synthesizing within-host and population-level selective pressures on viral populations: the impact of adaptive immunity on viral immune escape

    PubMed Central

    Volkov, Igor; Pepin, Kim M.; Lloyd-Smith, James O.; Banavar, Jayanth R.; Grenfell, Bryan T.

    2010-01-01

    The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these scales. Our epidemiological model incorporates within-host viral evolutionary dynamics for a virus that causes acute infections (e.g. influenza and norovirus) with changes in host immunity in response to genetic changes in the virus population. We use a deterministic description of the within-host replication dynamics of the virus, the pool of susceptible host cells and the host adaptive immune response. We find that viral immune escape is most effective at intermediate values of immune strength. At very low levels of immunity, selection is too weak to drive immune escape in recovered hosts, while very high levels of immunity impose such strong selection that viral subpopulations go extinct before acquiring enough genetic diversity to escape host immunity. This result echoes the predictions of simpler models, but our formulation allows us to dissect the combination of within-host and transmission-level processes that drive immune escape. PMID:20335194

  17. The Cnes2 locus on mouse chromosome 17 regulates host defense against cryptococcal infection through pleiotropic effects on host immunity.

    PubMed

    Shourian, Mitra; Flaczyk, Adam; Angers, Isabelle; Mindt, Barbara C; Fritz, Jörg H; Qureshi, Salman T

    2015-12-01

    The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b(+) dendritic cells, and CD4(+) cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.

  18. The First Line of Defense: The Effects of Alcohol on Post-Burn Intestinal Barrier, Immune Cells, and Microbiome.

    PubMed

    Hammer, Adam M; Morris, Niya L; Earley, Zachary M; Choudhry, Mashkoor A

    2015-01-01

    Alcohol (ethanol) is one of the most globally abused substances, and is one of the leading causes of premature death in the world. As a result of its complexity and direct contact with ingested alcohol, the intestine represents the primary source from which alcohol-associated pathologies stem. The gut is the largest reservoir of bacteria in the body, and under healthy conditions, it maintains a barrier preventing bacteria from translocating out of the intestinal lumen. The intestinal barrier is compromised following alcohol exposure, which can lead to life-threatening systemic complications including sepsis and multiple organ failure. Furthermore, alcohol is a major confounding factor in pathology associated with trauma. Experimental data from both human and animal studies suggest that alcohol perturbs the intestinal barrier and its function, which is exacerbated by a "second hit" from traumatic injury. This article highlights the role of alcohol-mediated alterations of the intestinal epithelia and its defense against bacteria within the gut, and the impact of alcohol on intestinal immunity, specifically on T cells and neutrophils. Finally, it discusses how the gut microbiome both contributes to and protects the intestines from dysbiosis after alcohol exposure and trauma.

  19. The Pelargonium sidoides Extract EPs 7630 Drives the Innate Immune Defense by Activating Selected MAP Kinase Pathways in Human Monocytes.

    PubMed

    Witte, Katrin; Koch, Egon; Volk, Hans-Dieter; Wolk, Kerstin; Sabat, Robert

    2015-01-01

    Pelargonium sidoides is a medical herb and respective extracts are used very frequently for the treatment of respiratory tract infections. However, the effects of Pelargonium sidoides and a special extract prepared from its roots (EPs 7630) on human immune cells are not fully understood. Here we demonstrate that EPs 7630 induced a rapid and dose-dependent production of TNF-α, IL-6, and IL-10 by human blood immune cells. This EPs 7630-induced cytokine profile was more pro-inflammatory in comparison with the profile induced by viral or bacterial infection-mimicking agents. The search for EPs 7630 target cells revealed that T-cells did not respond to EPs 7630 stimulation by production of TNF-α, IL-6, or IL-10. Furthermore, pretreatment of T-cells with EPs 7630 did not modulate their TNF-α, IL-6, and IL-10 secretion during subsequent activation. In contrast to lymphocytes, monocytes showed clear intracellular TNF-α staining after EPs 7630 treatment. Accordingly, EPs 7630 predominantly provoked activation of MAP kinases and inhibition of p38 strongly reduced the monocyte TNF-α production. The pretreatment of blood immune cells with EPs 7630 lowered their secretion of TNF-α and IL-10 and caused an IL-6 dominant response during second stimulation with viral or bacterial infection-mimicking agents. In summary, we demonstrate that EPs 7630 activates human monocytes, induces MAP kinase-dependent pro-inflammatory cytokines in these cells, and specifically modulates their production capacity of mediators known to lead to an increase of acute phase protein production in the liver, neutrophil generation in the bone marrow, and the generation of adaptive Th17 and Th22 cells.

  20. The Pelargonium sidoides Extract EPs 7630 Drives the Innate Immune Defense by Activating Selected MAP Kinase Pathways in Human Monocytes.

    PubMed

    Witte, Katrin; Koch, Egon; Volk, Hans-Dieter; Wolk, Kerstin; Sabat, Robert

    2015-01-01

    Pelargonium sidoides is a medical herb and respective extracts are used very frequently for the treatment of respiratory tract infections. However, the effects of Pelargonium sidoides and a special extract prepared from its roots (EPs 7630) on human immune cells are not fully understood. Here we demonstrate that EPs 7630 induced a rapid and dose-dependent production of TNF-α, IL-6, and IL-10 by human blood immune cells. This EPs 7630-induced cytokine profile was more pro-inflammatory in comparison with the profile induced by viral or bacterial infection-mimicking agents. The search for EPs 7630 target cells revealed that T-cells did not respond to EPs 7630 stimulation by production of TNF-α, IL-6, or IL-10. Furthermore, pretreatment of T-cells with EPs 7630 did not modulate their TNF-α, IL-6, and IL-10 secretion during subsequent activation. In contrast to lymphocytes, monocytes showed clear intracellular TNF-α staining after EPs 7630 treatment. Accordingly, EPs 7630 predominantly provoked activation of MAP kinases and inhibition of p38 strongly reduced the monocyte TNF-α production. The pretreatment of blood immune cells with EPs 7630 lowered their secretion of TNF-α and IL-10 and caused an IL-6 dominant response during second stimulation with viral or bacterial infection-mimicking agents. In summary, we demonstrate that EPs 7630 activates human monocytes, induces MAP kinase-dependent pro-inflammatory cytokines in these cells, and specifically modulates their production capacity of mediators known to lead to an increase of acute phase protein production in the liver, neutrophil generation in the bone marrow, and the generation of adaptive Th17 and Th22 cells. PMID:26406906

  1. Innate and adaptive immune responses in migrating spring-run adult chinook salmon, Oncorhynchus tshawytscha.

    PubMed

    Dolan, Brian P; Fisher, Kathleen M; Colvin, Michael E; Benda, Susan E; Peterson, James T; Kent, Michael L; Schreck, Carl B

    2016-01-01

    Adult Chinook salmon (Oncorhynchus tshawytscha) migrate from salt water to freshwater streams to spawn. Immune responses in migrating adult salmon are thought to diminish in the run up to spawning, though the exact mechanisms for diminished immune responses remain unknown. Here we examine both adaptive and innate immune responses as well as pathogen burdens in migrating adult Chinook salmon in the Upper Willamette River basin. Messenger RNA transcripts encoding antibody heavy chain molecules slightly diminish as a function of time, but are still present even after fish have successfully spawned. In contrast, the innate anti-bacterial effector proteins present in fish plasma rapidly decrease as spawning approaches. Fish also were examined for the presence and severity of eight different pathogens in different organs. While pathogen burden tended to increase during the migration, no specific pathogen signature was associated with diminished immune responses. Transcript levels of the immunosuppressive cytokines IL-10 and TGF beta were measured and did not change during the migration. These results suggest that loss of immune functions in adult migrating salmon are not due to pathogen infection or cytokine-mediated immune suppression, but is rather part of the life history of Chinook salmon likely induced by diminished energy reserves or hormonal changes which accompany spawning.

  2. Innate and adaptive immune responses in migrating spring-run adult chinook salmon, Oncorhynchus tshawytscha.

    PubMed

    Dolan, Brian P; Fisher, Kathleen M; Colvin, Michael E; Benda, Susan E; Peterson, James T; Kent, Michael L; Schreck, Carl B

    2016-01-01

    Adult Chinook salmon (Oncorhynchus tshawytscha) migrate from salt water to freshwater streams to spawn. Immune responses in migrating adult salmon are thought to diminish in the run up to spawning, though the exact mechanisms for diminished immune responses remain unknown. Here we examine both adaptive and innate immune responses as well as pathogen burdens in migrating adult Chinook salmon in the Upper Willamette River basin. Messenger RNA transcripts encoding antibody heavy chain molecules slightly diminish as a function of time, but are still present even after fish have successfully spawned. In contrast, the innate anti-bacterial effector proteins present in fish plasma rapidly decrease as spawning approaches. Fish also were examined for the presence and severity of eight different pathogens in different organs. While pathogen burden tended to increase during the migration, no specific pathogen signature was associated with diminished immune responses. Transcript levels of the immunosuppressive cytokines IL-10 and TGF beta were measured and did not change during the migration. These results suggest that loss of immune functions in adult migrating salmon are not due to pathogen infection or cytokine-mediated immune suppression, but is rather part of the life history of Chinook salmon likely induced by diminished energy reserves or hormonal changes which accompany spawning. PMID:26581919

  3. Innate and adaptive immune responses in migrating spring-run adult chinook salmon, Oncorhynchus tshawytscha

    USGS Publications Warehouse

    Dolan, Brian P.; Fisher, Kathleen M.; Colvin, Michael E.; Benda, Susan E.; Peterson, James T.; Kent, Michael L.; Schreck, Carl B.

    2016-01-01

    Adult Chinook salmon (Oncorhynchus tshawytscha) migrate from salt water to freshwater streams to spawn. Immune responses in migrating adult salmon are thought to diminish in the run up to spawning, though the exact mechanisms for diminished immune responses remain unknown. Here we examine both adaptive and innate immune responses as well as pathogen burdens in migrating adult Chinook salmon in the Upper Willamette River basin. Messenger RNA transcripts encoding antibody heavy chain molecules slightly diminish as a function of time, but are still present even after fish have successfully spawned. In contrast, the innate anti-bacterial effector proteins present in fish plasma rapidly decrease as spawning approaches. Fish also were examined for the presence and severity of eight different pathogens in different organs. While pathogen burden tended to increase during the migration, no specific pathogen signature was associated with diminished immune responses. Transcript levels of the immunosuppressive cytokines IL-10 and TGF beta were measured and did not change during the migration. These results suggest that loss of immune functions in adult migrating salmon are not due to pathogen infection or cytokine-mediated immune suppression, but is rather part of the life history of Chinook salmon likely induced by diminished energy reserves or hormonal changes which accompany spawning.

  4. Expression proteomics identifies biochemical adaptations and defense responses in transgenic plants with perturbed polyamine metabolism.

    PubMed

    Franceschetti, Marina; Perry, Barry; Thompson, Benjamin; Hanfrey, Colin; Michael, Anthony J

    2004-10-22

    Soluble proteins from leaves of transgenic tobacco plants with perturbed polyamine metabolism, caused by S-adenosylmethionine decarboxylase overexpression, were analysed by comparative proteomics. A group of proteins was found to be increasingly repressed, in parallel with the degree of polyamine perturbation, in each of the three independent transgenic lines. These were identified as isoforms of chloroplast ribonucleoproteins, known to be involved in chloroplast mRNA stability, processing and translation. Another group of eight proteins strongly induced in the most metabolically perturbed line was identified as multiple, uncharacterised isoforms of the defense protein PR-1, a known marker for systemic acquired resistance.

  5. A cascade reaction network mimicking the basic functional steps of adaptive immune response

    NASA Astrophysics Data System (ADS)

    Han, Da; Wu, Cuichen; You, Mingxu; Zhang, Tao; Wan, Shuo; Chen, Tao; Qiu, Liping; Zheng, Zheng; Liang, Hao; Tan, Weihong

    2015-10-01

    Biological systems use complex ‘information-processing cores’ composed of molecular networks to coordinate their external environment and internal states. An example of this is the acquired, or adaptive, immune system (AIS), which is composed of both humoral and cell-mediated components. Here we report the step-by-step construction of a prototype mimic of the AIS that we call an adaptive immune response simulator (AIRS). DNA and enzymes are used as simple artificial analogues of the components of the AIS to create a system that responds to specific molecular stimuli in vitro. We show that this network of reactions can function in a manner that is superficially similar to the most basic responses of the vertebrate AIS, including reaction sequences that mimic both humoral and cellular responses. As such, AIRS provides guidelines for the design and engineering of artificial reaction networks and molecular devices.

  6. Regulating adaptive immune responses using small molecule modulators of aminopeptidases that process antigenic peptides.

    PubMed

    Stratikos, Efstratios

    2014-12-01

    Antigenic peptide processing by intracellular aminopeptidases has emerged recently as an important pathway that regulates adaptive immune responses. Pathogens and cancer can manipulate the activity of key enzymes of this pathway to promote immune evasion. Furthermore, the activity of these enzymes is naturally variable due to polymorphic variation, contributing to predisposition to disease, most notably autoimmunity. Here, we review recent findings that suggest that the pharmacological regulation of the activity of these aminopeptidases constitutes a valid approach for regulating human immune responses. We furthermore review the state of the art in chemical tools for inhibiting these enzymes and how these tools can be useful for the development of innovative therapeutic approaches for a variety of diseases including cancer, viral infections and autoimmunity.

  7. Sebum Free Fatty Acids Enhance the Innate Immune Defense of Human Sebocytes by Upregulating β-Defensin-2 Expression

    PubMed Central

    Nakatsuji, Teruaki; Kao, Mandy C.; Zhang, Liangfang; Zouboulis, Christos C.; Gallo, Richard L; Huang, Chun-Ming

    2011-01-01

    Various sebum free fatty acids (FFAs) have shown antibacterial activity against a broad range of Gram-positive bacteria, resulting in the suggestion that they are accountable, at least partially, for the direct antimicrobial activity of the skin surface. In this study, we examined the effects of sebum FFAs on the antimicrobial peptide (AMP)-mediated innate immune defense of human sebocytes. Incubation of lauric acid, palmitic acid, or oleic acid (OA) with human sebocytes dramatically enhanced their expression of human β-defensin (hBD)-2, one of the predominant AMPs found in the skin, whereas remarkable increases in hBD-1, hBD-3, and human cathelicidin LL-37 were not observed. Secreted hBD-2 was detectable by western blotting in the supernatant of sebocyte culture incubated with each FFA, but not with a vehicle control. The supernatant of FFA-incubated sebocyte culture showed antimicrobial activity against Propionibacterium acnes, whereas the enhanced antimicrobial activity of human sebocytes was neutralized by anti-hBD-2 IgG. In addition, the FFA-induced hBD-2 expression was suppressed by blocking the cluster of differentiation (CD)36 fatty acid translocase on the surface of sebocytes with anti-human CD36 IgG or blocking the NF-κB signaling pathway with BMS-345541, a highly selective inhibitor of inhibitory κB kinase. These data suggest that sebum FFAs upregulate the expression of hBD-2 in human sebocytes, which may enhance the disinfecting activity of the human sebaceous gland. The FFA-induced upregulation of hBD-2 is facilitated by CD36-mediated FFA uptake and NF-κB-mediated transactivation. The upregulation of mouse β-defensin 4, a mouse ortholog for hBD-2, was also observed in the hair follicle sebaceous glands of mouse ear skin after an epicutaneous application of OA, the most hBD-2-inducible FFA tested. This report highlights the potential of using FFAs as a multifunctional antimicrobial therapy agent for acne vulgaris treatment; FFAs may provide direct

  8. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells.

    PubMed

    Tobar, Jaime A; Carreño, Leandro J; Bueno, Susan M; González, Pablo A; Mora, Jorge E; Quezada, Sergio A; Kalergis, Alexis M

    2006-11-01

    Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) in bacteria and by presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells able to prime naïve T cells and initiate adaptive immunity against bacteria. Therefore, interfering with DC function would promote bacterial survival and dissemination. Understanding the molecular mechanisms that have evolved in virulent bacteria to evade activation of adaptive immunity requires the characterization of virulence factors that interfere with DC function. Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, can prevent antigen presentation to T cells by avoiding lysosomal degradation in DCs. Here, we show that this feature of virulent Salmonella applies in vivo to prevent activation of adaptive immunity. In addition, this attribute of virulent Salmonella requires functional expression of a type three secretion system (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). In contrast to wild-type virulent Salmonella, mutant strains carrying specific deletions of SPI-2 genes encoding TTSS components or effectors proteins are targeted to lysosomes and are no longer able to prevent DCs from activating T cells in vitro or in vivo. SPI-2 mutant strains are attenuated in vivo, showing reduced tissue colonization and enhanced T-cell activation, which confers protection against a challenge with wild-type virulent Salmonella. Our data suggest that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.

  9. CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes.

    PubMed

    Koonin, Eugene V; Makarova, Kira S

    2013-05-01

    The CRISPR-Cas (clustered regularly interspaced short palindromic repeats, CRISPR-associated genes) is an adaptive immunity system in bacteria and archaea that functions via a distinct self-non-self recognition mechanism that is partially analogous to the mechanism of eukaryotic RNA interference (RNAi). The CRISPR-Cas system incorporates fragments of virus or plasmid DNA into the CRISPR repeat cassettes and employs the processed transcripts of these spacers as guide RNAs to cleave the cognate foreign DNA or RNA. The Cas proteins, however, are not homologous to the proteins involved in RNAi and comprise numerous, highly diverged families. The majority of the Cas proteins contain diverse variants of the RNA recognition motif (RRM), a widespread RNA-binding domain. Despite the fast evolution that is typical of the cas genes, the presence of diverse versions of the RRM in most Cas proteins provides for a simple scenario for the evolution of the three distinct types of CRISPR-cas systems. In addition to several proteins that are directly implicated in the immune response, the cas genes encode a variety of proteins that are homologous to prokaryotic toxins that typically possess nuclease activity. The predicted toxins associated with CRISPR-Cas systems include the essential Cas2 protein, proteins of COG1517 that, in addition to a ligand-binding domain and a helix-turn-helix domain, typically contain different nuclease domains and several other predicted nucleases. The tight association of the CRISPR-Cas immunity systems with predicted toxins that, upon activation, would induce dormancy or cell death suggests that adaptive immunity and dormancy/suicide response are functionally coupled. Such coupling could manifest in the persistence state being induced and potentially providing conditions for more effective action of the immune system or in cell death being triggered when immunity fails.

  10. Once Upon a Time: The Adaptive Immune Response in Atherosclerosis—a Fairy Tale No More

    PubMed Central

    Le Borgne, Marie; Caligiuri, Giuseppina; Nicoletti, Antonino

    2015-01-01

    Extensive research has been carried out to decipher the function of the adaptive immune response in atherosclerosis, with the expectation that it will pave the road for the design of immunomodulatory therapies that will prevent or reverse the progression of the disease. All this work has led to the concept that some T- and B-cell subsets are proatherogenic, whereas others are atheroprotective. In addition to the immune response occurring in the spleen and lymph nodes, it has been shown that lymphoid neo-genesis takes place in the adventitia of atherosclerotic vessels, leading to the formation of tertiary lymphoid organs where an adaptive immune response can be mounted. Whereas the mechanisms orchestrating the formation of these organs are becoming better understood, their impact on atherosclerosis progression remains unclear. Several potential therapeutic strategies against atherosclerosis, such as protective vaccination against atherosclerosis antigens or inhibiting the activation of proatherogenic B cells, have been proposed based on our improving knowledge of the role of the immune system in atherosclerosis. These strategies have shown success in preclinical studies, giving hope that they will lead to clinical applications. PMID:26605642

  11. Quantitative proteomics and terminomics to elucidate the role of ubiquitination and proteolysis in adaptive immunity

    PubMed Central

    Klein, Theo; Viner, Rosa I.

    2016-01-01

    Adaptive immunity is the specialized defence mechanism in vertebrates that evolved to eliminate pathogens. Specialized lymphocytes recognize specific protein epitopes through antigen receptors to mount potent immune responses, many of which are initiated by nuclear factor-kappa B activation and gene transcription. Most, if not all, pathways in adaptive immunity are further regulated by post-translational modification (PTM) of signalling proteins, e.g. phosphorylation, citrullination, ubiquitination and proteolytic processing. The importance of PTMs is reflected by genetic or acquired defects in these pathways that lead to a dysfunctional immune response. Here we discuss the state of the art in targeted proteomics and systems biology approaches to dissect the PTM landscape specifically regarding ubiquitination and proteolysis in B- and T-cell activation. Recent advances have occurred in methods for specific enrichment and targeted quantitation. Together with improved instrument sensitivity, these advances enable the accurate analysis of often rare PTM events that are opaque to conventional proteomics approaches, now rendering in-depth analysis and pathway dissection possible. We discuss published approaches, including as a case study the profiling of the N-terminome of lymphocytes of a rare patient with a genetic defect in the paracaspase protease MALT1, a key regulator protease in antigen-driven signalling, which was manifested by elevated linear ubiquitination. This article is part of the themed issue ‘Quantitative mass spectrometry’. PMID:27644975

  12. Quantitative proteomics and terminomics to elucidate the role of ubiquitination and proteolysis in adaptive immunity.

    PubMed

    Klein, Theo; Viner, Rosa I; Overall, Christopher M

    2016-10-28

    Adaptive immunity is the specialized defence mechanism in vertebrates that evolved to eliminate pathogens. Specialized lymphocytes recognize specific protein epitopes through antigen receptors to mount potent immune responses, many of which are initiated by nuclear factor-kappa B activation and gene transcription. Most, if not all, pathways in adaptive immunity are further regulated by post-translational modification (PTM) of signalling proteins, e.g. phosphorylation, citrullination, ubiquitination and proteolytic processing. The importance of PTMs is reflected by genetic or acquired defects in these pathways that lead to a dysfunctional immune response. Here we discuss the state of the art in targeted proteomics and systems biology approaches to dissect the PTM landscape specifically regarding ubiquitination and proteolysis in B- and T-cell activation. Recent advances have occurred in methods for specific enrichment and targeted quantitation. Together with improved instrument sensitivity, these advances enable the accurate analysis of often rare PTM events that are opaque to conventional proteomics approaches, now rendering in-depth analysis and pathway dissection possible. We discuss published approaches, including as a case study the profiling of the N-terminome of lymphocytes of a rare patient with a genetic defect in the paracaspase protease MALT1, a key regulator protease in antigen-driven signalling, which was manifested by elevated linear ubiquitination.This article is part of the themed issue 'Quantitative mass spectrometry'. PMID:27644975

  13. The adaptive immune response does not influence hantavirus disease or persistence in the Syrian hamster.

    PubMed

    Prescott, Joseph; Safronetz, David; Haddock, Elaine; Robertson, Shelly; Scott, Dana; Feldmann, Heinz

    2013-10-01

    Pathogenic New World hantaviruses cause severe disease in humans characterized by a vascular leak syndrome, leading to pulmonary oedema and respiratory distress with case fatality rates approaching 40%. Hantaviruses infect microvascular endothelial cells without conspicuous cytopathic effects, indicating that destruction of the endothelium is not a mechanism of disease. In humans, high levels of inflammatory cytokines are present in the lungs of patients that succumb to infection. This, along with other observations, suggests that disease has an immunopathogenic component. Currently the only animal model available to study hantavirus disease is the Syrian hamster, where infection with Andes virus (ANDV), the primary agent of disease in South America, results in disease that closely mimics that seen in humans. Conversely, inoculation of hamsters with a passaged Sin Nombre virus (SNV), the virus responsible for most cases of disease in North America, results in persistent infection with high levels of viral replication. We found that ANDV elicited a stronger innate immune response, whereas SNV elicited a more robust adaptive response in the lung. Additionally, ANDV infection resulted in significant changes in the blood lymphocyte populations. To determine whether the adaptive immune response influences infection outcome, we depleted hamsters of CD4(+) and CD8(+) T cells before infection with hantaviruses. Depletion resulted in inhibition of virus-specific antibody responses, although the pathogenesis and replication of these viruses were unaltered. These data show that neither hantavirus replication, nor pathogenesis caused by these viruses, is influenced by the adaptive immune response in the Syrian hamster.

  14. Physical model of the immune response of bacteria against bacteriophage through the adaptive CRISPR-Cas immune system

    NASA Astrophysics Data System (ADS)

    Han, Pu; Niestemski, Liang Ren; Barrick, Jeffrey E.; Deem, Michael W.

    2013-04-01

    Bacteria and archaea have evolved an adaptive, heritable immune system that recognizes and protects against viruses or plasmids. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences, called ‘spacers’ into its CRISPR system. Spacers in the CRISPR system provide a record of the history of bacteria and phage coevolution. We use a physical model to study the dynamics of this coevolution as it evolves stochastically over time. We focus on the impact of mutation and recombination on bacteria and phage evolution and evasion. We discuss the effect of different spacer deletion mechanisms on the coevolutionary dynamics. We make predictions about bacteria and phage population growth, spacer diversity within the CRISPR locus, and spacer protection against the phage population.

  15. Physical Model of the Immune Response of Bacteria Against Bacteriophage Through the Adaptive CRISPR-Cas Immune System

    PubMed Central

    Han, Pu; Niestemski, Liang Ren; Barrick, Jeffrey E.; Deem, Michael W.

    2013-01-01

    Bacteria and archaea have evolved an adaptive, heritable immune system that recognizes and protects against viruses or plasmids. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences, called ‘spacers’ into its CRISPR system. Spacers in the CRISPR system provide a record of the history of bacteria and phage coevolution. We use a physical model to study the dynamics of this coevolution as it evolves stochastically over time. We focus on the impact of mutation and recombination on bacteria and phage evolution and evasion. We discuss the effect of different spacer deletion mechanisms on the coevolutionary dynamics. We make predictions about bacteria and phage population growth, spacer diversity within the CRISPR locus, and spacer protection against the phage population. PMID:23492852

  16. Protein Defense Systems against the Lantibiotic Nisin: Function of the Immunity Protein NisI and the Resistance Protein NSR

    PubMed Central

    Khosa, Sakshi; Lagedroste, Marcel; Smits, Sander H. J.

    2016-01-01

    Lantibiotics are potential alternatives to antibiotics because of their broad-range killing spectrum. The producer strain is immune against its own synthesized lantibiotic via the expression of two proteins LanI and LanFEG. Recently, gene operons are found in mainly human pathogenic strains, which confer resistance against lantibiotics. Of all the lantibiotics discovered till date, nisin produced by some Lactococcus lactis strains is the most prominent member. Nisin has multiple mode of actions of which binding to the cell wall precursor lipid II and subsequent insertion into the bacterial membrane to form pores are the most effective. The nisin producing strains express the lipoprotein NisI to prevent a suicidal effect. NisI binds nisin, inducing a reversible cell clustering to prevent nisin from reaching the membrane. Importantly NisI does not modify nisin and releases it as soon as the concentration in the media drops below a certain level. The human pathogen Streptococcus agalactiae is naturally resistant against nisin by expressing a resistance protein called SaNSR, which is a nisin degrading enzyme. By cleaving off the last six amino acids of nisin, its effectiveness is 100-fold reduced. This cleavage reaction appears to be specific for nisin since SaNSR recognizes the C-terminal located lanthionine rings. Recently, the structures of both NisI and SaNSR were determined by NMR and X-ray crystallography, respectively. Furthermore, for both proteins the binding site for nisin was determined. Within this review, the structures of both proteins and their different defense mechanisms are described. PMID:27148193

  17. Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity

    PubMed Central

    Botelho, Danielle J.; Leo, Bey Fen; Massa, Christopher B.; Sarkar, Srijata; Tetley, Terry D.; Chung, Kian Fan; Chen, Shu; Ryan, Mary P.; Porter, Alexandra E.; Zhang, Junfeng; Schwander, Stephan K.; Gow, Andrew J.

    2016-01-01

    Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 µg/g body weight) 20 and 110nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered. PMID:26152688

  18. Identification and analysis of a Sciaenops ocellatus ISG15 homologue that is involved in host immune defense against bacterial infection.

    PubMed

    Liu, Chun-Sheng; Sun, Yun; Zhang, Min; Sun, Li

    2010-07-01

    ISG15 is an interferon-stimulated gene that encodes a ubiquitin-like protein. ISG15 homologues have been identified in a number of fish species, some of which are known to be regulated at expression level by virus infection and lipopolysaccharide (LPS) treatment. However, the relationship between ISG15 and live bacterial infection has not been investigated in piscine models. In this study, an ISG15 homologue, SoISG15, was identified from red drum Sciaenops ocellatus and analyzed at expression and functional levels. The open reading frame of SoISG15 is 477 base pairs (bp) and intronless, with a 5'-untranslated region (UTR) of 91 bp and a 3'-UTR of 415 bp. The deduced amino acid sequence of SoISG15 shares 60-67% overall identities with the ISG15 of several fish species. SoISG15 possesses two conserved ubiquitin-like domains and the canonical ubiquitin conjugation motif, LRGG, at the C-terminus. Expressional analysis showed that constitutive expression of SoISG15 was highest in blood and lowest in kidney. Experimental challenges with LPS and bacterial pathogens induced significant SoISG15 expression in the kidney but not in the liver. Similar differential induction was also observed at cellular level with primary hepatocytes and head kidney (HK) lymphocytes. Poly(I:C), however, effected drastic induction of SoISG15 expression in kidney and liver at both tissue and cellular levels. Immunoblot analysis showed that SoISG15 was secreted by cultured HK lymphocytes into the extracellular milieu. Recombinant SoISG15 expressed in and purified from Escherichia coli was able to enhance the respiratory burst activity, acid phosphatase activity, and bactericidal activity of HK macrophages. Taken together, the results of this study indicated that SoISG15 possesses apparent immunological property and is likely to be involved in host immune defense against bacterial infection. PMID:20385242

  19. Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

    PubMed

    Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

    2016-01-01

    Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

  20. A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

    Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications.

  1. Apical Organelle Secretion by Toxoplasma Controls Innate and Adaptive Immunity and Mediates Long-Term Protection.

    PubMed

    Sloves, Pierre-Julien; Mouveaux, Thomas; Ait-Yahia, Saliha; Vorng, Han; Everaere, Laetitia; Sangare, Lamba Omar; Tsicopoulos, Anne; Tomavo, Stanislas

    2015-11-01

    Apicomplexan parasites have unique apical rhoptry and microneme secretory organelles that are crucial for host infection, although their role in protection against Toxoplasma gondii infection is not thoroughly understood. Here, we report a novel function of the endolysosomal T. gondii sortilin-like receptor (TgSORTLR), which mediates trafficking to functional apical organelles and their subsequent secretion of virulence factors that are critical to the induction of sterile immunity against parasite reinfection. We further demonstrate that the T. gondii armadillo repeats-only protein (TgARO) mutant, which is deficient only in apical secretion of rhoptries, is also critical in mounting protective immunity. The lack of TgSORTLR and TgARO proteins completely inhibited T-helper 1-dependent adaptive immunity and compromised the function of natural killer T-cell-mediated innate immunity. Our findings reveal an essential role for apical secretion in promoting sterile protection against T. gondii and provide strong evidence for rhoptry-regulated discharge of antigens as a key effector for inducing protective immunity.

  2. Involvement of an antioxidant defense system in the adaptive response to cadmium in maize seedlings (Zea mays L.).

    PubMed

    Xu, Xianghua; Liu, Cuiying; Zhao, Xiaoyan; Li, Renying; Deng, Wenjing

    2014-11-01

    Chemical and biological analyses were used to investigate the growth response and antioxidant defense mechanism of maize seedlings (Zea mays L.) grown in soils with 0-100 mg kg(-1) Cd. Results showed that maize seedlings have strong abilities to accumulate and tolerate high concentrations of Cd. For soil with 50 mg kg(-1) Cd, the Cd contents in roots and shoots of maize seedlings are as large as 295.6 and 153.0 mg kg(-1) DW, respectively, without visible symptoms of toxicity. Lower soil Cd concentrations lead to a decrease in reduced glutathione (GSH) content in leaves of maize seedlings, whereas higher soil Cd concentrations resulted in an increase in the activities of superoxide dismutase, guaiacol peroxidase, catalase, and ascorbate peroxidase. Maize seedlings have strong capacities to adapt to low concentrations of Cd by consuming GSH and to develop an antioxidative enzyme system to defend against high-Cd stress.

  3. Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation

    PubMed Central

    Takagi, Hideaki; Arimura, Keiichi; Uto, Tomofumi; Fukaya, Tomohiro; Nakamura, Takeshi; Choijookhuu, Narantsog; Hishikawa, Yoshitaka; Sato, Katsuaki

    2016-01-01

    Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Plasmacytoid dendritic cells (pDCs) are cells specialized in robust IFN-I secretion by the engagement of endosomal TLRs, and predominantly express sialic acid-binding Ig-like lectin (Siglec)-H. However, how pDCs control endosomal TLR-mediated immune responses that cause autoimmunity remains unclear. Here we show a critical role of pDCs in TLR7-mediated autoimmunity using gene-modified mice with impaired expression of Siglec-H and selective ablation of pDCs. pDCs were shown to be indispensable for the induction of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. pDCs aggravated psoriasiform dermatitis mediated through the hyperproliferation of keratinocytes and enhanced dermal infiltration of granulocytes and γδ T cells. Furthermore, pDCs promoted the production of anti-self NA antibodies and glomerulonephritis in lupus-like disease by activating inflammatory monocytes. On the other hand, Siglec-H regulated the TLR7-mediated activation of pDCs. Thus, our findings reveal that pDCs provide an essential link between TLR7-mediated innate and adaptive immunity for the initiation of IFN-I-associated autoimmune inflammation. PMID:27075414

  4. Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation.

    PubMed

    Takagi, Hideaki; Arimura, Keiichi; Uto, Tomofumi; Fukaya, Tomohiro; Nakamura, Takeshi; Choijookhuu, Narantsog; Hishikawa, Yoshitaka; Sato, Katsuaki

    2016-01-01

    Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Plasmacytoid dendritic cells (pDCs) are cells specialized in robust IFN-I secretion by the engagement of endosomal TLRs, and predominantly express sialic acid-binding Ig-like lectin (Siglec)-H. However, how pDCs control endosomal TLR-mediated immune responses that cause autoimmunity remains unclear. Here we show a critical role of pDCs in TLR7-mediated autoimmunity using gene-modified mice with impaired expression of Siglec-H and selective ablation of pDCs. pDCs were shown to be indispensable for the induction of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. pDCs aggravated psoriasiform dermatitis mediated through the hyperproliferation of keratinocytes and enhanced dermal infiltration of granulocytes and γδ T cells. Furthermore, pDCs promoted the production of anti-self NA antibodies and glomerulonephritis in lupus-like disease by activating inflammatory monocytes. On the other hand, Siglec-H regulated the TLR7-mediated activation of pDCs. Thus, our findings reveal that pDCs provide an essential link between TLR7-mediated innate and adaptive immunity for the initiation of IFN-I-associated autoimmune inflammation. PMID:27075414

  5. Complex Adaptive Immunity to Enteric Fevers in Humans: Lessons Learned and the Path Forward

    PubMed Central

    Sztein, Marcelo B.; Salerno-Goncalves, Rosangela; McArthur, Monica A.

    2014-01-01

    Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, and S. Paratyphi A and B, causative agents of paratyphoid fever, are major public health threats throughout the world. Although two licensed typhoid vaccines are currently available, they are only moderately protective and immunogenic necessitating the development of novel vaccines. A major obstacle in the development of improved typhoid, as well as paratyphoid vaccines is the lack of known immunological correlates of protection in humans. Considerable progress has been made in recent years in understanding the complex adaptive host responses against S. Typhi. Although the induction of S. Typhi-specific antibodies (including their functional properties) and memory B cells, as well as their cross-reactivity with S. Paratyphi A and S. Paratyphi B has been shown, the role of humoral immunity in protection remains undefined. Cell mediated immunity (CMI) is likely to play a dominant role in protection against enteric fever pathogens. Detailed measurements of CMI performed in volunteers immunized with attenuated strains of S. Typhi have shown, among others, the induction of lymphoproliferation, multifunctional type 1 cytokine production, and CD8+ cytotoxic T-cell responses. In addition to systemic responses, the local microenvironment of the gut is likely to be of paramount importance in protection from these infections. In this review, we will critically assess current knowledge regarding the role of CMI and humoral immunity following natural S. Typhi and S. Paratyphi infections, experimental challenge, and immunization in humans. We will also address recent advances regarding cross-talk between the host’s gut microbiota and immunization with attenuated S. Typhi, mechanisms of systemic immune responses, and the homing potential of S. Typhi-specific B- and T-cells to the gut and other tissues. PMID:25386175

  6. Genome complexity in the coelacanth is reflected in its adaptive immune system

    USGS Publications Warehouse

    Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W.; Hansen, John; Parra, Zuly; Hsu, Ellen; Buonocore, Francesco; Canapa, Adriana; Cheng, Jan-Fang; Amemiya, Chris T.

    2014-01-01

    We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding α/β and γ/δ T-cell receptors, and CD3, CD4, and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR α/δ locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations.

  7. Genome complexity in the coelacanth is reflected in its adaptive immune system.

    PubMed

    Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W; Hansen, John; Parra, Zuly; Hsu, Ellen; Buonocore, Francesco; Canapa, Adriana; Cheng, Jan-Fang; Amemiya, Chris T

    2014-09-01

    We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding α/β and γ/δ T-cell receptors, and CD3, CD4, and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR α/δ locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations.

  8. Genome complexity in the coelacanth is reflected in its adaptive immune system

    PubMed Central

    Ota, Tatsuya; Litman, Gary W.; Hansen, John; Parra, Zuly; Hsu, Ellen; Buonocore, Francesco; Canapa, Adriana; Cheng, Jan-Fang; Amemiya, Chris T.

    2014-01-01

    We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding α/β and γ/δ T-cell receptors, and CD3, CD4 and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR α/δ locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations. PMID:24464682

  9. HLA alleles associated with the adaptive immune response to smallpox vaccine: a replication study.

    PubMed

    Ovsyannikova, Inna G; Pankratz, V Shane; Salk, Hannah M; Kennedy, Richard B; Poland, Gregory A

    2014-09-01

    We previously reported HLA allelic associations with vaccinia virus (VACV)-induced adaptive immune responses in a cohort of healthy individuals (n = 1,071 subjects) after a single dose of the licensed smallpox (Dryvax) vaccine. This study demonstrated that specific HLA alleles were significantly associated with VACV-induced neutralizing antibody (NA) titers (HLA-B*13:02, *38:02, *44:03, *48:01, and HLA-DQB1*03:02, *06:04) and cytokine (HLA-DRB1*01:03, *03:01, *10:01, *13:01, *15:01) immune responses. We undertook an independent study of 1,053 healthy individuals and examined associations between HLA alleles and measures of adaptive immunity after a single dose of Dryvax-derived ACAM2000 vaccine to evaluate previously discovered HLA allelic associations from the Dryvax study and determine if these associations are replicated with ACAM2000. Females had significantly higher NA titers than male subjects in both study cohorts [median ID50 discovery cohort 159 (93, 256) vs. 125 (75, 186), p < 0.001; replication cohort 144 (82, 204) vs. 110 (61, 189), p = 0.024]. The association between the DQB1*03:02 allele (median ID50 discovery cohort 152, p = 0.015; replication cohort 134, p = 0.010) and higher NA titers was replicated. Two HLA associations of comparable magnitudes were consistently found between DRB1*04:03 and DRB1*08:01 alleles and IFN-γ ELISPOT responses. The association between the DRB1*15:01 allele with IFN-γ secretion was also replicated (median pg/mL discovery cohort 182, p = 0.052; replication cohort 203, p = 0.014). Our results suggest that smallpox vaccine-induced adaptive immune responses are significantly influenced by HLA gene polymorphisms. These data provide information for functional studies and design of novel candidate smallpox vaccines.

  10. Administration of DNA Encoding the Interleukin-27 Gene Augments Antitumour Responses through Non-adaptive Immunity.

    PubMed

    Li, Q; Sato, A; Shimozato, O; Shingyoji, M; Tada, Y; Tatsumi, K; Shimada, H; Hiroshima, K; Tagawa, M

    2015-10-01

    DNA-mediated immunization of a tumour antigen is a possible immunotherapy for cancer, and interleukin (IL)-27 has diverse functions in adaptive immunity. In this study, we examined whether IL-27 DNA administration enhanced antitumour effects in mice vaccinated with DNA encoding a putative tumour antigen, β-galactosidase (β-gal). An intramuscular injection of cardiotoxin before DNA administration facilitated the exogenous gene expression. In mice received β-gal and IL-27 DNA, growth of β-gal-positive P815 tumours was retarded and survival of the mice was prolonged. Development of β-gal-positive Colon 26 tumours was suppressed by vaccination of β-gal DNA and further inhibited by additional IL-27 DNA administration or IL-12 family cytokines. Nevertheless, a population of β-gal-specific CD8(+) T cells did not increase, and production of anti-β-gal antibody was not enhanced by IL-27 DNA administration. Spleen cells from mice bearing IL-27-expressing Colon 26 tumours showed greater YAC-1-targeted cytotoxicity although CD3(-)/DX5(+) natural killer (NK) cell numbers remained unchanged. Recombinant IL-27 enhanced YAC-1-targeted cytotoxicity of IL-2-primed splenic NK cells and augmented a phosphorylation of signal transducer and activator of transcription 3 and an expression of perforin. These data collectively indicate that IL-27 DNA administration activates NK cells and augments vaccination effects of DNA encoding a tumour antigen through non-adaptive immune responses. PMID:26095954

  11. Disease-specific adaptive immune biomarkers in Alzheimer's disease and related pathologies.

    PubMed

    Dorothée, G; Sarazin, M; Aucouturier, P

    2013-10-01

    Identification of disease-specific diagnostic and prognostic biomarkers allowing for an early characterization and accurate clinical follow-up of Alzheimer's disease (AD) patients is a major clinical objective. Increasing evidences implicate both humoral and cellular adaptive immune responses in the pathophysiology of AD. Such disease-related B- and T-cell responses constitute a promising source of potential specific early biomarkers. Among them, levels of anti-Aβ antibodies in the serum and/or cerebrospinal fluid of patients may correlate with AD progression, clinical presentation of the disease, and occurrence of associated pathologies related to cerebral amyloid angiopathy. In the same line, Aβ-specific T cell responses and immune regulatory populations implicated in their modulation appear to play a role in the pathophysiology of AD and cerebral amyloid angiopathy. Further characterization of both autoantibodies and T cell responses specific for disease-related proteins, i.e. Aβ and hyperphosphorylated Tau, will allow better deciphering their interest as early diagnostic and prognostic markers in AD. Biomarkers of adaptive immune responses specific for other pathological proteins may also apply to other neurological disorders associated with abnormal protein deposition.

  12. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection.

    PubMed

    Fujimura, Kei E; Demoor, Tine; Rauch, Marcus; Faruqi, Ali A; Jang, Sihyug; Johnson, Christine C; Boushey, Homer A; Zoratti, Edward; Ownby, Dennis; Lukacs, Nicholas W; Lynch, Susan V

    2014-01-14

    Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults. PMID:24344318

  13. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection

    PubMed Central

    Fujimura, Kei E.; Demoor, Tine; Rauch, Marcus; Faruqi, Ali A.; Jang, Sihyug; Johnson, Christine C.; Boushey, Homer A.; Zoratti, Edward; Ownby, Dennis; Lukacs, Nicholas W.; Lynch, Susan V.

    2014-01-01

    Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c+/CD11b+ and CD11c+/CD8+ cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults. PMID:24344318

  14. Enhancement of adaptive immunity to Neisseria gonorrhoeae by local intravaginal administration of microencapsulated interleukin 12.

    PubMed

    Liu, Yingru; Egilmez, Nejat K; Russell, Michael W

    2013-12-01

    Gonorrhea remains one of the most frequent infectious diseases, and Neisseria gonorrhoeae is emerging as resistant to most available antibiotics, yet it does not induce a state of specific protective immunity against reinfection. Our recent studies have demonstrated that N. gonorrhoeae proactively suppresses host T-helper (Th) 1/Th2-mediated adaptive immune responses, which can be manipulated to generate protective immunity. Here we show that intravaginally administered interleukin 12 (IL-12) encapsulated in sustained-release polymer microspheres significantly enhanced both Th1 and humoral immune responses in a mouse model of genital gonococcal infection. Treatment of mice with IL-12 microspheres during gonococcal challenge led to faster clearance of infection and induced resistance to reinfection, with the generation of gonococcus-specific circulating immunoglobulin G and vaginal immunoglobulin A and G antibodies. These results suggest that local administration of microencapsulated IL-12 can serve as a novel therapeutic and prophylactic strategy against gonorrhea, with implications for the development of an effective vaccine. PMID:24048962

  15. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems.

    PubMed

    Nishida, Keiji; Arazoe, Takayuki; Yachie, Nozomu; Banno, Satomi; Kakimoto, Mika; Tabata, Mayura; Mochizuki, Masao; Miyabe, Aya; Araki, Michihiro; Hara, Kiyotaka Y; Shimatani, Zenpei; Kondo, Akihiko

    2016-09-16

    The generation of genetic variation (somatic hypermutation) is an essential process for the adaptive immune system in vertebrates. We demonstrate the targeted single-nucleotide substitution of DNA using hybrid vertebrate and bacterial immune systems components. Nuclease-deficient type II CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated) and the activation-induced cytidine deaminase (AID) ortholog PmCDA1 were engineered to form a synthetic complex (Target-AID) that performs highly efficient target-specific mutagenesis. Specific point mutation was induced primarily at cytidines within the target range of five bases. The toxicity associated with the nuclease-based CRISPR/Cas9 system was greatly reduced. Although combination of nickase Cas9(D10A) and the deaminase was highly effective in yeasts, it also induced insertion and deletion (indel) in mammalian cells. Use of uracil DNA glycosylase inhibitor suppressed the indel formation and improved the efficiency. PMID:27492474

  16. Hepatitis C virus evasion of adaptive immune responses: a model for viral persistence.

    PubMed

    Burke, Kelly P; Cox, Andrea L

    2010-07-01

    Hepatitis C virus (HCV) infects over 170 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. Approximately 20% [corrected] of those acutely infected clear the infection, whereas the remaining 80% [corrected] progress to chronic infection. Hepatitis C thus provides a model in which successful and unsuccessful responses can be compared to better understand the human response to viral infection. Our laboratory studies the strategies by which HCV evades the adaptive immune response. This review describes the impact of viral mutation on T cell recognition, the role of cell surface inhibitory receptors in recognition of HCV, and the development of antibodies that neutralize HCV infection. Understanding what constitutes an effective immune response in the control of HCV may enable the development of prophylactic and therapeutic vaccines for HCV and other chronic viral infections.

  17. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems.

    PubMed

    Nishida, Keiji; Arazoe, Takayuki; Yachie, Nozomu; Banno, Satomi; Kakimoto, Mika; Tabata, Mayura; Mochizuki, Masao; Miyabe, Aya; Araki, Michihiro; Hara, Kiyotaka Y; Shimatani, Zenpei; Kondo, Akihiko

    2016-09-16

    The generation of genetic variation (somatic hypermutation) is an essential process for the adaptive immune system in vertebrates. We demonstrate the targeted single-nucleotide substitution of DNA using hybrid vertebrate and bacterial immune systems components. Nuclease-deficient type II CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated) and the activation-induced cytidine deaminase (AID) ortholog PmCDA1 were engineered to form a synthetic complex (Target-AID) that performs highly efficient target-specific mutagenesis. Specific point mutation was induced primarily at cytidines within the target range of five bases. The toxicity associated with the nuclease-based CRISPR/Cas9 system was greatly reduced. Although combination of nickase Cas9(D10A) and the deaminase was highly effective in yeasts, it also induced insertion and deletion (indel) in mammalian cells. Use of uracil DNA glycosylase inhibitor suppressed the indel formation and improved the efficiency.

  18. Seasonality influences cuticle melanization and immune defense in a cricket: support for a temperature-dependent immune investment hypothesis in insects

    SciTech Connect

    Fedorka, K. M.; Copeland, E. K.; Winterhalter, W. E.

    2013-07-18

    To improve thermoregulation in colder environments, insects are expected to darken their cuticles with melanin via the phenoloxidase cascade, a phenomenon predicted by the thermal melanin hypothesis. However, the phenoloxidase cascade also plays a significant role in insect immunity, leading to the additional hypothesis that the thermal environment indirectly shapes immune function via direct selection on cuticle color. Support for the latter hypothesis comes from the cricket Allonemobius socius, where cuticle darkness and immune-related phenoloxidase activity increase with latitude. However, thermal environments vary seasonally as well as geographically, suggesting that seasonal plasticity in immunity may also exist. Although seasonal fluctuations in vertebrate immune function are common (because of flux in breeding or resource abundance), seasonality in invertebrate immunity has not been widely explored. We addressed this possibility by rearing crickets in simulated summer and fall environments and assayed their cuticle color and immune function. Prior to estimating immunity, crickets were placed in a common environment to minimize metabolic rate differences. Individuals reared under fall-like conditions exhibited darker cuticles, greater phenoloxidase activity and greater resistance to the bacteria Serratia marcescens. These data support the hypothesis that changes in the thermal environment modify cuticle color, which indirectly shapes immune investment through pleiotropy. This hypothesis may represent a widespread mechanism governing immunity in numerous systems, considering that most insects operate in seasonally and geographically variable thermal environments.

  19. Seasonality influences cuticle melanization and immune defense in a cricket: support for a temperature-dependent immune investment hypothesis in insects.

    PubMed

    Fedorka, Kenneth M; Copeland, Emily K; Winterhalter, Wade E

    2013-11-01

    To improve thermoregulation in colder environments, insects are expected to darken their cuticles with melanin via the phenoloxidase cascade, a phenomenon predicted by the thermal melanin hypothesis. However, the phenoloxidase cascade also plays a significant role in insect immunity, leading to the additional hypothesis that the thermal environment indirectly shapes immune function via direct selection on cuticle color. Support for the latter hypothesis comes from the cricket Allonemobius socius, where cuticle darkness and immune-related phenoloxidase activity increase with latitude. However, thermal environments vary seasonally as well as geographically, suggesting that seasonal plasticity in immunity may also exist. Although seasonal fluctuations in vertebrate immune function are common (because of flux in breeding or resource abundance), seasonality in invertebrate immunity has not been widely explored. We addressed this possibility by rearing crickets in simulated summer and fall environments and assayed their cuticle color and immune function. Prior to estimating immunity, crickets were placed in a common environment to minimize metabolic rate differences. Individuals reared under fall-like conditions exhibited darker cuticles, greater phenoloxidase activity and greater resistance to the bacteria Serratia marcescens. These data support the hypothesis that changes in the thermal environment modify cuticle color, which indirectly shapes immune investment through pleiotropy. This hypothesis may represent a widespread mechanism governing immunity in numerous systems, considering that most insects operate in seasonally and geographically variable thermal environments.

  20. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity.

    PubMed

    Arts, Rob J W; Blok, Bastiaan A; Aaby, Peter; Joosten, Leo A B; de Jong, Dirk; van der Meer, Jos W M; Benn, Christine Stabell; van Crevel, Reinout; Netea, Mihai G

    2015-12-01

    BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited.

  1. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation

    PubMed Central

    Saita, Diego; Ferrarese, Roberto; Foglieni, Chiara; Esposito, Antonio; Canu, Tamara; Perani, Laura; Ceresola, Elisa Rita; Visconti, Laura; Burioni, Roberto; Clementi, Massimo; Canducci, Filippo

    2016-01-01

    Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases. PMID:27383250

  2. Ebolavirus evolves in human to minimize the detection by immune cells by accumulating adaptive mutations.

    PubMed

    Ramaiah, Arunachalam; Arumugaswami, Vaithilingaraja

    2016-06-01

    The current outbreak of Zaire ebolavirus (EBOV) lasted longer than the previous outbreaks and there is as yet no proven treatment or vaccine available. Understanding host immune pressure and associated EBOV immune evasion that drive the evolution of EBOV is vital for diagnosis as well as designing a highly effective vaccine. The aim of this study was to deduce adaptive selection pressure acting on each amino acid sites of EBOV responsible for the recent 2014 outbreak. Multiple statistical methods employed in the study include SLAC, FEL, REL, IFEL, FUBAR and MEME. Results show that a total of 11 amino acid sites from sGP and ssGP, and 14 sites from NP, VP40, VP24 and L proteins were inferred as positively and negatively selected, respectively. Overall, the function of 11 out of 25 amino acid sites under selection pressure exactly found to be involved in T cell and B-cell epitopes. We identified that the EBOV had evolved through purifying selection pressure, which is a predictor that is known to aid the virus to adapt better to the human host and subsequently reduce the efficiency of existing immunity. Furthermore, computational RNA structure prediction showed that the three synonymous nucleotide mutations in NP gene altered the RNA secondary structure and optimal base-pairing energy, implicating a possible effect on genome replication. Here, we have provided evidence that the EBOV strains involved in the recent 2014 outbreak have evolved to minimize the detection by T and B cells by accumulating adaptive mutations to increase the survival fitness. PMID:27366764

  3. Essential Role for Neutrophils in Pathogenesis and Adaptive Immunity in Chlamydia caviae Ocular Infections ▿

    PubMed Central

    Lacy, H. Marie; Bowlin, Anne K.; Hennings, Leah; Scurlock, Amy M.; Nagarajan, Uma M.; Rank, Roger G.

    2011-01-01

    Trachoma, the world's leading cause of preventable blindness, is produced by chronic ocular infection with Chlamydia trachomatis, an obligate intracellular bacterium. While many studies have focused on immune mechanisms for trachoma during chronic stages of infection, less research has targeted immune mechanisms in primary ocular infections, events that could impact chronic responses. The goal of this study was to investigate the function of neutrophils during primary chlamydial ocular infection by using the guinea pig model of Chlamydia caviae inclusion conjunctivitis. We hypothesized that neutrophils help modulate the adaptive response and promote host tissue damage. To test these hypotheses, guinea pigs with primary C. caviae ocular infections were depleted of neutrophils by using rabbit antineutrophil antiserum, and immune responses and immunopathology were evaluated during the first 7 days of infection. Results showed that neutrophil depletion dramatically decreased ocular pathology, both clinically and histologically. The adaptive response was also altered, with increased C. caviae-specific IgA titers in tears and serum and decreased numbers of CD4+ and CD8+ T cells in infected conjunctivae. Additionally, there were changes in conjunctival chemokines and cytokines, such as increased expression of IgA-promoting interleukin-5 and anti-inflammatory transforming growth factor β, along with decreased expression of T cell-recruiting CCL5 (RANTES). This study, the first to investigate the role of neutrophils in primary chlamydial ocular infection, indicates a previously unappreciated role for neutrophils in modulating the adaptive response and suggests a prominent role for neutrophils in chlamydia-associated ocular pathology. PMID:21402767

  4. Essential role for neutrophils in pathogenesis and adaptive immunity in Chlamydia caviae ocular infections.

    PubMed

    Lacy, H Marie; Bowlin, Anne K; Hennings, Leah; Scurlock, Amy M; Nagarajan, Uma M; Rank, Roger G

    2011-05-01

    Trachoma, the world's leading cause of preventable blindness, is produced by chronic ocular infection with Chlamydia trachomatis, an obligate intracellular bacterium. While many studies have focused on immune mechanisms for trachoma during chronic stages of infection, less research has targeted immune mechanisms in primary ocular infections, events that could impact chronic responses. The goal of this study was to investigate the function of neutrophils during primary chlamydial ocular infection by using the guinea pig model of Chlamydia caviae inclusion conjunctivitis. We hypothesized that neutrophils help modulate the adaptive response and promote host tissue damage. To test these hypotheses, guinea pigs with primary C. caviae ocular infections were depleted of neutrophils by using rabbit antineutrophil antiserum, and immune responses and immunopathology were evaluated during the first 7 days of infection. Results showed that neutrophil depletion dramatically decreased ocular pathology, both clinically and histologically. The adaptive response was also altered, with increased C. caviae-specific IgA titers in tears and serum and decreased numbers of CD4(+) and CD8(+) T cells in infected conjunctivae. Additionally, there were changes in conjunctival chemokines and cytokines, such as increased expression of IgA-promoting interleukin-5 and anti-inflammatory transforming growth factor β, along with decreased expression of T cell-recruiting CCL5 (RANTES). This study, the first to investigate the role of neutrophils in primary chlamydial ocular infection, indicates a previously unappreciated role for neutrophils in modulating the adaptive response and suggests a prominent role for neutrophils in chlamydia-associated ocular pathology. PMID:21402767

  5. Steroid Sulfates from Ophiuroids (Brittle Stars): Action on Some Factors of Innate and Adaptive Immunity.

    PubMed

    Gazha, Anna K; Ivanushko, Lyudmila A; Levina, Eleonora V; Fedorov, Sergey N; Zaporozets, Tatyana S; Stonik, Valentin A; Besednova, Nataliya N

    2016-06-01

    The action of seven polyhydroxylated sterol mono- and disulfates (1-7), isolated from ophiuroids, on innate and adaptive immunity was examined in in vitro and in vivo experiments. At least, three of them (1, 2 and 4) increased the functional activities of neutrophils, including levels of oxygen-dependent metabolism, adhesive and phagocytic properties, and induced the expression of pro-inflammatory cytokines TNF-α and IL-8. Compound 4 was the most active for enhancing the production of antibody forming cells in the mouse spleen. PMID:27534108

  6. Targeting the adaptive immune system: new strategies in the treatment of atherosclerosis.

    PubMed

    Zarzycka, Barbara; Nicolaes, Gerry A F; Lutgens, Esther

    2015-05-01

    Atherosclerosis is a lipid-driven chronic inflammatory disease of the arterial wall. Current treatment of atherosclerosis is focused on limiting its risk factors, such as hyperlipidemia or hypertension. However, treatments that target the inflammatory nature of atherosclerosis are still under development. Discovery of novel targets involved in the inflammation of the arterial wall creates opportunities to design new therapeutics that successfully modulate atherosclerosis. Here, we review drug targets that have proven to play pivotal roles in the adaptive immune system in atherosclerosis, and we discuss their potential as novel therapeutics.

  7. Differential effects on innate versus adaptive immune responses by WF10.

    PubMed

    Giese, Thomas; McGrath, Michael S; Stumm, Susanne; Schempp, Harald; Elstner, Erich; Meuer, Stefan C

    2004-06-01

    Oxidative compounds that are physiologically generated in vivo can induce natural defense mechanisms to enhance the elimination of pathogens and to limit inflammatory tissue damage in the course of inflammation. Here, we have investigated WF10, a chlorite-based non-toxic compound for its functional activities on human PBMC in vitro. WF10 exerts potent immune-modulatory effects through generating endogenous oxidative compounds such as taurine chloramine. Proliferation and IL-2 production of anti-CD3 stimulated PBMC were inhibited by WF10, as was the nuclear translocation of the transcription factor NFATc. In PBMC and monocytes, however, WF10 induced pro-inflammatory cytokines like IL-1beta, IL-8, and TNF-alpha. In the monocytic cell line THP-1, the activation of the transcription factors AP-1 and NFkappaB by WF10 was demonstrated. Inhibition of NFAT regulated genes in activated lymphocytes in concert with the induction of several myeloid cell associated pro-inflammatory genes in monocytes represents a novel mechanism of immune modulation.

  8. An adaptive neural swarm approach for intrusion defense in ad hoc networks

    NASA Astrophysics Data System (ADS)

    Cannady, James

    2011-06-01

    Wireless sensor networks (WSN) and mobile ad hoc networks (MANET) are being increasingly deployed in critical applications due to the flexibility and extensibility of the technology. While these networks possess numerous advantages over traditional wireless systems in dynamic environments they are still vulnerable to many of the same types of host-based and distributed attacks common to those systems. Unfortunately, the limited power and bandwidth available in WSNs and MANETs, combined with the dynamic connectivity that is a defining characteristic of the technology, makes it extremely difficult to utilize traditional intrusion detection techniques. This paper describes an approach to accurately and efficiently detect potentially damaging activity in WSNs and MANETs. It enables the network as a whole to recognize attacks, anomalies, and potential vulnerabilities in a distributive manner that reflects the autonomic processes of biological systems. Each component of the network recognizes activity in its local environment and then contributes to the overall situational awareness of the entire system. The approach utilizes agent-based swarm intelligence to adaptively identify potential data sources on each node and on adjacent nodes throughout the network. The swarm agents then self-organize into modular neural networks that utilize a reinforcement learning algorithm to identify relevant behavior patterns in the data without supervision. Once the modular neural networks have established interconnectivity both locally and with neighboring nodes the analysis of events within the network can be conducted collectively in real-time. The approach has been shown to be extremely effective in identifying distributed network attacks.

  9. Host-pathogen interactions between the human innate immune system and Candida albicans-understanding and modeling defense and evasion strategies.

    PubMed

    Dühring, Sybille; Germerodt, Sebastian; Skerka, Christine; Zipfel, Peter F; Dandekar, Thomas; Schuster, Stefan

    2015-01-01

    The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.

  10. Host-pathogen interactions between the human innate immune system and Candida albicans—understanding and modeling defense and evasion strategies

    PubMed Central

    Dühring, Sybille; Germerodt, Sebastian; Skerka, Christine; Zipfel, Peter F.; Dandekar, Thomas; Schuster, Stefan

    2015-01-01

    The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given. PMID:26175718

  11. Persistence of Gut Mucosal Innate Immune Defenses by Enteric α-Defensin Expression in the Simian Immunodeficiency Virus Model of AIDS

    PubMed Central

    Zaragoza, Melinda M.; Sankaran, Sumathi; Canfield, Don R.; Hung, Jason KS; Martinez, Enrique; Ouellette, André J.; Dandekar, Satya

    2014-01-01

    Gastrointestinal mucosa is an early target of HIV and a site of viral replication and severe CD4+ T-cell depletion. However, effects of HIV infection on gut mucosal innate immune defense have not been fully investigated. Intestinal Paneth cell (PC)-derived α-defensins constitute an integral part of the gut mucosal innate defense against microbial pathogens. Using the simian immunodeficiency virus (SIV) infected rhesus macaque model of AIDS, we examined the level of expression of rhesus enteric α-defensins (REDs) in jejunal mucosa of rhesus macaques during all stages of SIV infection, using real-time PCR, in situ hybridization, and immunohistochemistry. An increased expression of RED mRNAs was found in PC at the base of the crypts in jejunum at all stages of SIV infection as compared to uninfected controls. This increase correlated with active viral replication in gut associated lymphoid tissue (GALT). Loss of RED protein accumulation in PC was seen in animals with simian AIDS (SAIDS). This was associated with the loss of secretory granules in PC, suggesting an increase in degranulation during advanced SIV disease. The α-defensin-mediated innate mucosal immunity was maintained in PC throughout the course of SIV infection despite the mucosal CD4+ T-cell depletion. The loss of RED protein accumulation and secretion was associated with an increased incidence of opportunistic enteric infections and disease progression. Our findings suggest that local innate immune defense exerted by PC derived defensins contributes to the protection of gut mucosa from opportunistic infections during the course of SIV infection. PMID:21178012

  12. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses

    PubMed Central

    Madhumitha, Haridoss

    2016-01-01

    Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed.

  13. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses

    PubMed Central

    Madhumitha, Haridoss

    2016-01-01

    Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. PMID:27610390

  14. Within-host co-evolution of chronic viruses and the adaptive immune system

    NASA Astrophysics Data System (ADS)

    Nourmohammad, Armita

    We normally think of evolution occurring in a population of organisms, in response to their external environment. Rapid evolution of cellular populations also occurs within our bodies, as the adaptive immune system works to eliminate infection. Some pathogens, such as HIV, are able to persist in a host for extended periods of time, during which they also evolve to evade the immune response. In this talk I will introduce an analytical framework for the rapid co-evolution of B-cell and viral populations, based on the molecular interactions between them. Since the co-evolution of antibodies and viruses is perpetually out of equilibrium, I will show how to quantify the amount of adaptation in each of the two populations by analysis of their co-evolutionary history. I will discuss the consequences of competition between lineages of antibodies, and characterize the fate of a given lineage dependent on the state of the antibody and viral populations. In particular, I will discuss the conditions for emergence of highly potent broadly neutralizing antibodies, which are now recognized as critical for designing an effective vaccine against HIV.

  15. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses.

    PubMed

    Aravindhan, Vivekanandhan; Madhumitha, Haridoss

    2016-01-01

    Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. PMID:27610390

  16. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection

    PubMed Central

    Stevens, Natalie E.; Hatjopolous, Antoinette; Fraser, Cara K.; Alsharifi, Mohammed; Diener, Kerrilyn R.; Hayball, John D.

    2016-01-01

    Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus. PMID:27380890

  17. Risk factors that may modify the innate and adaptive immune responses in periodontal diseases.

    PubMed

    Knight, Ellie T; Liu, Jenny; Seymour, Gregory J; Faggion, Clovis M; Cullinan, Mary P

    2016-06-01

    Plaque-induced periodontal diseases occur in response to the accumulation of dental plaque. Disease manifestation and progression is determined by the nature of the immune response to the bacterial complexes in plaque. In general, predisposing factors for these periodontal diseases can be defined as those factors which retain or hinder the removal of plaque and, depending upon the nature of the immune response to this plaque, the disease will either remain stable and not progress or it may progress and result in chronic periodontitis. In contrast, modifying factors can be defined as those factors that alter the nature or course of the inflammatory lesion. These factors do not cause the disease but rather modify the chronic inflammatory response, which, in turn, is determined by the nature of the innate and adaptive immune responses and the local cytokine and inflammatory mediator networks. Chronic inflammation is characterized by vascular, cellular and repair responses within the tissues. This paper will focus on how common modifying factors, such as smoking, stress, hormonal changes, diabetes, metabolic syndrome and HIV/AIDS, influence each of these responses, together with treatment implications. As treatment planning in periodontics requires an understanding of the etiology and pathogenesis of the disease, it is important for all modifying factors to be taken into account. For some of these, such as smoking, stress and diabetic control, supportive health behavior advice within the dental setting should be an integral component for overall patient management. PMID:27045429

  18. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus.

    PubMed

    Wolf, Susanne A; Steiner, Barbara; Wengner, Antje; Lipp, Martin; Kammertoens, Thomas; Kempermann, Gerd

    2009-09-01

    To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 microg/microl methylated BSA) or staphylococcus enterotoxin B (EC(50) of 0.25 microg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC(50) of 0.5 microg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.

  19. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

    PubMed Central

    Weih, Falk; Gräbner, Rolf; Hu, Desheng; Beer, Michael; Habenicht, Andreas J. R.

    2012-01-01

    Tertiary lymphoid organs (TLOs) emerge in tissues in response to non-resolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE−/− mice. ATLOs are structured into T cell areas harboring conventional dendritic cells and monocyte-derived DCs; B cell follicles containing follicular dendritic cells within activated germinal centers; and peripheral niches of plasma cells. ATLOs also show extensive neoangiogenesis, aberrant lymphangiogenesis, and high endothelial venule (HEV) neogenesis. Newly formed conduit networks connect the external lamina of the artery with HEVs in T cell areas. ATLOs recruit and generate lymphocyte subsets with opposing activities including activated CD4+ and CD8+ effector T cells, natural and induced CD4+ T regulatory (nTregs; iTregs) cells as well as B-1 and B-2 cells at different stages of differentiation. These data indicate that ATLOs organize dichotomic innate and adaptive immune responses in atherosclerosis. In this review we discuss the novel concept that dichotomic immune responses toward atherosclerosis-specific antigens are carried out by ATLOs in the adventitia of the arterial wall and that malfunction of the tolerogenic arm of ATLO immunity triggers transition from silent autoimmune reactivity to clinically overt disease. PMID:22783198

  20. Hormonal Contraception and HIV-1 Infection: Medroxyprogesterone Acetate Suppresses Innate and Adaptive Immune Mechanisms

    PubMed Central

    Huijbregts, Richard P. H.; Helton, E. Scott; Michel, Katherine G.; Sabbaj, Steffanie; Richter, Holly E.; Goepfert, Paul A.

    2013-01-01

    Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens. PMID:23354099

  1. Aircraft Abnormal Conditions Detection, Identification, and Evaluation Using Innate and Adaptive Immune Systems Interaction

    NASA Astrophysics Data System (ADS)

    Al Azzawi, Dia

    Abnormal flight conditions play a major role in aircraft accidents frequently causing loss of control. To ensure aircraft operation safety in all situations, intelligent system monitoring and adaptation must rely on accurately detecting the presence of abnormal conditions as soon as they take place, identifying their root cause(s), estimating their nature and severity, and predicting their impact on the flight envelope. Due to the complexity and multidimensionality of the aircraft system under abnormal conditions, these requirements are extremely difficult to satisfy using existing analytical and/or statistical approaches. Moreover, current methodologies have addressed only isolated classes of abnormal conditions and a reduced number of aircraft dynamic parameters within a limited region of the flight envelope. This research effort aims at developing an integrated and comprehensive framework for the aircraft abnormal conditions detection, identification, and evaluation based on the artificial immune systems paradigm, which has the capability to address the complexity and multidimensionality issues related to aircraft systems. Within the proposed framework, a novel algorithm was developed for the abnormal conditions detection problem and extended to the abnormal conditions identification and evaluation. The algorithm and its extensions were inspired from the functionality of the biological dendritic cells (an important part of the innate immune system) and their interaction with the different components of the adaptive immune system. Immunity-based methodologies for re-assessing the flight envelope at post-failure and predicting the impact of the abnormal conditions on the performance and handling qualities are also proposed and investigated in this study. The generality of the approach makes it applicable to any system. Data for artificial immune system development were collected from flight tests of a supersonic research aircraft within a motion-based flight

  2. Investigating the adaptive immune response in influenza and secondary bacterial pneumonia and nanoparticle based therapeutic delivery

    NASA Astrophysics Data System (ADS)

    Chakravarthy, Krishnan V.

    In early 2000, influenza and its associated complications were the 7 th leading cause of death in the United States[1-4]. As of today, this major health problem has become even more of a concern, with the possibility of a potentially devastating avian flu (H5N1) or swine flu pandemic (H1N1). According to the Centers for Disease Control (CDC), over 10 countries have reported transmission of influenza A (H5N1) virus to humans as of June 2006 [5]. In response to this growing concern, the United States pledged over $334 million dollars in international aid for battling influenza[1-4]. The major flu pandemic of the early 1900's provided the first evidence that secondary bacterial pneumonia (not primary viral pneumonia) was the major cause of death in both community and hospital-based settings. Secondary bacterial infections currently account for 35-40% mortality following a primary influenza viral infection [1, 6]. The first component of this work addresses the immunological mechanisms that predispose patients to secondary bacterial infections following a primary influenza viral infection. By assessing host immune responses through various immune-modulatory tools, such as use of volatile anesthetics (i.e. halothane) and Apilimod/STA-5326 (an IL-12/Il-23 transcription blocker), we provide experimental evidence that demonstrates that the overactive adaptive Th1 immune response is critical in mediating increased susceptibility to secondary bacterial infections. We also present data that shows that suppressing the adaptive Th1 immune response enhances innate immunity, specifically in alveolar macrophages, by favoring a pro anti-bacterial phenotype. The second component of this work addresses the use of nanotechnology to deliver therapeutic modalities that affect the primary viral and associated secondary bacterial infections post influenza. First, we used surface functionalized quantum dots for selective targeting of lung alveolar macrophages both in vitro and in vivo

  3. Role of passive and adaptive immunity in influencing enterocyte-specific gene expression.

    PubMed

    Jenkins, Shannon L; Wang, Jiafang; Vazir, Mukta; Vela, Jose; Sahagun, Omar; Gabbay, Peter; Hoang, Lisa; Diaz, Rosa L; Aranda, Richard; Martín, Martín G

    2003-10-01

    Numerous genes expressed by intestinal epithelial cells are developmentally regulated, and the influence that adaptive (AI) and passive (PI) immunity have in controlling their expression has not been evaluated. In this study, we tested the hypothesis that both PI and AI influenced enterocyte gene expression by developing a breeding scheme that used T and B cell-deficient recombination-activating gene (RAG) mice. RNA was isolated from the liver and proximal/distal small intestine at various ages, and the steady-state levels of six different transcripts were evaluated by RNase protection assay. In wild-type (WT) pups, all transcripts [Fc receptor of the neonate (FcRn), polymeric IgA receptor (pIgR), GLUT5, lactase-phlorizin hydrolase (lactase), apical sodium-dependent bile acid transporter (ASBT), and Na+/glucose cotransporter (SGLT1)] studied were developmentally regulated at the time of weaning, and all transcripts except ASBT had the highest levels of expression in the proximal small intestine. In WT suckling pups reared in the absence of PI, pIgR mRNA levels were increased 100% during the early phase of development. In mice lacking AI, the expression of pIgR and lactase were significantly attenuated, whereas FcRn and GLUT5 levels were higher compared with WT mice. Finally, in the absence of both passive and active immunity, expression levels of pIgR and lactase were significantly lower than similarly aged WT mice. In summary, we report that the adaptive and passive immune status of mice influences steady-state mRNA levels of several important, developmentally regulated enterocyte genes during the suckling and weaning periods of life.

  4. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search.

    PubMed

    Fricke, G Matthew; Letendre, Kenneth A; Moses, Melanie E; Cannon, Judy L

    2016-03-01

    Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1) a lognormal distribution of step lengths, 2) motion that is directionally persistent over short time scales, and 3) heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call "hotspots" within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search.

  5. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search

    PubMed Central

    Fricke, G. Matthew; Letendre, Kenneth A.; Moses, Melanie E.; Cannon, Judy L.

    2016-01-01

    Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1) a lognormal distribution of step lengths, 2) motion that is directionally persistent over short time scales, and 3) heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call “hotspots” within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search. PMID:26990103

  6. An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes.

    PubMed

    Toben, Catherine; Baune, Bernhard T

    2015-12-01

    Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better

  7. The immune system is limited by oxidative stress: Dietary selenium promotes optimal antioxidative status and greatest immune defense in pacu Piaractus mesopotamicus.

    PubMed

    Biller-Takahashi, Jaqueline D; Takahashi, Leonardo S; Mingatto, Fábio E; Urbinati, Elisabeth C

    2015-11-01

    Reactive oxygen species (ROS) are reactive molecules containing oxygen, that form as byproducts of aerobic metabolism, including immune system processes. Too much ROS may cause oxidative stress. In this study, we examined whether it can also limit the production of immune system compounds. To assess the relationship between antioxidant status and immunity we evaluated the effect of dietary supplementation with organic selenium, given at various levels for 10 days, on the antioxidant and immune system of the pacu fish (Piaractus mesopotamicus). Fish fed a diet containing 0.6 mg Se-yeast kg(-1) showed significant improvement in antioxidant status, as well as in hematological and immunological profiles. Specifically, they had the highest counts for catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), red blood cells, and thrombocytes; the highest leukocyte count (particularly for monocytes); and the highest serum lysozyme activity. There was also a positive correlation between GPx and lysozyme in this group of fish. These findings indicate that short-term supplementation with 0.6 mg Se-yeast kg(-1) reestablished the antioxidative status, allowing the production of innate components which can boost immunity without the risk of oxidative stress. This study shows a relationship between oxidative stress and immunity, and, from a practical perspective, shows that improving immunity and health in pacu through the administration of selenium could improve their growth performance. PMID:26370542

  8. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  9. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  10. Enhancement of Innate and Adaptive Immune Functions by Multiple Echinacea Species

    PubMed Central

    Zhai, Zili; Liu, Yi; Wu, Lankun; Senchina, David S.; Wurtele, Eve S.; Murphy, Patricia A.; Kohut, Marian L.; Cunnick, Joan E.

    2008-01-01

    Echinacea preparations are commonly used as nonspecific immunomodulatory agents. Alcohol extracts from three widely used Echinacea species, Echinacea angustifolia, Echinacea pallida, and Echinacea purpurea, were investigated for immunomodulating properties. The three Echinacea species demonstrated a broad difference in concentrations of individual lipophilic amides and hydrophilic caffeic acid derivatives. Mice were gavaged once a day (for 7 days) with one of the Echinacea extracts (130 mg/kg) or vehicle and immunized with sheep red blood cells (sRBC) 4 days prior to collection of immune cells for multiple immunological assays. The three herb extracts induced similar, but differential, changes in the percentage of immune cell populations and their biological functions, including increased percentages of CD49+ and CD19+ lymphocytes in spleen and natural killer cell cytotoxicity. Antibody response to sRBC was significantly increased equally by extracts of all three Echinacea species. Concanavalin A-stimulated splenocytes from E. angustifolia- and E. pallida-treated mice demonstrated significantly higher T cell proliferation. In addition, the Echinacea treatment significantly altered the cytokine production by mitogen-stimulated splenic cells. The three herbal extracts significantly increased interferon-γ production, but inhibited the release of tumor necrosis factor-α and interleukin (IL)-1β. Only E. angustifolia- and E. pallida-treated mice demonstrated significantly higher production of IL-4 and increased IL-10 production. Taken together, these findings demonstrated that Echinacea is a wide-spectrum immunomodulator that modulates both innate and adaptive immune responses. In particular, E. angustifolia or E. pallida may have more anti-inflammatory potential. PMID:17887935

  11. Construction of a full-length cDNA library of Solen grandis dunker and identification of defense- and immune-related genes

    NASA Astrophysics Data System (ADS)

    Sun, Guohua; Liu, Xiangquan; Ren, Lihua; Yang, Jianmin; Wei, Xiumei; Yang, Jialong

    2013-11-01

    The basic genetic characteristics, important functional genes, and entire transcriptome of Solen grandis Dunker were investigated by constructing a full-length cDNA library with the `switching mechanism at the 5'-end of the RNA transcript' (SMART) technique. Total RNA was isolated from the immune-relevant tissues, gills and hemocytes, using the Trizol reagent, and cDNA fragments were digested with Sfi I before being ligated to the pBluescript II SK* vector. The cDNA library had a titer of 1048 cfu μL-1 and a storage capacity of 1.05×106 cfu. Approximately 98% of the clones in the library were recombinants, and the fragment lengths of insert cDNA ranged from 0.8 kb to 3.0 kb. A total of 2038 expressed sequence tags were successfully sequenced and clustered into 965 unigenes. BLASTN analysis showed that 240 sequences were highly similar to the known genes (E-value < 1e -5; percent identity >80%), accounting for 25% of the total unigenes. According to the Gene Ontology, these unigenes were related to several biological processes, including cell structure, signal transport, protein synthesis, transcription, energy metabolism, and immunity. Fifteen of the identified sequences were related to defense and immunity. The full-length cDNA sequence of HSC70 was obtained. The cDNA library of S. grandis provided a useful resource for future researches of functional genomics related to stress tolerance, immunity, and other physiological activities.

  12. Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death

    PubMed Central

    DeLaney, Alexandra; Santos-Marrero, Melanie; Grier, Jennifer T.; Sun, Yan; Zwack, Erin E.; Hu, Baofeng; Olsen, Tayla M.; Rongvaux, Anthony; López, Carolina B.; Oberst, Andrew; Beiting, Daniel P.; Brodsky, Igor E.

    2016-01-01

    Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense. PMID:27737018

  13. In Vivo Synthesis of Cyclic-di-GMP Using a Recombinant Adenovirus Preferentially Improves Adaptive Immune Responses against Extracellular Antigens.

    PubMed

    Alyaqoub, Fadel S; Aldhamen, Yasser A; Koestler, Benjamin J; Bruger, Eric L; Seregin, Sergey S; Pereira-Hicks, Cristiane; Godbehere, Sarah; Waters, Christopher M; Amalfitano, Andrea

    2016-02-15

    There is a compelling need for more effective vaccine adjuvants to augment induction of Ag-specific adaptive immune responses. Recent reports suggested the bacterial second messenger bis-(3'-5')-cyclic-dimeric-guanosine monophosphate (c-di-GMP) acts as an innate immune system modulator. We recently incorporated a Vibrio cholerae diguanylate cyclase into an adenovirus vaccine, fostering production of c-di-GMP as well as proinflammatory responses in mice. In this study, we recombined a more potent diguanylate cyclase gene, VCA0848, into a nonreplicating adenovirus serotype 5 (AdVCA0848) that produces elevated amounts of c-di-GMP when expressed in mammalian cells in vivo. This novel platform further improved induction of type I IFN-β and activation of innate and adaptive immune cells early after administration into mice as compared with control vectors. Coadministration of the extracellular protein OVA and the AdVCA0848 adjuvant significantly improved OVA-specific T cell responses as detected by IFN-γ and IL-2 ELISPOT, while also improving OVA-specific humoral B cell adaptive responses. In addition, we found that coadministration of AdVCA0848 with another adenovirus serotype 5 vector expressing the HIV-1-derived Gag Ag or the Clostridium difficile-derived toxin B resulted in significant inhibitory effects on the induction of Gag and toxin B-specific adaptive immune responses. As a proof of principle, these data confirm that in vivo synthesis of c-di-GMP stimulates strong innate immune responses that correlate with enhanced adaptive immune responses to concomitantly administered extracellular Ag, which can be used as an adjuvant to heighten effective immune responses for protein-based vaccine platforms against microbial infections and cancers. PMID:26792800

  14. In Vivo Synthesis of Cyclic-di-GMP Using a Recombinant Adenovirus Preferentially Improves Adaptive Immune Responses against Extracellular Antigens.

    PubMed

    Alyaqoub, Fadel S; Aldhamen, Yasser A; Koestler, Benjamin J; Bruger, Eric L; Seregin, Sergey S; Pereira-Hicks, Cristiane; Godbehere, Sarah; Waters, Christopher M; Amalfitano, Andrea

    2016-02-15

    There is a compelling need for more effective vaccine adjuvants to augment induction of Ag-specific adaptive immune responses. Recent reports suggested the bacterial second messenger bis-(3'-5')-cyclic-dimeric-guanosine monophosphate (c-di-GMP) acts as an innate immune system modulator. We recently incorporated a Vibrio cholerae diguanylate cyclase into an adenovirus vaccine, fostering production of c-di-GMP as well as proinflammatory responses in mice. In this study, we recombined a more potent diguanylate cyclase gene, VCA0848, into a nonreplicating adenovirus serotype 5 (AdVCA0848) that produces elevated amounts of c-di-GMP when expressed in mammalian cells in vivo. This novel platform further improved induction of type I IFN-β and activation of innate and adaptive immune cells early after administration into mice as compared with control vectors. Coadministration of the extracellular protein OVA and the AdVCA0848 adjuvant significantly improved OVA-specific T cell responses as detected by IFN-γ and IL-2 ELISPOT, while also improving OVA-specific humoral B cell adaptive responses. In addition, we found that coadministration of AdVCA0848 with another adenovirus serotype 5 vector expressing the HIV-1-derived Gag Ag or the Clostridium difficile-derived toxin B resulted in significant inhibitory effects on the induction of Gag and toxin B-specific adaptive immune responses. As a proof of principle, these data confirm that in vivo synthesis of c-di-GMP stimulates strong innate immune responses that correlate with enhanced adaptive immune responses to concomitantly administered extracellular Ag, which can be used as an adjuvant to heighten effective immune responses for protein-based vaccine platforms against microbial infections and cancers.

  15. CRISPR-Cas Adaptive Immune Systems of the Sulfolobales: Unravelling Their Complexity and Diversity

    PubMed Central

    Garrett, Roger A.; Shah, Shiraz A.; Erdmann, Susanne; Liu, Guannan; Mousaei, Marzieh; León-Sobrino, Carlos; Peng, Wenfang; Gudbergsdottir, Soley; Deng, Ling; Vestergaard, Gisle; Peng, Xu; She, Qunxin

    2015-01-01

    The Sulfolobales have provided good model organisms for studying CRISPR-Cas systems of the crenarchaeal kingdom of the archaea. These organisms are infected by a wide range of exceptional archaea-specific viruses and conjugative plasmids, and their CRISPR-Cas systems generally exhibit extensive structural and functional diversity. They carry large and multiple CRISPR loci and often multiple copies of diverse Type I and Type III interference modules as well as more homogeneous adaptation modules. These acidothermophilic organisms have recently provided seminal insights into both the adaptation process, the diverse modes of interference, and their modes of regulation. The functions of the adaptation and interference modules tend to be loosely coupled and the stringency of the crRNA-DNA sequence matching during DNA interference is relatively low, in contrast to some more streamlined CRISPR-Cas systems of bacteria. Despite this, there is evidence for a complex and differential regulation of expression of the diverse functional modules in response to viral infection. Recent work also supports critical roles for non-core Cas proteins, especially during Type III-directed interference, and this is consistent with these proteins tending to coevolve with core Cas proteins. Various novel aspects of CRISPR-Cas systems of the Sulfolobales are considered including an alternative spacer acquisition mechanism, reversible spacer acquisition, the formation and significance of antisense CRISPR RNAs, and a novel mechanism for avoidance of CRISPR-Cas defense. Finally, questions regarding the basis for the complexity, diversity, and apparent redundancy, of the intracellular CRISPR-Cas systems are discussed. PMID:25764276

  16. TIM-4, a Receptor for Phosphatidylserine, Controls Adaptive Immunity by Regulating the Removal of Antigen-Specific T Cells

    PubMed Central

    Albacker, Lee A.; Karisola, Piia; Chang, Ya-Jen; Umetsu, Sarah E.; Zhou, Meixia; Akbari, Omid; Kobayashi, Norimoto; Baumgarth, Nicole; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

    2010-01-01

    Adaptive immunity is characterized by the expansion of an Ag-specific T cell population following Ag exposure. The precise mechanisms, however, that control the expansion and subsequent contraction in the number of Ag-specific T cells are not fully understood. We show that T cell/transmembrane, Ig, and mucin (TIM)-4, a receptor for phosphatidylserine, a marker of apoptotic cells, regulates adaptive immunity in part by mediating the removal of Ag-specific T cells during the contraction phase of the response. During Ag immunization or during infection with influenza A virus, blockade of TIM-4 on APCs increased the expansion of Ag-specific T cells, resulting in an increase in secondary immune responses. Conversely, overexpression of TIM-4 on APCs in transgenic mice reduced the number of Ag-specific T cells that remained after immunization, resulting in reduced secondary T cell responses. There was no change in the total number of cell divisions that T cells completed, no change in the per cell proliferative capacity of the remaining Ag-specific T cells, and no increase in the development of Ag-specific regulatory T cells in TIM-4 transgenic mice. Thus, TIM-4–expressing cells regulate adaptive immunity by mediating the removal of phosphatidylserine-expressing apoptotic, Ag-specific T cells, thereby controlling the number of Ag-specific T cells that remain after the clearance of Ag or infection. PMID:21037090

  17. CRISPR-Cas: From the Bacterial Adaptive Immune System to a Versatile Tool for Genome Engineering.

    PubMed

    Kirchner, Marion; Schneider, Sabine

    2015-11-01

    The field of biology has been revolutionized by the recent advancement of an adaptive bacterial immune system as a universal genome engineering tool. Bacteria and archaea use repetitive genomic elements termed clustered regularly interspaced short palindromic repeats (CRISPR) in combination with an RNA-guided nuclease (CRISPR-associated nuclease: Cas) to target and destroy invading DNA. By choosing the appropriate sequence of the guide RNA, this two-component system can be used to efficiently modify, target, and edit genomic loci of interest in plants, insects, fungi, mammalian cells, and whole organisms. This has opened up new frontiers in genome engineering, including the potential to treat or cure human genetic disorders. Now the potential risks as well as the ethical, social, and legal implications of this powerful new technique move into the limelight. PMID:26382836

  18. An adaptive immune optimization algorithm with dynamic lattice searching operation for fast optimization of atomic clusters

    NASA Astrophysics Data System (ADS)

    Wu, Xia; Wu, Genhua

    2014-08-01

    Geometrical optimization of atomic clusters is performed by a development of adaptive immune optimization algorithm (AIOA) with dynamic lattice searching (DLS) operation (AIOA-DLS method). By a cycle of construction and searching of the dynamic lattice (DL), DLS algorithm rapidly makes the clusters more regular and greatly reduces the potential energy. DLS can thus be used as an operation acting on the new individuals after mutation operation in AIOA to improve the performance of the AIOA. The AIOA-DLS method combines the merit of evolutionary algorithm and idea of dynamic lattice. The performance of the proposed method is investigated in the optimization of Lennard-Jones clusters within 250 atoms and silver clusters described by many-body Gupta potential within 150 atoms. Results reported in the literature are reproduced, and the motif of Ag61 cluster is found to be stacking-fault face-centered cubic, whose energy is lower than that of previously obtained icosahedron.

  19. Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury

    PubMed Central

    Ankeny, Daniel P.; Popovich, Phillip G.

    2009-01-01

    Traumatic spinal cord injury (SCI) in mammals causes widespread glial activation and recruitment to the CNS of innate (e.g., neutrophils, monocytes) and adaptive (e.g., T and B lymphocytes) immune cells. To date, most studies have sought to understand or manipulate the post-traumatic functions of astrocytes, microglia, neutrophils or monocytes. Significantly less is known about the consequences of SCI-induced lymphocyte activation. Yet, emerging data suggest that T and B cells are activated by SCI and play significant roles in shaping post-traumatic inflammation and downstream cascades of neurodegeneration and repair. Here, we provide neurobiologists with a timely review of the mechanisms and implications of SCI-induced lymphocyte activation, including a discussion of different experimental strategies that have been designed to manipulate lymphocyte function for therapeutic gain. PMID:18674593

  20. CRISPR-Cas: From the Bacterial Adaptive Immune System to a Versatile Tool for Genome Engineering.

    PubMed

    Kirchner, Marion; Schneider, Sabine

    2015-11-01

    The field of biology has been revolutionized by the recent advancement of an adaptive bacterial immune system as a universal genome engineering tool. Bacteria and archaea use repetitive genomic elements termed clustered regularly interspaced short palindromic repeats (CRISPR) in combination with an RNA-guided nuclease (CRISPR-associated nuclease: Cas) to target and destroy invading DNA. By choosing the appropriate sequence of the guide RNA, this two-component system can be used to efficiently modify, target, and edit genomic loci of interest in plants, insects, fungi, mammalian cells, and whole organisms. This has opened up new frontiers in genome engineering, including the potential to treat or cure human genetic disorders. Now the potential risks as well as the ethical, social, and legal implications of this powerful new technique move into the limelight.

  1. A Shortened Norwegian Adaptation of the Lie Scale for Children (LSC) and the Defensiveness Scale for Children (DSC)

    ERIC Educational Resources Information Center

    Haugen, Richard

    1978-01-01

    Ten items consisting of five DSC items and five LSC items were translated into Norwegian in order (a) to control the verbal anxiety responses from defensive tendencies, (b) to handle the problem of response set (the tendency to answer a questionnaire in a stereotyped way), and (c) to permit research concerning the nature of defensiveness itself.…

  2. Formulation of the respiratory syncytial virus fusion protein with a polymer-based combination adjuvant promotes transient and local innate immune responses and leads to improved adaptive immunity.

    PubMed

    Sarkar, Indranil; Garg, Ravendra; van Drunen Littel-van den Hurk, Sylvia

    2016-09-30

    Respiratory syncytial virus (RSV) causes serious upper and lower respiratory tract infections in newborns and infants. Presently, there is no licensed vaccine against RSV. We previously reported the safety and efficacy of a novel vaccine candidate (ΔF/TriAdj) in rodent and lamb models following intranasal immunization. However, the effects of the vaccine on the innate immune system in the upper and lower respiratory tracts, when delivered intranasally, have not been characterized. In the present study, we found that ΔF/TriAdj triggered transient production of chemokines, cytokines and interferons in the nasal tissues and lungs of BALB/c mice. The types of chemokines produced were consistent with the populations of immune cells recruited, i.e. dendritic cells, macrophages and neutrophils, in the nose-associated lymphoid tissue (NALT), lung and their draining lymph nodes of the ΔF/TriAdj-immunized group. In addition, ΔF/TriAdj stimulated cellular activation with generation of mucosal and systemic antibody responses, and conferred complete protection from viral infection in the lungs upon RSV challenge. The effect of ΔF/TriAdj was short-lived in the nasal tissues and more prolonged in the lungs. In addition, both innate and adaptive immune responses were lower when mice were immunized with ΔF alone. These results suggest that ΔF/TriAdj modulates the innate mucosal environment in both upper and lower respiratory tracts, which contributes to robust adaptive immune responses and long-term protective efficacy of this novel vaccine formulation. PMID:27591951

  3. Behavioral Immunity in Insects

    PubMed Central

    de Roode, Jacobus C.; Lefèvre, Thierry

    2012-01-01

    Parasites can dramatically reduce the fitness of their hosts, and natural selection should favor defense mechanisms that can protect hosts against disease. Much work has focused on understanding genetic and physiological immunity against parasites, but hosts can also use behaviors to avoid infection, reduce parasite growth or alleviate disease symptoms. It is increasingly recognized that such behaviors are common in insects, providing strong protection against parasites and parasitoids. We review the current evidence for behavioral immunity in insects, present a framework for investigating such behavior, and emphasize that behavioral immunity may act through indirect rather than direct fitness benefits. We also discuss the implications for host-parasite co-evolution, local adaptation, and the evolution of non-behavioral physiological immune systems. Finally, we argue that the study of behavioral immunity in insects has much to offer for investigations in vertebrates, in which this topic has traditionally been studied. PMID:26466629

  4. Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances.

    PubMed

    Haapakoski, Rita; Ebmeier, Klaus P; Alenius, Harri; Kivimäki, Mika

    2016-04-01

    The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.

  5. Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances

    PubMed Central

    Haapakoski, Rita; Ebmeier, Klaus P.; Alenius, Harri; Kivimäki, Mika

    2016-01-01

    The inflammation theory of depression, proposed over 20 years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced ‘omics’ technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account. PMID:26631274

  6. Immune adaptive response induced by Bicotylophora trachinoti (Monogenea: Diclidophoridae) infestation in pompano Trachinotus marginatus (Perciformes: Carangidae).

    PubMed

    Chaves, I S; Luvizzotto-Santos, R; Sampaio, L A N; Bianchini, A; Martínez, P E

    2006-09-01

    Fish have developed protective strategies against monogeneans through immunological responses. In this study, immune adaptive response to parasites was analysed in the pompano Trachinotus marginatus infested by Bicotylophora trachinoti. Hosts were pre-treated with formalin and after 10 days assigned to one of the following experimental treatments: (1) fish infested with remaining eggs of B. trachinoti; (2) fish infested with remaining eggs of B. trachinoti and experimentally re-infested by exposure to T. marginatus heavily infested with B. trachinoti. Samples were collected at 0, 15, and 30 days. Gills were dissected to check the presence of B. trachinoti. Blood was collected for haematological and biochemical assays. Spleen and head-kidney were dissected for phagocytosis assay. The spleen-somatic index was also calculated. Re-infested fish showed a faster and higher parasite infestation than infested ones. The parasite mean abundance at 15 days was 24.86+/-13.32 and 11.67+/-8.57 for re-infested and infested fish, respectively. In both groups, hosts showed an immune adaptive response to parasite infestation that was marked by an increased number of leukocytes. Also, phagocytosis (%) in spleen and head-kidney cells was stimulated after parasite infestation (92.50+/-3.73 and 66.00+/-9.54, respectively), becoming later depressed (77.39+/-6.69 and 53.23+/-9.14, respectively). These results support the hypothesis that monogenean infestation induces a biphasic response of the non-specific defence mechanisms in the pompano T. marginatus. This response is marked by an initial stimulation followed by a later depression of the non-specific defence mechanisms.

  7. The DosR Regulon Modulates Adaptive Immunity and Is Essential for Mycobacterium tuberculosis Persistence

    PubMed Central

    Mehra, Smriti; Foreman, Taylor W.; Didier, Peter J.; Ahsan, Muhammad H.; Hudock, Teresa A.; Kissee, Ryan; Golden, Nadia A.; Gautam, Uma S.; Johnson, Ann-Marie; Alvarez, Xavier; Russell-Lodrigue, Kasi E.; Doyle, Lara A.; Roy, Chad J.; Niu, Tianhua; Blanchard, James L.; Khader, Shabaana A.; Lackner, Andrew A.; Sherman, David R.

    2015-01-01

    Rationale: Hypoxia promotes dormancy by causing physiologic changes to actively replicating Mycobacterium tuberculosis. DosR controls the response of M. tuberculosis to hypoxia. Objectives: To understand DosR's contribution in the persistence of M. tuberculosis, we compared the phenotype of various DosR regulon mutants and a complemented strain to M. tuberculosis in macaques, which faithfully model M. tuberculosis infection. Methods: We measured clinical and microbiologic correlates of infection with M. tuberculosis relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia, and compared immune responses in lung using transcriptomics and flow cytometry. Measurements and Main Results: Despite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, M. tuberculosis and a complemented strain were able to establish infection and tuberculosis. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organization of hypoxic lesions wherein M. tuberculosis expressed dosR. The lungs of animals infected with the mutants (but not the complemented strain) exhibited early transcriptional signatures of T-cell recruitment, activation, and proliferation associated with an increase of T cells expressing homing and proliferation markers. Conclusions: Delayed adaptive responses, a hallmark of M. tuberculosis infection, not only lead to persistence but also interfere with the development of effective antituberculosis vaccines. The DosR regulon therefore modulates both the magnitude and the timing of adaptive immune responses in response to hypoxia in vivo, resulting in persistent infection. Hence, DosR regulates key aspects of the M. tuberculosis life cycle and limits lung pathology. PMID:25730547

  8. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    SciTech Connect

    Miyata, Ryohei; Eeden, Stephan F. van

    2011-12-15

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}m or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  9. The role of idiotypic interactions in the adaptive immune system: a belief-propagation approach

    NASA Astrophysics Data System (ADS)

    Bartolucci, Silvia; Mozeika, Alexander; Annibale, Alessia

    2016-08-01

    In this work we use belief-propagation techniques to study the equilibrium behaviour of a minimal model for the immune system comprising interacting T and B clones. We investigate the effect of the so-called idiotypic interactions among complementary B clones on the system’s activation. Our results show that B-B interactions increase the system’s resilience to noise, making clonal activation more stable, while increasing the cross-talk between different clones. We derive analytically the noise level at which a B clone gets activated, in the absence of cross-talk, and find that this increases with the strength of idiotypic interactions and with the number of T cells sending signals to the B clones. We also derive, analytically and numerically, via population dynamics, the critical line where clonal cross-talk arises. Our approach allows us to derive the B clone size distribution, which can be experimentally measured and gives important information about the adaptive immune system response to antigens and vaccination.

  10. The role of idiotypic interactions in the adaptive immune system: a belief-propagation approach

    NASA Astrophysics Data System (ADS)

    Bartolucci, Silvia; Mozeika, Alexander; Annibale, Alessia

    2016-08-01

    In this work we use belief-propagation techniques to study the equilibrium behaviour of a minimal model for the immune system comprising interacting T and B clones. We investigate the effect of the so-called idiotypic interactions among complementary B clones on the system’s activation. Our results show that B–B interactions increase the system’s resilience to noise, making clonal activation more stable, while increasing the cross-talk between different clones. We derive analytically the noise level at which a B clone gets activated, in the absence of cross-talk, and find that this increases with the strength of idiotypic interactions and with the number of T cells sending signals to the B clones. We also derive, analytically and numerically, via population dynamics, the critical line where clonal cross-talk arises. Our approach allows us to derive the B clone size distribution, which can be experimentally measured and gives important information about the adaptive immune system response to antigens and vaccination.

  11. Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection.

    PubMed

    Bendor, Liron; Weyrich, Laura S; Linz, Bodo; Rolin, Olivier Y; Taylor, Dawn L; Goodfield, Laura L; Smallridge, William E; Kennett, Mary J; Harvill, Eric T

    2015-01-01

    The Type Six Secretion System (T6SS) is required for Bordetella bronchiseptica cytotoxicity, cytokine modulation, infection, and persistence. However, one-third of recently sequenced Bordetella bronchiseptica strains of the predominantly human-associated Complex IV have lost their T6SS through gene deletion or degradation. Since most human B. bronchiseptica infections occur in immunocompromised patients, we determine here whether loss of Type Six Secretion is beneficial to B. bronchiseptica during infection of immunocompromised mice. Infection of mice lacking adaptive immunity (Rag1-/- mice) with a T6SS-deficient mutant results in a hypervirulent phenotype that is characterized by high numbers of intracellular bacteria in systemic organs. In contrast, wild-type B. bronchiseptica kill their eukaryotic cellular hosts via a T6SS-dependent mechanism that prevents survival in systemic organs. High numbers of intracellular bacteria recovered from immunodeficient mice but only low numbers from wild-type mice demonstrates that B. bronchiseptica survival in an intracellular niche is limited by B and T cell responses. Understanding the nature of intracellular survival during infection, and its effects on the generation and function of the host immune response, are important to contain and control the spread of Bordetella-caused disease. PMID:26485303

  12. Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

    PubMed

    Del Mar Amador, Maria; Vandenberghe, Nadia; Berhoune, Nawel; Camdessanché, Jean-Philippe; Gronier, Sophie; Delmont, Emilien; Desnuelle, Claude; Cintas, Pascal; Pittion, Sophie; Louis, Sarah; Demeret, Sophie; Lenglet, Timothée; Meininger, Vincent; Salachas, François; Pradat, Pierre-François; Bruneteau, Gaëlle

    2016-06-01

    Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.

  13. Influence of phthalates on in vitro innate and adaptive immune responses.

    PubMed

    Hansen, Juliana Frohnert; Nielsen, Claus Henrik; Brorson, Marianne Møller; Frederiksen, Hanne; Hartoft-Nielsen, Marie-Louise; Rasmussen, Åse Krogh; Bendtzen, Klaus; Feldt-Rasmussen, Ulla

    2015-01-01

    Phthalates are a group of endocrine disrupting chemicals, suspected to influence the immune system. The aim of this study was to investigate the influence of phthalates on cytokine secretion from human peripheral blood mononuclear cells. Escherichia coli lipopolysaccharide and phytohemagglutinin-P were used for stimulation of monocytes/macrophages and T cells, respectively. Cells were exposed for 20 to 22 hours to either di-ethyl, di-n-butyl or mono-n-butyl phthalate at two different concentrations. Both diesters were metabolised to their respective monoester and influenced cytokine secretion from both monocytes/macrophages and T cells in a similar pattern: the secretion of interleukin (IL)-6, IL-10 and the chemokine CXCL8 by monocytes/macrophages was enhanced, while tumour necrosis factor (TNF)-α secretion by monocytes/macrophages was impaired, as was the secretion of IL-2 and IL-4, TNF-α and interferon-γ by T cells. The investigated phthalate monoester also influenced cytokine secretion from monocytes/macrophages similar to that of the diesters. In T cells, however, the effect of the monoester was different compared to the diesters. The influence of the phthalates on the cytokine secretion did not seem to be a result of cell death. Thus, results indicate that both human innate and adaptive immunity is influenced in vitro by phthalates, and that phthalates therefore may affect cell differentiation and regenerative and inflammatory processes in vivo.

  14. Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection.

    PubMed

    Bendor, Liron; Weyrich, Laura S; Linz, Bodo; Rolin, Olivier Y; Taylor, Dawn L; Goodfield, Laura L; Smallridge, William E; Kennett, Mary J; Harvill, Eric T

    2015-01-01

    The Type Six Secretion System (T6SS) is required for Bordetella bronchiseptica cytotoxicity, cytokine modulation, infection, and persistence. However, one-third of recently sequenced Bordetella bronchiseptica strains of the predominantly human-associated Complex IV have lost their T6SS through gene deletion or degradation. Since most human B. bronchiseptica infections occur in immunocompromised patients, we determine here whether loss of Type Six Secretion is beneficial to B. bronchiseptica during infection of immunocompromised mice. Infection of mice lacking adaptive immunity (Rag1-/- mice) with a T6SS-deficient mutant results in a hypervirulent phenotype that is characterized by high numbers of intracellular bacteria in systemic organs. In contrast, wild-type B. bronchiseptica kill their eukaryotic cellular hosts via a T6SS-dependent mechanism that prevents survival in systemic organs. High numbers of intracellular bacteria recovered from immunodeficient mice but only low numbers from wild-type mice demonstrates that B. bronchiseptica survival in an intracellular niche is limited by B and T cell responses. Understanding the nature of intracellular survival during infection, and its effects on the generation and function of the host immune response, are important to contain and control the spread of Bordetella-caused disease.

  15. Synthetic innate defense regulator peptide combination using CpG ODN as a novel adjuvant induces long‑lasting and balanced immune responses.

    PubMed

    Yu, Chao-Heng; Luo, Zi-Chao; Li, Meng; Lu, Lian; Li, Zhan; Wu, Xiao-Zhe; Fan, Ying-Zi; Zhang, Hai-Long; Zhou, Bai-Ling; Wan, Yang; Men, Ke; Tian, Yao-Mei; Chen, Shuang; Yuan, Feng-Jiao; Xiang, Rong; Yang, Li

    2016-01-01

    Vaccines are critical tools for the prevention and treatment of several diseases. Adjuvants have been traditionally used to enhance immunity to vaccines and experimental antigens. In the present study, the adjuvant combination of CpG oligodeoxynucleotides (CpG ODN) and the innate defense regulator (IDR) peptide, IDR‑HH2, was evaluated for its ability to enhance and modulate the immune response when formulated with alum and the recombinant hepatitis B surface antigen (HBsAg). The CpG‑HH2 complex enhanced the secretions of tumor necrosis factor‑α, monocyte chemotactic protein 1 and interferon‑γ by human peripheral blood mononuclear cells and promoted murine bone marrow dentritic cell maturation. In addition, the present study demonstrated that IDR‑HH2 was chemotactic for human neutrophils, THP‑1 cells and RAW264.7 cells at concentrations between 2.5 and 40 µg/ml. The present study also observed that significantly higher anti‑HBs antibody titers, which were sustained at high levels for as long as 35 weeks following the boost immunization, were induced by the combination adjuvant, even when co‑administered with a commercial hepatitis B vaccine at a low antigen dose (0.1 µg HBsAg). Notably, the level of IgG2a was almost equal to the level of IgG1, indicating that a balanced T helper (Th)1/Th2 immune response was elicited by the novel vaccine, which was consistent with the ELISpot results. These data suggest that the CpG‑HH2 complex may be a potential effective adjuvant, which facilitates a reduction in the dose of antigen and induces long‑lasting, balanced immune responses. PMID:26647852

  16. Effects of interaction between temperature conditions and copper exposure on immune defense and other life-history traits of the blow fly Protophormia terraenovae.

    PubMed

    Pölkki, Mari; Kangassalo, Katariina; Rantala, Markus J

    2014-01-01

    Environmental pollution is considered one of the major threats to organisms. Direct effects of heavy metal pollution on various life-history traits are well recognized, while the effects of potential interactions between two distinct environmental conditions on different traits are poorly understood. Here, we have tested the effects of interactions between temperature conditions and heavy metal exposure on innate immunity and other life-history traits. Maggots of the blow fly Protophormia terraenovae were reared on either copper-contaminated or uncontaminated food, under three different temperature environments. Encapsulation response, body mass, and development time were measured for adult flies that were not directly exposed to copper. We found that the effects of copper exposure on immunity and other traits are temperature-dependent, suggesting that the ability to regulate toxic compounds in body tissues might depend on temperature conditions. Furthermore, we found that temperature has an effect on sex differences in immune defense. Males had an encapsulation response at higher temperatures stronger than that of females. Our results indicate that the effects of environmental conditions on different traits are much more intricate than what can be predicted. This is something that should be considered when conducting immunological experiments or comparing results of previous studies.

  17. Fault-Tolerant Trajectory Tracking of Unmanned Aerial Vehicles Using Immunity-Based Model Reference Adaptive Control

    NASA Astrophysics Data System (ADS)

    Wilburn, Brenton K.

    This dissertation presents the design, development, and simulation testing of an adaptive trajectory tracking algorithm capable of compensating for various aircraft subsystem failures and upset conditions. A comprehensive adaptive control framework, here within referred to as the immune model reference adaptive control (IMRAC) algorithm, is developed by synergistically merging core concepts from the biologically- inspired artificial immune system (AIS) paradigm with more traditional optimal and adaptive control techniques. In particular, a model reference adaptive control (MRAC) algorithm is enhanced with the detection and learning capabilities of a novel, artificial neural network augmented AIS scheme. With the given modifications, the MRAC scheme is capable of detecting and identifying a given failure or upset condition, learning how to adapt to the problem, responding in a manner specific to the given failure condition, and retaining the learning parameters for quicker adaptation to subsequent failures of the same nature. The IMRAC algorithm developed in this dissertation is applicable to a wide range of control problems. However, the proposed methodology is demonstrated in simulation for an unmanned aerial vehicle. The results presented show that the IMRAC algorithm is an effective and valuable extension to traditional optimal and adaptive control techniques. The implementation of this methodology can potentially have significant impacts on the operational safety of many complex systems.

  18. Neuronal adaptations, neuroendocrine and immune correlates of heroin self-administration.

    PubMed

    Weber, R J; Gomez-Flores, R; Smith, J E; Martin, T J

    2009-10-01

    Opioid receptor-mediated action in the central nervous system (CNS) has been consistently shown to trigger changes in the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) and suppress a variety of parameters of immune function in investigator-delivered paradigms. Overwhelming evidence supports the concept that the CNS undergoes numerous and complex neuronal adaptive changes in addicts, and in animal models of heroin addiction as a result of the training of drug stimuli to serve as reinforcers, altering the function of individual neurons and the larger neural circuits within which the neurons operate. Taken together, these advances suggest that since plastic neuronal changes occur in drug addiction and related animal model paradigms, profiles of neuroendocrine and immune function would differ in a rat model of heroin self-administration compared to passive infusion of drug. Self-administration of heroin induces neuronal circuitry adaptations in specific brain regions that may be related to alterations in neuroendocrine and T lymphocyte function also observed. Animals self-administering (SA) heroin exhibit increased mu-opioid receptor agonist ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO))-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding in the anterior hypothalamus (50% and 33%) and rostral medial thalamus (33% and 36%) compared with control animals receiving identical non-contingent injections of yoked-heroin (YH) or yoked-saline (YS), respectively. No changes in agonist-stimulated G-protein sensitization were observed in 14 other brain regions studied. No changes in mu-opioid receptor density, ((3)H-DAMGO binding) were seen in all brain regions examined. The neuronal changes in SA animals were correlated with elevated adrenocorticotrophic hormone (ACTH) (64% and 104%) and glucocorticoid production (198% and 79%) compared with YH and YS groups, respectively. Neuroendocrine adaptive changes in SA

  19. Protective immune response of live attenuated thermo-adapted peste des petits ruminants vaccine in goats.

    PubMed

    Balamurugan, V; Sen, A; Venkatesan, G; Bhanuprakash, V; Singh, R K

    2014-01-01

    Virulent isolate of peste des petits ruminants virus (PPRV) of Indian origin (PPRV Jhansi 2003) initially adapted in Vero cells was further propagated in thermo-adapted (Ta) Vero cells grown at 40 °C for attaining thermo-adaption and attenuation of virus for development of Ta vaccine against PPR in goats and sheep. The virus was attenuated up to 50 passages in Ta Vero cells, at which, the virus was found sterile, innocuous in mice and guinea pigs and safe in seronegative goats and sheep. The developed vaccine was tested for its immunogenicity in goats and sheep by subcutaneous inoculation of 100 TCID50 (0.1 field dose), 10(3) TCID50 (one field dose) and 10(5) TCID50 (100 field doses) of the attenuated virus along with controls as per OIE described protocols for PPR vaccine testing and were assessed for PPRV-specific antibodies 7-28 days post vaccination (dpv) by PPR competitive ELISA and serum neutralization tests. The PPRV antibodies were detected in all immunized goats and sheep and goats were protective when challenged with virulent PPRV at 28th dpv along with controls for potency testing of the vaccine. The attenuated vaccine did not induce any adverse reaction at high dose (10(5) TCID50) in goats and sheep and provided complete protection even at low dose (10(2) TCID50) in goats when challenged with virulent virus. There was no shedding and horizontal transmission of the attenuated virus to in-contact controls. The results indicate that the developed PPR Ta attenuated virus is innocuous, safe, immunogenic and potent or efficacious vaccine candidate alternative to the existing vaccines for the protection of goats and sheep against PPR in the tropical countries like India. PMID:25674603

  20. Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection.

    PubMed

    Nguyen, Philip V; Kafka, Jessica K; Ferreira, Victor H; Roth, Kristy; Kaushic, Charu

    2014-09-01

    The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections.

  1. Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection

    PubMed Central

    Nguyen, Philip V; Kafka, Jessica K; Ferreira, Victor H; Roth, Kristy; Kaushic, Charu

    2014-01-01

    The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections. PMID:24976268

  2. Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type-1 infection.

    PubMed

    Cunningham-Rundles, Susanna; Ahrné, Siv; Johann-Liang, Rosemary; Abuav, Rachel; Dunn-Navarra, Ann-Margaret; Grassey, Claudia; Bengmark, Stig; Cervia, Joseph S

    2011-12-01

    The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone

  3. Effect of Probiotic Bacteria on Microbial Host Defense, Growth, and Immune Function in Human Immunodeficiency Virus Type-1 Infection

    PubMed Central

    Cunningham-Rundles, Susanna; Ahrné, Siv; Johann-Liang, Rosemary; Abuav, Rachel; Dunn-Navarra, Ann-Margaret; Grassey, Claudia; Bengmark, Stig; Cervia, Joseph S.

    2011-01-01

    The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone

  4. Reciprocal Interactions of the Intestinal Microbiota and Immune System

    PubMed Central

    Maynard, Craig L.; Elson, Charles O.; Hatton, Robin D.; Weaver, Casey T.

    2013-01-01

    Preface Emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defense. These same attributes carry risk for immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how it integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks in order to treat and prevent disease. PMID:22972296

  5. Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

    PubMed Central

    Inkeles, Megan S.; Teles, Rosane M.B.; Pouldar, Delila; Andrade, Priscila R.; Madigan, Cressida A.; Ambrose, Mike; Sarno, Euzenir N.; Rea, Thomas H.; Ochoa, Maria T.; Iruela-Arispe, M. Luisa; Swindell, William R.; Ottenhoff, Tom H.M.; Geluk, Annemieke; Bloom, Barry R.

    2016-01-01

    Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease. PMID:27699251

  6. Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

    PubMed Central

    Inkeles, Megan S.; Teles, Rosane M.B.; Pouldar, Delila; Andrade, Priscila R.; Madigan, Cressida A.; Ambrose, Mike; Sarno, Euzenir N.; Rea, Thomas H.; Ochoa, Maria T.; Iruela-Arispe, M. Luisa; Swindell, William R.; Ottenhoff, Tom H.M.; Geluk, Annemieke; Bloom, Barry R.

    2016-01-01

    Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.

  7. Innate and adaptive cellular phenotypes contributing to pulmonary disease in mice after respiratory syncytial virus immunization and infection.

    PubMed

    Lee, Young-Tae; Kim, Ki-Hye; Hwang, Hye Suk; Lee, Youri; Kwon, Young-Man; Ko, Eun-Ju; Jung, Yu-Jin; Lee, Yu-Na; Kim, Min-Chul; Kang, Sang-Moo

    2015-11-01

    Respiratory syncytial virus (RSV) is the major leading cause of infantile viral bronchiolitis. However, cellular phenotypes contributing to the RSV protection and vaccine-enhanced disease remain largely unknown. Upon RSV challenge, we analyzed phenotypes and cellularity in the lung of mice that were naïve, immunized with formalin inactivated RSV (FI-RSV), or re-infected with RSV. In comparison with naïve and live RSV re-infected mice, the high levels of eosinophils, neutrophils, plasmacytoid and CD11b(+) dendritic cells, and IL-4(+) CD4(+) T cells were found to be contributing to pulmonary inflammation in FI-RSV immune mice despite lung viral clearance. Alveolar macrophages appeared to play differential roles in protection and inflammation upon RSV infection of different RSV immune mice. These results suggest that multiple innate and adaptive immune components differentially contribute to RSV disease and inflammation.

  8. Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity.

    PubMed Central

    Siegal, F P; Lopez, C; Fitzgerald, P A; Shah, K; Baron, P; Leiderman, I Z; Imperato, D; Landesman, S

    1986-01-01

    We evaluated the cellular immunity of 408 clinically stratified subjects at risk for acquired immune deficiency syndrome (AIDS), to define the role of interferon-alpha production deficits in the pathogenesis of opportunistic infections (OI). We followed 115 prospectively for up to 45 mo. Onset of OI was associated with, and predicted by, deficiency both of interferon-alpha generation in vitro, and of circulating Leu-3a+ cells. Interferon-alpha production is an index of the function of certain non-T, non-B, large granular lymphocytes (LGL) that are independent of T cell help. Leu-3a+ cell counts are a marker of T cell function. OI did not usually develop until both of these mutually independent immune functions were simultaneously critically depressed, leading to a synergistic interaction. These data suggest that the AIDS virus affects a subset of LGL, and that cytokine production by these cells is an important component of the host defense against intracellular pathogens that becomes crucial in the presence of severe T cell immunodeficiency. PMID:3088039

  9. Comparative proteomic analysis of oil palm leaves infected with Ganoderma boninense revealed changes in proteins involved in photosynthesis, carbohydrate metabolism, and immunity and defense.

    PubMed

    Jeffery Daim, Leona Daniela; Ooi, Tony Eng Keong; Ithnin, Nalisha; Mohd Yusof, Hirzun; Kulaveerasingam, Harikrishna; Abdul Majid, Nazia; Karsani, Saiful Anuar

    2015-08-01

    The basidiomycete fungal pathogen Ganoderma boninense is the causative agent for the incurable basal stem rot (BSR) disease in oil palm. This disease causes significant annual crop losses in the oil palm industry. Currently, there is no effective method for disease control and elimination, nor is any molecular marker for early detection of the disease available. An understanding of how BSR affects protein expression in plants may help identify and/or assist in the development of an early detection protocol. Although the mode of infection of BSR disease is primarily via the root system, defense-related genes have been shown to be expressed in both the root and leafs. Thus, to provide an insight into the changes in the global protein expression profile in infected plants, comparative 2DE was performed on leaf tissues sampled from palms with and without artificial inoculation of the Ganoderma fungus. Comparative 2DE revealed that 54 protein spots changed in abundance. A total of 51 protein spots were successfully identified by LC-QTOF MS/MS. The majority of these proteins were those involved in photosynthesis, carbohydrate metabolism as well as immunity and defense.

  10. Comparative proteomic analysis of oil palm leaves infected with Ganoderma boninense revealed changes in proteins involved in photosynthesis, carbohydrate metabolism, and immunity and defense.

    PubMed

    Jeffery Daim, Leona Daniela; Ooi, Tony Eng Keong; Ithnin, Nalisha; Mohd Yusof, Hirzun; Kulaveerasingam, Harikrishna; Abdul Majid, Nazia; Karsani, Saiful Anuar

    2015-08-01

    The basidiomycete fungal pathogen Ganoderma boninense is the causative agent for the incurable basal stem rot (BSR) disease in oil palm. This disease causes significant annual crop losses in the oil palm industry. Currently, there is no effective method for disease control and elimination, nor is any molecular marker for early detection of the disease available. An understanding of how BSR affects protein expression in plants may help identify and/or assist in the development of an early detection protocol. Although the mode of infection of BSR disease is primarily via the root system, defense-related genes have been shown to be expressed in both the root and leafs. Thus, to provide an insight into the changes in the global protein expression profile in infected plants, comparative 2DE was performed on leaf tissues sampled from palms with and without artificial inoculation of the Ganoderma fungus. Comparative 2DE revealed that 54 protein spots changed in abundance. A total of 51 protein spots were successfully identified by LC-QTOF MS/MS. The majority of these proteins were those involved in photosynthesis, carbohydrate metabolism as well as immunity and defense. PMID:25930948

  11. Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

    PubMed Central

    Kinloch, Natalie N.; MacMillan, Daniel R.; Le, Anh Q.; Cotton, Laura A.; Bangsberg, David R.; Buchbinder, Susan; Carrington, Mary; Fuchs, Jonathan; Harrigan, P. Richard; Koblin, Beryl; Kushel, Margot; Markowitz, Martin; Mayer, Kenneth; Milloy, M. J.; Schechter, Martin T.; Wagner, Theresa; Walker, Bruce D.; Carlson, Jonathan M.; Poon, Art F. Y.

    2015-01-01

    ABSTRACT Human leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era. IMPORTANCE HLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may

  12. Genotype-by-environment interactions and adaptation to local temperature affect immunity and fecundity in Drosophila melanogaster.

    PubMed

    Lazzaro, Brian P; Flores, Heather A; Lorigan, James G; Yourth, Christopher P

    2008-03-01

    Natural populations of most organisms harbor substantial genetic variation for resistance to infection. The continued existence of such variation is unexpected under simple evolutionary models that either posit direct and continuous natural selection on the immune system or an evolved life history "balance" between immunity and other fitness traits in a constant environment. However, both local adaptation to heterogeneous environments and genotype-by-environment interactions can maintain genetic variation in a species. In this study, we test Drosophila melanogaster genotypes sampled from tropical Africa, temperate northeastern North America, and semi-tropical southeastern North America for resistance to bacterial infection and fecundity at three different environmental temperatures. Environmental temperature had absolute effects on all traits, but there were also marked genotype-by-environment interactions that may limit the global efficiency of natural selection on both traits. African flies performed more poorly than North American flies in both immunity and fecundity at the lowest temperature, but not at the higher temperatures, suggesting that the African population is maladapted to low temperature. In contrast, there was no evidence for clinal variation driven by thermal adaptation within North America for either trait. Resistance to infection and reproductive success were generally uncorrelated across genotypes, so this study finds no evidence for a fitness tradeoff between immunity and fecundity under the conditions tested. Both local adaptation to geographically heterogeneous environments and genotype-by-environment interactions may explain the persistence of genetic variation for resistance to infection in natural populations.

  13. Genotype-by-Environment Interactions and Adaptation to Local Temperature Affect Immunity and Fecundity in Drosophila melanogaster

    PubMed Central

    Lazzaro, Brian P.; Flores, Heather A.; Lorigan, James G.; Yourth, Christopher P.

    2008-01-01

    Natural populations of most organisms harbor substantial genetic variation for resistance to infection. The continued existence of such variation is unexpected under simple evolutionary models that either posit direct and continuous natural selection on the immune system or an evolved life history “balance” between immunity and other fitness traits in a constant environment. However, both local adaptation to heterogeneous environments and genotype-by-environment interactions can maintain genetic variation in a species. In this study, we test Drosophila melanogaster genotypes sampled from tropical Africa, temperate northeastern North America, and semi-tropical southeastern North America for resistance to bacterial infection and fecundity at three different environmental temperatures. Environmental temperature had absolute effects on all traits, but there were also marked genotype-by-environment interactions that may limit the global efficiency of natural selection on both traits. African flies performed more poorly than North American flies in both immunity and fecundity at the lowest temperature, but not at the higher temperatures, suggesting that the African population is maladapted to low temperature. In contrast, there was no evidence for clinal variation driven by thermal adaptation within North America for either trait. Resistance to infection and reproductive success were generally uncorrelated across genotypes, so this study finds no evidence for a fitness tradeoff between immunity and fecundity under the conditions tested. Both local adaptation to geographically heterogeneous environments and genotype-by-environment interactions may explain the persistence of genetic variation for resistance to infection in natural populations. PMID:18369474

  14. Tribolium castaneum immune defense genes are differentially expressed in response to Bacillus thuringiensis toxins sharing common receptor molecules and exhibiting disparate toxicity.

    PubMed

    Contreras, Estefanía; Benito-Jardón, María; López-Galiano, M José; Real, M Dolores; Rausell, Carolina

    2015-06-01

    In Tribolium castaneum larvae we have demonstrated by RNA interference knockdown that the Bacillus thuringiensis Cry3Ba toxin receptors Cadherin-like and Sodium solute symporter proteins are also functional receptors of the less active Cry3Aa toxin. Differences in susceptibility to B. thuringiensis infection might not only rely on toxin-receptor interaction but also on host defense mechanisms. We compared the expression of the immune related genes encoding Apolipophorin-III and two antimicrobial peptides, Defensin3 and Defensin2 after B. thuringiensis challenge. All three genes were up-regulated following Cry3Ba spore-crystal intoxication whereas only Defensins gene expression was induced upon Cry3Aa spore-crystal treatment, evidencing a possible association between host immune response and larval susceptibility to B. thuringiensis. We assessed the antimicrobial activity spectra of T. castaneum defensins peptide fragments and found that a peptide fragment of Defensin3 was effective against the human microbial pathogens, Escherichia coli, Staphylococcus aureus and Candida albicans, being S. aureus the most susceptible one.

  15. An Active Immune Defense with a Minimal CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) RNA and without the Cas6 Protein*

    PubMed Central

    Maier, Lisa-Katharina; Stachler, Aris-Edda; Saunders, Sita J.; Backofen, Rolf; Marchfelder, Anita

    2015-01-01

    The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3′ handle are still active in triggering an interference reaction. The complete 3′ handle could be removed without loss of activity. However, manipulations of the 5′ handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Δcas6b) is still active in interference. PMID:25512373

  16. An active immune defense with a minimal CRISPR (clustered regularly interspaced short palindromic repeats) RNA and without the Cas6 protein.

    PubMed

    Maier, Lisa-Katharina; Stachler, Aris-Edda; Saunders, Sita J; Backofen, Rolf; Marchfelder, Anita

    2015-02-13

    The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3' handle are still active in triggering an interference reaction. The complete 3' handle could be removed without loss of activity. However, manipulations of the 5' handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Δcas6b) is still active in interference.

  17. An active immune defense with a minimal CRISPR (clustered regularly interspaced short palindromic repeats) RNA and without the Cas6 protein.

    PubMed

    Maier, Lisa-Katharina; Stachler, Aris-Edda; Saunders, Sita J; Backofen, Rolf; Marchfelder, Anita

    2015-02-13

    The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3' handle are still active in triggering an interference reaction. The complete 3' handle could be removed without loss of activity. However, manipulations of the 5' handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Δcas6b) is still active in interference. PMID:25512373

  18. Repeated vaccinations do not improve specific immune defenses against Hepatitis B in non-responder health care workers.

    PubMed

    Zaffina, Salvatore; Marcellini, Valentina; Santoro, Anna Paola; Scarsella, Marco; Camisa, Vincenzo; Vinci, Maria Rosaria; Musolino, Anna Maria; Nicolosi, Luciana; Rosado, M Manuela; Carsetti, Rita

    2014-12-01

    Hepatitis B is a major infectious occupational hazard for health care workers and can be prevented with a safe and effective vaccine. The serum titer of anti-HBsAg antibodies is the most commonly used correlate of protection and post-vaccination anti-HBsAg concentrations of ≥ 10 mIU/ml are considered protective. Subjects with post-vaccination anti-HBsAg titers of <10 mIU/ml 1-6 months post-vaccination, who tested negative for HBsAg and anti-HBc, are defined as non-responders. The question of whether non-responders should be repeatedly vaccinated is still open. The aim of the study was to (i) evaluate the distribution of lymphocyte subpopulations and the percentage of HBsAg-specific memory B cells in responders and non-responders (ii) assess whether non-responders can be induced to produce antibodies after administration of a booster dose of vaccine (iii) determine whether booster vaccination increases the number of specific memory B cells in non-responders. Combining flow-cytometry, ELISPOT and serology we tested the integrity and function of the immune system in 24 health care workers, confirmed to be non-responders after at least three vaccine injections. We compared the results with those obtained in 21 responders working in the same institution. We found that the great majority of the non-responders had a functional immune system and a preserved ability to respond to other conventional antigens. Our most important findings are that the frequency of HBsAg-specific memory B cells is comparable in non-responders and controls and that booster immunization does not lead either to antibody production or memory B cell increase in non-responders.

  19. The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells.

    PubMed

    Chorny, Alejo; Casas-Recasens, Sandra; Sintes, Jordi; Shan, Meimei; Polentarutti, Nadia; García-Escudero, Ramón; Walland, A Cooper; Yeiser, John R; Cassis, Linda; Carrillo, Jorge; Puga, Irene; Cunha, Cristina; Bastos, Hélder; Rodrigues, Fernando; Lacerda, João F; Morais, António; Dieguez-Gonzalez, Rebeca; Heeger, Peter S; Salvatori, Giovanni; Carvalho, Agostinho; Garcia-Sastre, Adolfo; Blander, J Magarian; Mantovani, Alberto; Garlanda, Cecilia; Cerutti, Andrea

    2016-09-19

    Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens. PMID:27621420

  20. Fusokine interleukin-2/interleukin-18, a novel potent innate and adaptive immune stimulator with decreased toxicity.

    PubMed

    Acres, Bruce; Gantzer, Murielle; Remy, Christelle; Futin, Nicolas; Accart, Nathalie; Chaloin, Olivier; Hoebeke, Johan; Balloul, Jean-Marc; Paul, Stéphane

    2005-10-15

    To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity. PMID:16230419

  1. Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef

    SciTech Connect

    Jia, Xiaofei; Singh, Rajendra; Homann, Stefanie; Yang, Haitao; Guatelli, John; Xiong, Yong

    2012-10-24

    The HIV-1 protein Nef inhibits antigen presentation by class I major histocompatibility complex (MHC-I). We determined the mechanism of this activity by solving the crystal structure of a protein complex comprising Nef, the MHC-I cytoplasmic domain (MHC-I CD) and the {mu}1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-{mu}1 interface, which encompasses the cargo-recognition site of {mu}1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in {mu}1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on {mu}1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity.

  2. Structural Basis of Evasion of Cellular Adaptive Immunity by HIV-1 Nef

    PubMed Central

    Jia, Xiaofei; Singh, Rajendra; Homann, Stefanie; Yang, Haitao; Guatelli, John; Xiong, Yong

    2012-01-01

    The HIV-1 protein Nef inhibits antigen presentation by class I MHC (MHC-I). Here the mechanism of this activity is revealed by the crystal structure of a protein complex consisting of Nef, the MHC-I cytoplasmic domain (MHC-I CD), and the μ1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-μ1 interface encompassing the cargo-recognition site of μ1 and the proline rich strand of Nef. The Nef C-terminus induces a novel conformational change in μ1, while the N-terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on μ1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity. PMID:22705789

  3. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  4. Salmonella enterica Serovar Enteritidis Antimicrobial Peptide Resistance Genes Aid in Defense against Chicken Innate Immunity, Fecal Shedding, and Egg Deposition

    PubMed Central

    McKelvey, Jessica A.; Yang, Ming; Jiang, Yanhua

    2014-01-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major etiologic agent of nontyphoid salmonellosis in the United States. S. Enteritidis persistently and silently colonizes the intestinal and reproductive tract of laying hens, resulting in contaminated poultry products. The consumption of contaminated poultry products has been identified as a significant risk factor for human salmonellosis. To understand the mechanisms S. Enteritidis utilizes to colonize and persist in laying hens, we used selective capture of transcribed sequences to identify genes overexpressed in the HD11 chicken macrophage cell line and in primary chicken oviduct epithelial cells. From the 15 genes found to be overexpressed in both cell types, we characterized the antimicrobial peptide resistance (AMPR) genes, virK and ybjX, in vitro and in vivo. In vitro, AMPR genes were required for natural morphology, motility, secretion, defense against detergents such as EDTA and bile salts, and resistance to antimicrobial peptides polymyxin B and avian β-defensins. From this, we inferred the AMPR genes play a role in outer membrane stability and/or modulation. In the intestinal tract, AMPR genes were involved in early intestinal colonization and fecal shedding. In the reproductive tract, virK was required in early colonization whereas a deletion of ybjX caused prolonged ovary colonization and egg deposition. Data from the present study indicate that AMPR genes are differentially utilized in various host environments, which may ultimately assist S. Enteritidis in persistent and silent colonization of chickens. PMID:25267840

  5. Salmonella enterica serovar enteritidis antimicrobial peptide resistance genes aid in defense against chicken innate immunity, fecal shedding, and egg deposition.

    PubMed

    McKelvey, Jessica A; Yang, Ming; Jiang, Yanhua; Zhang, Shuping

    2014-12-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major etiologic agent of nontyphoid salmonellosis in the United States. S. Enteritidis persistently and silently colonizes the intestinal and reproductive tract of laying hens, resulting in contaminated poultry products. The consumption of contaminated poultry products has been identified as a significant risk factor for human salmonellosis. To understand the mechanisms S. Enteritidis utilizes to colonize and persist in laying hens, we used selective capture of transcribed sequences to identify genes overexpressed in the HD11 chicken macrophage cell line and in primary chicken oviduct epithelial cells. From the 15 genes found to be overexpressed in both cell types, we characterized the antimicrobial peptide resistance (AMPR) genes, virK and ybjX, in vitro and in vivo. In vitro, AMPR genes were required for natural morphology, motility, secretion, defense against detergents such as EDTA and bile salts, and resistance to antimicrobial peptides polymyxin B and avian β-defensins. From this, we inferred the AMPR genes play a role in outer membrane stability and/or modulation. In the intestinal tract, AMPR genes were involved in early intestinal colonization and fecal shedding. In the reproductive tract, virK was required in early colonization whereas a deletion of ybjX caused prolonged ovary colonization and egg deposition. Data from the present study indicate that AMPR genes are differentially utilized in various host environments, which may ultimately assist S. Enteritidis in persistent and silent colonization of chickens.

  6. Human and Animal Isolates of Yersinia enterocolitica Show Significant Serotype-Specific Colonization and Host-Specific Immune Defense Properties

    PubMed Central

    Schaake, Julia; Kronshage, Malte; Uliczka, Frank; Rohde, Manfred; Knuuti, Tobias; Strauch, Eckhard; Fruth, Angelika; Wos-Oxley, Melissa

    2013-01-01

    Yersinia enterocolitica is a human pathogen that is ubiquitous in livestock, especially pigs. The bacteria are able to colonize the intestinal tract of a variety of mammalian hosts, but the severity of induced gut-associated diseases (yersiniosis) differs significantly between hosts. To gain more information about the individual virulence determinants that contribute to colonization and induction of immune responses in different hosts, we analyzed and compared the interactions of different human- and animal-derived isolates of serotypes O:3, O:5,27, O:8, and O:9 with murine, porcine, and human intestinal cells and macrophages. The examined strains exhibited significant serotype-specific cell binding and entry characteristics, but adhesion and uptake into different host cells were not host specific and were independent of the source of the isolate. In contrast, survival and replication within macrophages and the induced proinflammatory response differed between murine, porcine, and human macrophages, suggesting a host-specific immune response. In fact, similar levels of the proinflammatory cytokine macrophage inflammatory protein 2 (MIP-2) were secreted by murine bone marrow-derived macrophages with all tested isolates, but the equivalent interleukin-8 (IL-8) response of porcine bone marrow-derived macrophages was strongly serotype specific and considerably lower in O:3 than in O:8 strains. In addition, all tested Y. enterocolitica strains caused a considerably higher level of secretion of the anti-inflammatory cytokine IL-10 by porcine than by murine macrophages. This could contribute to limiting the severity of the infection (in particular of serotype O:3 strains) in pigs, which are the primary reservoir of Y. enterocolitica strains pathogenic to humans. PMID:23959720

  7. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity

    PubMed Central

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-01-01

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed ‘Adaptation’, which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed ‘Interference’. Adaptation can interact with interference (‘primed’), or is independent of it (‘naïve’). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration. PMID:26578567

  8. Natural History of Innate Host Defense Peptides.

    PubMed

    Linde, A; Wachter, B; Höner, O P; Dib, L; Ross, C; Tamayo, A R; Blecha, F; Melgarejo, T

    2009-12-01

    Host defense peptides act on the forefront of innate immunity, thus playing a central role in the survival of animals and plants. Despite vast morphological changes in species through evolutionary history, all animals examined to date share common features in their innate immune defense strategies, hereunder expression of host defense peptides (HDPs). Most studies on HDPs have focused on humans, domestic and laboratory animals. More than a thousand different sequences have been identified, yet data on HDPs in wild-living animals are sparse. The biological functions of HDPs include broad-spectrum antimicrobial activity and immunomodulation. Natural selection and coevolutionary host-pathogen arms race theory suggest that the extent and specificity of the microbial load influences the spectrum and potency of HDPs in different species. Individuals of extant species-that have lived for an extended period in evolutionary history amid populations with intact processes of natural selection-likely possess the most powerful and well-adapted "natural antibiotics". Research on the evolutionary history of the innate defense system and the host in context of the consequences of challenges as well as the efficacy of the innate immune system under natural conditions is therefore of immediate interest. This review focuses on evolutionary aspects of immunophysiology, with emphasis on innate effector molecules. Studies on host defense in wild-living animals may significantly enhance our understanding of inborn immune mechanisms, and help identify molecules that may assist us to cope better with the increasing microbial challenges that likely follow from the continuous amplification of biodiversity levels on Earth. PMID:26783164

  9. Mathematical Model of Innate and Adaptive Immunity of Sepsis: A Modeling and Simulation Study of Infectious Disease

    PubMed Central

    Shi, Zhenzhen; Wu, Chih-Hang J.; Ben-Arieh, David; Simpson, Steven Q.

    2015-01-01

    Sepsis is a systemic inflammatory response (SIR) to infection. In this work, a system dynamics mathematical model (SDMM) is examined to describe the basic components of SIR and sepsis progression. Both innate and adaptive immunities are included, and simulated results in silico have shown that adaptive immunity has significant impacts on the outcomes of sepsis progression. Further investigation has found that the intervention timing, intensity of anti-inflammatory cytokines, and initial pathogen load are highly predictive of outcomes of a sepsis episode. Sensitivity and stability analysis were carried out using bifurcation analysis to explore system stability with various initial and boundary conditions. The stability analysis suggested that the system could diverge at an unstable equilibrium after perturbations if rt2max (maximum release rate of Tumor Necrosis Factor- (TNF-) α by neutrophil) falls below a certain level. This finding conforms to clinical findings and existing literature regarding the lack of efficacy of anti-TNF antibody therapy. PMID:26446682

  10. Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model.

    PubMed

    Xu, Xiao-Gang; Hu, Jing-Fang; Ma, Jun-Xia; Nie, Li; Shao, Tong; Xiang, Li-Xin; Shao, Jian-Zhong

    2016-02-15

    TIM-1 and TIM-4 proteins have become increasingly attractive for their critical functions in immune modulation, particularly in CD4(+) Th2 cell activation. Thus, these proteins were hypothesized to regulate adaptive humoral immunity. However, further evidence is needed to validate this hypothesis. This study describes the molecular and functional characteristics of TIM-1 and TIM-4 homologs from a zebrafish (Danio rerio) model (D. rerio TIM [DrTIM]-1 and DrTIM-4). DrTIM-1 and DrTIM-4 were predominantly expressed in CD4(+) T cells and MHC class II(+) APCs under the induction of Ag stimulation. Blockade or knockdown of both DrTIM-1 and DrTIM-4 significantly decreased Ag-specific CD4(+) T cell activation, B cell proliferation, Ab production, and vaccinated immunoprotection against bacterial infection. This result suggests that DrTIM-1 and DrTIM-4 serve as costimulatory molecules required for the full activation of adaptive humoral immunity. DrTIM-1 was detected to be a trafficking protein located in the cytoplasm of CD4(+) T cells. It can translocate onto the cell surface under stimulation by TIM-4-expressing APCs, which might be a precise regulatory strategy for CD4(+) T cells to avoid self-activation before APCs stimulation. Furthermore, a unique alternatively spliced soluble DrTIM-4 variant was identified to exert a negative regulatory effect on the proliferation of CD4(+) T cells. The above findings highlight a novel costimulatory mechanism underlying adaptive immunity. This study enriches the current knowledge on TIM-mediated immunity and provides a cross-species understanding of the evolutionary history of costimulatory systems throughout vertebrate evolution.

  11. The role of alveolar epithelial cells in initiating and shaping pulmonary immune responses: communication between innate and adaptive immune systems.

    PubMed

    Chuquimia, Olga D; Petursdottir, Dagbjort H; Rahman, Muhammad J; Hartl, Katharina; Singh, Mahavir; Fernández, Carmen

    2012-01-01

    Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guérin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.

  12. Spray-dried plasma promotes growth, modulates the activity of antioxidant defenses, and enhances the immune status of gilthead sea bream (Sparus aurata) fingerlings.

    PubMed

    Gisbert, E; Skalli, A; Campbell, J; Solovyev, M M; Rodríguez, C; Dias, J; Polo, J

    2015-01-01

    Terrestrial animal byproduct meals, including nonruminant blood meal and blood products, represent the largest and largely untapped safe source of animal protein available within the international market for the aquafeed industry. Spray-dried blood and spray-dried plasma (SDP) proteins have long been recognized as high-quality feed ingredients for farmed animals. In this study, we evaluated the inclusion of SDP from porcine blood (SDPP) in growing diets for gilthead sea bream. Three isonitrogenous (CP = 51.2%) and isolipidic (fat = 12.4%) diets manufactured by cold extrusion (0.8 to 1.5 mm pellet size) were prepared by substituting high-quality fish meal with 0, 3, and 6% SDPP. The diets were tested for a period of 60 d at 22°C with 4 replicates each (400-L cylindroconical tanks, 150 fish per tank, and initial density = 0.5 kg/m(3)). The SDPP inclusion in diets for gilthead sea bream fingerlings were evaluated in terms of growth performance, feed utilization, histological organization of the intestinal mucosa, activity of oxidative stress enzymes (catalase, glutathione S-transferase, glutathione peroxidase, and glutathione reductase) in the intestine, and nonspecific serum immune parameters (lysozyme and bactericidal activity). Results from this study indicated that dietary SDPP promoted fish growth in terms of BW and length; fish fed 3% SDPP were 10.5% heavier (P < 0.05) than those fed the control diet. Spray-dried plasma from porcine blood modulated the activity of the antioxidative defenses in the intestine (P < 0.05) and increased the density of goblet cells in the intestine (P < 0.05) and benefited the host by providing an effective immune barrier against gut pathogenic microbiota. The nonspecific serum immune response in fish fed diets with SDPP was greater (P < 0.05) than in fish fed the control diet. These results indicated that the inclusion of SDPP in gilthead sea bream feed could be beneficial for the fish by enhancing intestinal and serum innate immune

  13. Spray-dried plasma promotes growth, modulates the activity of antioxidant defenses, and enhances the immune status of gilthead sea bream (Sparus aurata) fingerlings.

    PubMed

    Gisbert, E; Skalli, A; Campbell, J; Solovyev, M M; Rodríguez, C; Dias, J; Polo, J

    2015-01-01

    Terrestrial animal byproduct meals, including nonruminant blood meal and blood products, represent the largest and largely untapped safe source of animal protein available within the international market for the aquafeed industry. Spray-dried blood and spray-dried plasma (SDP) proteins have long been recognized as high-quality feed ingredients for farmed animals. In this study, we evaluated the inclusion of SDP from porcine blood (SDPP) in growing diets for gilthead sea bream. Three isonitrogenous (CP = 51.2%) and isolipidic (fat = 12.4%) diets manufactured by cold extrusion (0.8 to 1.5 mm pellet size) were prepared by substituting high-quality fish meal with 0, 3, and 6% SDPP. The diets were tested for a period of 60 d at 22°C with 4 replicates each (400-L cylindroconical tanks, 150 fish per tank, and initial density = 0.5 kg/m(3)). The SDPP inclusion in diets for gilthead sea bream fingerlings were evaluated in terms of growth performance, feed utilization, histological organization of the intestinal mucosa, activity of oxidative stress enzymes (catalase, glutathione S-transferase, glutathione peroxidase, and glutathione reductase) in the intestine, and nonspecific serum immune parameters (lysozyme and bactericidal activity). Results from this study indicated that dietary SDPP promoted fish growth in terms of BW and length; fish fed 3% SDPP were 10.5% heavier (P < 0.05) than those fed the control diet. Spray-dried plasma from porcine blood modulated the activity of the antioxidative defenses in the intestine (P < 0.05) and increased the density of goblet cells in the intestine (P < 0.05) and benefited the host by providing an effective immune barrier against gut pathogenic microbiota. The nonspecific serum immune response in fish fed diets with SDPP was greater (P < 0.05) than in fish fed the control diet. These results indicated that the inclusion of SDPP in gilthead sea bream feed could be beneficial for the fish by enhancing intestinal and serum innate immune

  14. Identification and characterization of a ferritin gene involved in the immune defense response of scallop Chlamys farreri.

    PubMed

    Chen, Guofu; Zhang, Chunyun; Wang, Yuanyuan; Guo, Changlu; Sang, Fuming; Wang, Chongming

    2016-08-01

    Scallop Chlamys farreri is an important aquaculture species in northern China. However, its mass mortality caused by several pathogens can result in great economic loss and negative impacts to the sustainable development of the scallop industry. Thus, improving the overall understanding of immune response mechanisms involved in host-pathogen interactions is necessary. Ferritins are conserved molecules in organisms that are involved in diverse biological processes, such as mediating host-pathogen responses. In this study, we report a novel ferritin gene from C. farreri (denoted as CfFER). The full length of CfFER is 848 bp and contains a 5'-UTR of 113 bp, a 3'-UTR of 219 bp, and a complete open reading frame (ORF) of 516 bp. The ORF encodes a polypeptide of 171 amino acid residues with a molecular weight of approximately 19.95 kDa and an isoelectric point of 5.07. The CfFER protein exhibited typical ferritin structures, namely, a ferroxidase diiron center, a ferrihydrite nucleation center, and an iron-binding response signature. Phylogenetic analysis revealed that CfFER was closely related to other mollusk ferritin proteins. Expression of CfFER in different tissues was analyzed by quantitative real-time PCR, and results showed that CfFER was ubiquitously expressed in all examined tissues. The highest and lowest expression levels of CfFER were measured in the muscle and hemocyte, respectively. The relative mRNA expression of CfFER in response to bacterial (Vibrio anguillarum) and viral (acute viral necrobiotic virus) challenges sharply increased by ca. 5-fold about12 h post-infection (hpi) and then normalized at 48 hpi. Western blot analysis with polyclonal antibodies generated from the recombinant product of CfFER also demonstrated the presence of ferritin protein in hemocytes. These findings strongly suggest that CfFER is involved in the immune response of C. farreri and protection against pathogen challenge. PMID:27134078

  15. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

    PubMed Central

    Binder, Christoph J.; Hartvigsen, Karsten; Chang, Mi-Kyung; Miller, Marina; Broide, David; Palinski, Wulf; Curtiss, Linda K.; Corr, Maripat; Witztum, Joseph L.

    2004-01-01

    During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs). These epitopes are recognized by both adaptive T cell–dependent (TD) and innate T cell–independent type 2 (TI-2) immune responses. We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection. In addition, a PC-based immunization strategy that leads to a TI-2 expansion of innate B-1 cells and secretion of T15/EO6 clonotype natural IgM antibodies, which bind the PC of OxPLs within oxidized LDL (OxLDL), also reduces atherogenesis. T15/EO6 antibodies inhibit OxLDL uptake by macrophages. We now report that immunization with MDA-LDL, which does not contain OxPL, unexpectedly led to the expansion of T15/EO6 antibodies. MDA-LDL immunization caused a preferential expansion of MDA-LDL–specific Th2 cells that prominently secreted IL-5. In turn, IL-5 provided noncognate stimulation to innate B-1 cells, leading to increased secretion of T15/EO6 IgM. Using a bone marrow transplant model, we also demonstrated that IL-5 deficiency led to decreased titers of T15/EO6 and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specific to epitopes of OxLDL and protects from atherosclerosis, in part by stimulating the expansion of atheroprotective natural IgM specific for OxLDL. PMID:15286809

  16. Lipoxin A₄ modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism.

    PubMed

    Ramon, Sesquile; Bancos, Simona; Serhan, Charles N; Phipps, Richard P

    2014-02-01

    Specialized proresolving mediators are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. Lipoxins and other specialized proresolving mediators have been identified in important immunological tissues including bone marrow, spleen, and blood. Lipoxins regulate functions of the innate immune system including the promotion of monocyte recruitment and increase macrophage phagocytosis of apoptotic neutrophils. A major knowledge gap is whether lipoxins influence adaptive immune cells. Here, we analyzed the actions of lipoxin A₄ (LXA₄) and its receptor ALX/FPR2 on human and mouse B cells. LXA₄ decreased IgM and IgG production on activated human B cells through ALX/FPR2-dependent signaling, which downregulated NF-κB p65 nuclear translocation. LXA₄ also inhibited human memory B-cell antibody production and proliferation, but not naïve B-cell function. Lastly, LXA₄ decreased antigen-specific antibody production in an OVA immunization mouse model. To our knowledge, this is the first description of the actions of lipoxins on human B cells, demonstrating a link between resolution signals and adaptive immunity. Regulating antibody production is crucial to prevent unwanted inflammation. Harnessing the ability of lipoxins to decrease memory B-cell antibody production can be beneficial to threat inflammatory and autoimmune disorders.

  17. Elevated mitochondrial superoxide disrupts normal T-cell development to impair adaptive immune responses to an influenza challenge

    PubMed Central

    Case, Adam J.; McGill, Jodi L.; Tygrett, Lorraine T.; Shirasawa, Takuji; Spitz, Douglas R.; Waldschmidt, Thomas J.; Legge, Kevin L.; Domann, Frederick E.

    2010-01-01

    Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. The current work provides the first clear demonstration that thymus specific elevation of mitochondrial superoxide (O2·−) disrupts normal T-cell development to impair function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell specific knockout of manganese superoxide dismutase (i.e. SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T-cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T-cell population resulting in immunodeficiency and susceptibility to influenza A virus (IAV), H1N1. This phenotype was rescued with mitochondrially targeted superoxide scavenging drugs. These new findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T-cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection. PMID:21130157

  18. Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection.

    PubMed

    Filbey, Kara J; Grainger, John R; Smith, Katherine A; Boon, Louis; van Rooijen, Nico; Harcus, Yvonne; Jenkins, Stephen; Hewitson, James P; Maizels, Rick M

    2014-01-01

    The nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2-3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations. In addition, the titer and specificity range of the serum antibody response is maximal in resistant mice. In susceptible strains, Th2 responses were found to be counterbalanced by IFN-γ-producing CD4(+) and CD8(+) cells, but these are not solely responsible for susceptibility as mice deficient in either CD8(+) T cells or IFN-γ remain unable to expel the parasites. Foxp3(+) Treg numbers were comparable in all strains, but in the most resistant SJL strain, this population does not upregulate CD103 in infection, and in the lamina propria the frequency of Foxp3(+)CD103(+) T cells is significantly lower than in susceptible mice. The more resistant SJL and BALB/c mice develop macrophage-rich IL-4Rα-dependent Type 2 granulomas around intestinal sites of larval invasion, and expression of alternative activation markers Arginase-1, Ch3L3 (Ym1) and RELM-α within the intestine and the peritoneal lavage was also strongly correlated with helminth elimination in these strains. Clodronate depletion of phagocytic cells compromises resistance of BALB/c mice and slows expulsion in the SJL strain. Thus, Type 2 immunity involves IL-4Rα-dependent innate cells including but not limited to a phagocyte population, the latter likely involving the action of specific antibodies.

  19. The role of leukocytes from L-PRP/L-PRF in wound healing and immune defense: new perspectives.

    PubMed

    Bielecki, Tomasz; Dohan Ehrenfest, David M; Everts, Peter A; Wiczkowski, Andrzej

    2012-06-01

    Platelet concentrates for topical use are innovative tools of regenerative medicine and their effects in various therapeutical situations are hotly debated. Unfortunately, this field of research mainly focused on the platelet growth factors, and the fibrin architecture and the leukocyte content of these products are too often neglected. In the four families of platelet concentrates, 2 families contain significant concentrations of leukocytes: L-PRP (Leukocyte- and Platelet-Rich Plasma) and L-PRF (Leukocyte- and Platelet-Rich Fibrin). The presence of leukocytes has a great impact on the biology of these products, not only because of their immune and antibacterial properties, but also because they are turntables of the wound healing process and the local factor regulation. In this article, the various kinds of leukocytes present in a platelet concentrate are described (particularly the various populations of granulocytes and lymphocytes), and we insist on the large diversity of factors and pathways that these cells can use to defend the wound site against infections and to regulate the healing process. Finally, the impact of these cells in the healing properties of the L-PRP and L-PRF is also discussed: if antimicrobial properties were already pointed out, effects in the regulation of cell proliferation and differentiation were also hypothesized. Leukocytes are key actors of many platelet concentrates, and a better understanding of their effects is an important issue for the development of these technologies.

  20. Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action.

    PubMed

    Rosenfeld, Yosef; Papo, Niv; Shai, Yechiel

    2006-01-20

    Binding of lipopolysaccharide (LPS) to macrophages results in proinflammatory cytokine secretion. In extreme cases it leads to endotoxic shock. A few innate immunity antimicrobial peptides (AMPs) neutralize LPS activity. However, the underlying mechanism and properties of the peptides are not yet clear. Toward meeting this goal we investigated four AMPs and their fluorescently labeled analogs. These AMPs varied in composition, length, structure, and selectivity toward cells. The list included human LL-37 (37-mer), magainin (24-mer), a 15-mer amphipathic alpha-helix, and its D,L-amino acid structurally altered analog. The peptides were investigated for their ability to inhibit LPS-mediated cytokine release from RAW264.7 and bone marrow-derived primary macrophages, to bind LPS in solution, and when LPS is already bound to macrophages (fluorescence spectroscopy and confocal microscopy), to compete with LPS for its binding site on the CD14 receptor (flow cytometry) and affect LPS oligomerization. We conclude that a strong binding of a peptide to LPS aggregates accompanied by aggregate dissociation prevents LPS from binding to the carrier protein lipopolysaccharide-binding protein, or alternatively to its receptor, and hence inhibits cytokine secretion.

  1. CsTNF1, a teleost tumor necrosis factor that promotes antibacterial and antiviral immune defense in a manner that depends on the conserved receptor binding site.

    PubMed

    Li, Mo-fei; Zhang, Jian

    2016-02-01

    Tumor necrosis factor (TNF) is one of the most important cytokines involved in inflammation, apoptosis, cell proliferation, and stimulation of the immune system. The TNF gene has been cloned in teleost fish; however, the in vivo function of fish TNF is essentially unknown. In this study, we report the identification of a TNF homologue, CsTNF1, from tongue sole (Cynoglossus semilaevis) and analysis of its expression and biological effect. CsTNF1 is composed of 242 amino acid residues and possesses a TNF domain and conserved receptor binding sites. Expression of CsTNF1 was detected in a wide range of tissues and up-regulated in a time-dependent manner by experimental challenge with bacterial and viral pathogens. Bacterial infection of peripheral blood leukocytes (PBL) caused extracellular secretion of CsTNF1. Purified recombinant CsTNF1 (rCsTNF1) was able to bind to PBL and stimulate the respiratory burst activity of PBL. In contrast, rCsTNF1M1 and rCsTNF1M2, the mutant CsTNF1 bearing substitutions at the receptor binding site, failed to activate PBL. Fish administered with rCsTNF1, but not with rCsTNF1M1 and rCsTNF1M2, exhibited enhanced expression of IL-1, IL-6, IL-8, IL-27, TLR9 and G3BP in a time-dependent manner and augmented resistance against bacterial and viral infection. These results provide the first evidence that the receptor binding sites are essential to a fish TNF, and that CsTNF1 is involved in the innate immune defense of fish against microbial pathogens. PMID:26478190

  2. Lack of acetylcholine nicotine alpha 7 receptor suppresses development of collagen-induced arthritis and adaptive immunity.

    PubMed

    Westman, M; Saha, S; Morshed, M; Lampa, J

    2010-10-01

    Activation of the alpha7 receptor (α7nAChR) has been shown to be important in inflammation and immune regulation, and is also essential in the neural cholinergic anti-inflammatory pathway. The aim of this study was to investigate the role of α7nAChR in the development of experimental arthritis and immune activation. Mice lacking the α7nAChR were immunized with collagen II and the development of arthritis was assessed. Another group of α7nAChR-deficient mice was immunized with ovalbumin, spleen and lymph node cells were isolated and the proliferative responses to restimulation with ovalbumin or concanavalin A were investigated. We could demonstrate significantly milder arthritis and less cartilage destruction, together with a decrease of T cell content in lymph nodes in mice lacking the α7nAChR compared to wild-type controls. In addition, mice lacking the α7nAChR had a deficient proliferative response to concanavalin A, whereas antigen presentation-dependent proliferation was not affected. These results indicate important roles for α7nAChR in arthritis development as well as in regulation of T cell-dependent immunological mechanisms. In addition, the data implicate α7nAChR as a therapeutic target for modulation of adaptive immune responses.

  3. Evolutionary implications of the adaptation to different immune systems in a parasite with a complex life cycle.

    PubMed

    Hammerschmidt, Katrin; Kurtz, Joachim

    2005-12-01

    Many diseases are caused by parasites with complex life cycles that involve several hosts. If parasites cope better with only one of the different types of immune systems of their host species, we might expect a trade-off in parasite performance in the different hosts, that likely influences the evolution of virulence. We tested this hypothesis in a naturally co-evolving host-parasite system consisting of the tapeworm Schistocephalus solidus and its intermediate hosts, a copepod, Macrocyclops albidus, and the three-spined stickleback Gasterosteus aculeatus. We did not find a trade-off between infection success in the two hosts. Rather, tapeworms seem to trade-off adaptation towards different parts of their hosts' immune systems. Worm sibships that performed better in the invertebrate host also seem to be able to evade detection by the fish innate defence systems, i.e. induce lower levels of activation of innate immune components. These worm variants were less harmful for the fish host likely due to reduced costs of an activated innate immune system. These findings substantiate the impact of both hosts' immune systems on parasite performance and virulence.

  4. The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.

    PubMed

    Anz, D; Kruger, S; Haubner, S; Rapp, M; Bourquin, C; Endres, S

    2014-06-01

    Inhibitors of dipeptidylpeptidase IV (DPP-IV) represent a novel class of frequently used anti-diabetic drugs. In addition to its function in metabolic regulation, DPP-IV also plays a role in the immune system. Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. Here, we investigated the effect of these agents on both innate and adaptive immunity. We found that the DPP-IV inhibitors did not affect the innate immune response induced by Toll-like receptor (TLR) ligands, as cytokine secretion and induction of co-stimulatory molecules by human blood mononuclear cells was not impaired. Furthermore, proliferation of T cells and suppressive function of regulatory T cells was preserved. Mice treated with vildagliptin showed normal cytokine production, immune cell activation and lymphocyte trafficking upon TLR activation. Thus, crucial immunological parameters remain unaffected upon treatment with DPP-IV inhibitors, a fact that is reassuring with respect to safety of these drugs. PMID:24320733

  5. Adaptive immune response inhibits ectopic mature bone formation induced by BMSCs/BCP/plasma composite in immune-competent mice.

    PubMed

    Bouvet-Gerbettaz, Sébastien; Boukhechba, Florian; Balaguer, Thierry; Schmid-Antomarchi, Heidy; Michiels, Jean-François; Scimeca, Jean-Claude; Rochet, Nathalie

    2014-11-01

    A combination of autologous bone marrow stromal cells (BMSCs) and biomaterials is a strategy largely developed in bone tissue engineering, and subcutaneous implantation in rodents or large animals is often a first step to evaluate the potential of new biomaterials. This study aimed at investigating the influence of the immune status of the recipient animal on BMSCs-induced bone formation. BMSCs prepared from C57BL/6 mice, composed of a mixture of mesenchymal stromal and monocytic cells, were combined with a biomaterial that consisted of biphasic calcium phosphate (BCP) particles and plasma clot. This composite was implanted subcutaneously either in syngenic C57BL/6 immune-competent mice or in T-lymphocyte-deficient Nude (Nude) mice. Using histology, immunohistochemistry, and histomorphometry, we show here that this BMSC/BCP/plasma clot composite implanted in Nude mice induces the formation of mature lamellar bone associated to hematopoietic areas and numerous vessels. Comparatively, implantation in C57BL/6 results in the formation of woven bone without hematopoietic tissue, a lower number of new vessels, and numerous multinucleated giant cells (MNGCs). In situ hybridization, which enabled to follow the fate of the BMSCs, revealed that BMSCs implanted in Nude mice survived longer than BMSCs implanted in C57BL/6 mice. Quantitative expression analysis of 280 genes in the implants indicated that the differences between C57BL/6 and Nude implants corresponded almost exclusively to genes related to the immune response. Gene expression profile in C57BL/6 implants was consistent with a mild chronic inflammation reaction characterized by Th1, Th2, and cytotoxic T-lymphocyte activation. In the implants retrieved from T-deficient Nude mice, Mmp14, Il6st, and Tgfbr3 genes were over-expressed, suggesting their putative role in bone regeneration and hematopoiesis. In conclusion, we show here that the T-mediated inflammatory microenvironment is detrimental to BMSCs-induced bone

  6. Immune Defenses of the Invasive Apple Snail Pomacea canaliculata (Caenogastropoda, Ampullariidae): Phagocytic Hemocytes in the Circulation and the Kidney

    PubMed Central

    Vega, Israel A.; Castro-Vazquez, Alfredo

    2015-01-01

    participate in the storage and circulation of this compound. Injection of microorganisms in the foot results in phagocytosis by hemocytes in the islets, and the different phagosomes formed are similar to those in circulating hyalinocytes. Dispersed hemocytes were obtained after kidney collagenase digestion and cell sorting, and they were able to phagocytize fluorescent beads. A role for the kidney as an immune barrier is proposed for this snail. PMID:25893243

  7. Immune Defenses of the Invasive Apple Snail Pomacea canaliculata (Caenogastropoda, Ampullariidae): Phagocytic Hemocytes in the Circulation and the Kidney.

    PubMed

    Cueto, Juan A; Rodriguez, Cristian; Vega, Israel A; Castro-Vazquez, Alfredo

    2015-01-01

    participate in the storage and circulation of this compound. Injection of microorganisms in the foot results in phagocytosis by hemocytes in the islets, and the different phagosomes formed are similar to those in circulating hyalinocytes. Dispersed hemocytes were obtained after kidney collagenase digestion and cell sorting, and they were able to phagocytize fluorescent beads. A role for the kidney as an immune barrier is proposed for this snail.

  8. Oral tungstate (Na2WO4) exposure reduces adaptive immune responses in mice after challenge.

    PubMed

    Osterburg, Andrew R; Robinson, Chad T; Mokashi, Vishwesh; Stockelman, Michael; Schwemberger, Sandy J; Chapman, Gail; Babcock, George F

    2014-01-01

    Tungstate (WO²⁻₄) has been identified as a ground water contaminant at military firing ranges and can be absorbed by ingestion. In this study, C57BL6 mice were exposed to sodium tungstate (Na2WO4·2H2O) (0, 2, 62.5, 125, and 200 mg/kg/day) in their drinking water for an initial 28-day screen and in a one-generation (one-gen) model. Twenty-four hours prior to euthanasia, mice were intraperitoneally injected with Staphylococcal enterotoxin B (SEB) (20 μg/mouse) or saline as controls. After euthanasia, splenocytes and blood were collected and stained with lymphocyte and/or myeloid immunophenotyping panels and analyzed by flow cytometry. In the 28-day and one-gen exposure, statistically significant reductions were observed in the quantities of activated cytotoxic T-cells (TCTL; CD3(+)CD8(+)CD71(+)) and helper T-cells (TH; CD3(+)CD4(+)CD71(+)) from spleens of SEB-treated mice. In the 28-day exposures, CD71(+) TCTL cells were 12.87 ± 2.05% (SE) in the 0 tungstate (control) group compared to 4.44 ± 1.42% in the 200 mg/kg/day (p < 0.001) group. TH cells were 4.85 ± 1.23% in controls and 2.76 ± 0.51% in the 200 mg/kg/day (p < 0.003) group. In the one-gen exposures, TCTL cells were 7.98 ± 0.49% and 6.33 ± 0.49% for P and F1 mice after 0 mg/kg/day tungstate vs 1.58 ± 0.23% and 2.52 ± 0.25% after 200 mg/kg/day of tungstate (p < 0.001). Similarly, TH cells were reduced to 6.21 ± 0.39% and 7.20 ± 0.76%, respectively, for the 0 mg/kg/day P and F1 mice, and 2.28 ± 0.41% and 2.85 ± 0.53%, respectively, for the 200 mg/kg/day tungstate P and F1 groups (p < 0.001). In delayed-type hypersensitivity Type IV experiments, tungstate exposure prior to primary and secondary antigen challenge significantly reduced footpad swelling at 20 and 200 mg/kg/day. These data indicate that exposure to tungstate can result in immune suppression that may, in turn, reduce host defense against

  9. The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?

    PubMed

    Doty, Kevin R; Guillot-Sestier, Marie-Victoire; Town, Terrence

    2015-08-18

    Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

  10. Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection

    PubMed Central

    2010-01-01

    Introduction Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. Methods The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. Results Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. Conclusions Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics. PMID:20504311

  11. Two homologues of inhibitor of NF-kappa B (IκB) are involved in the immune defense of the Pacific oyster, Crassostrea gigas.

    PubMed

    Zhang, Yang; He, Xiaocui; Yu, Ziniu

    2011-06-01

    A novel homologue of IκB was cloned from a hemocyte cDNA of Crassostrea gigas (designed as CgIκB2). The complete cDNA of CgIκB2 includes an open reading frame (ORF) of 1032 bp, and 3' and 5'untranslated regions (UTR's) of 141 bp and 279 bp, respectively. The ORF encodes a putative protein of 343 amino acids with a calculated molecular weight of approximately 37.8 kDa. Alignment analysis reveals that CgIκB2 contains a conserved degradation motif and six ankyrin repeats. A phylogenetic analysis suggests that a gene duplication event prior to the gastropod-bivalve divergence resulted in the emergence of two IκB homologues in C. gigas. Distinct maximal expression patterns of CgIκB1 in hemocytes and CgIκB2 in the gonad were observed. CgIκB1 and CgIκB2 expression in response to bacterial challenge is similar and inducible. Moreover, both CgIκB1 and CgIκB2 are able to inhibit NF-κb/Rel activating transcription in S2 or HEK293 cells. Our findings demonstrate that both CgIκB1 and CgIκB2 are involved in immune defense in C. gigas through regulation of NF-κB/Rel activity.

  12. Innate and adaptive immunity against Porcine Reproductive and Respiratory Syndrome Virus.

    PubMed

    Loving, Crystal L; Osorio, Fernando A; Murtaugh, Michael P; Zuckermann, Federico A

    2015-09-15

    Many highly effective vaccines have been produced against viruses whose virulent infection elicits strong and durable protective immunity. In these cases, characterization of immune effector mechanisms and identification of protective epitopes/immunogens has been informative for the development of successful vaccine programs. Diseases in which the immune system does not rapidly clear the acute infection and/or convalescent immunity does not provide highly effective protection against secondary challenge pose a major hurdle for clinicians and scientists. Porcine reproductive and respiratory syndrome virus (PRRSV) falls primarily into this category, though not entirely. PRRSV causes a prolonged infection, though the host eventually clears the virus. Neutralizing antibodies can provide passive protection when present prior to challenge, though infection can be controlled in the absence of detectable neutralizing antibodies. In addition, primed pigs (through natural exposure or vaccination with a modified-live vaccine) show some protection against secondary challenge. While peripheral PRRSV-specific T cell responses have been examined, their direct contribution to antibody-mediated immunity and viral clearance have not been fully elucidated. The innate immune response following PRRSV infection, particularly the antiviral type I interferon response, is meager, but when provided exogenously, IFN-α enhances PRRSV immunity and viral control. Overall, the quality of immunity induced by natural PRRSV infection is not ideal for informing vaccine development programs. The epitopes necessary for protection may be identified through natural exposure or modified-live vaccines and subsequently applied to vaccine delivery platforms to accelerate induction of protective immunity following vaccination. Collectively, further work to identify protective B and T cell epitopes and mechanisms by which PRRSV eludes innate immunity will enhance our ability to develop more effective methods

  13. Food-Nonfood Discrimination in Ancestral Vertebrates: Gamete Cannibalism and the Origin of the Adaptive Immune System.

    PubMed

    Corcos, D

    2015-11-01

    Adaptive immunity is a complex system that appeared twice in vertebrates (in gnathostomes and in jawless fish) although it is not required for invertebrate defence. The adaptive immune system is tightly associated with self-non-self discrimination, and it is now clear that this interplay is not limited to the prevention of autoreactivity. Micro-organisms are usually considered for their pathogenicity or symbiotic ability, but, for most small metazoans, they mainly constitute food. Vertebrates are characterized by feeding by predation on larger preys, when compared to their ancestors who were filter feeders and ate micro-organisms. Predation gives a strong selective advantage, not only due to the availability of new food resources but also by the ability to eliminate competitors for environmental resources (intraguild predation (IGP)). Unlike size-structured IGP, intraspecific predation of juveniles, zygotes or gametes can be detrimental for species fitness in some circumstances. The ability of individuals to recognize highly polymorphic molecules on the surface of gametes present in the plankton and so distinguish self versus non-self gametes might have constituted a strong selective advantage in intraspecific competition. Here, I propose the theory that the capacity to rearrange receptors has been selected in ancestral vertebrates as a consequence of this strong need for discriminating between hetero-cannibalism versus filial cannibalism. This evolutionary origin sheds light on presently unexplained features of the immune system, including the existence of regulatory T cells and of non-pathogenic natural autoimmunity. PMID:26286030

  14. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines

    PubMed Central

    Laws, Thomas R.; Kuchuloria, Tinatin; Chitadze, Nazibriola; Little, Stephen F.; Webster, Wendy M.; Debes, Amanda K.; Saginadze, Salome; Tsertsvadze, Nikoloz; Chubinidze, Mariam; Rivard, Robert G.; Tsanava, Shota; Dyson, Edward H.; Simpson, Andrew J. H.; Hepburn, Matthew J.; Trapaidze, Nino

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens. PMID:27007118

  15. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines.

    PubMed

    Laws, Thomas R; Kuchuloria, Tinatin; Chitadze, Nazibriola; Little, Stephen F; Webster, Wendy M; Debes, Amanda K; Saginadze, Salome; Tsertsvadze, Nikoloz; Chubinidze, Mariam; Rivard, Robert G; Tsanava, Shota; Dyson, Edward H; Simpson, Andrew J H; Hepburn, Matthew J; Trapaidze, Nino

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens. PMID:27007118

  16. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines.

    PubMed

    Laws, Thomas R; Kuchuloria, Tinatin; Chitadze, Nazibriola; Little, Stephen F; Webster, Wendy M; Debes, Amanda K; Saginadze, Salome; Tsertsvadze, Nikoloz; Chubinidze, Mariam; Rivard, Robert G; Tsanava, Shota; Dyson, Edward H; Simpson, Andrew J H; Hepburn, Matthew J; Trapaidze, Nino

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens.

  17. Control of antiviral immunity by pattern recognition and the microbiome

    PubMed Central

    Pang, Iris K.; Iwasaki, Akiko

    2013-01-01

    Summary Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential link between viruses, microbiota and the host immune system. Further, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease, and speculate on the benefit for probiotic therapies against such diseases. PMID:22168422

  18. Potent adaptive immune responses induced against HIV-1 gp140 and influenza virus HA by a polyanionic carbomer.

    PubMed

    Krashias, George; Simon, Anna-Katharina; Wegmann, Frank; Kok, Wai-Ling; Ho, Ling-Pei; Stevens, David; Skehel, John; Heeney, Jonathan L; Moghaddam, Amin E; Sattentau, Quentin J

    2010-03-16

    Carbopol is a polyanionic carbomer gel used in man for a variety of topical applications and drug delivery purposes. Here we show that subcutaneous administration of carbopol with glycoprotein antigens elicits unusually strong specific adaptive immune responses in mice. Recombinant soluble HIV-1 envelope glycoprotein (Env)-based antigen formulated in carbopol was at least as potent at stimulating Env-specific B and T cell responses as Freund's Complete Adjuvant, and significantly more potent than aluminium salts. The antigen-specific T cell immune response elicited both Th1 and Th2 cytokines including high titers of IFN-gamma, IL-2 and IL-4, and drove a Th1 isotype-switched antibody response. Mice immunized with a low dose of purified influenza HA in carbopol generated high titers of anti-HA antibodies and were protected from lethal challenge and disease with live virus. Similarly, immunization of mice with the melanoma cell line B16F10 formulated in carbopol significantly delayed tumor growth. We propose that carbopol, or related cross-linked polyacrylic acid analogues, may have promise for use as systemic vaccine adjuvants in man. PMID:20132920

  19. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice.

    PubMed

    Lin, Lin; Ibrahim, Ashraf S; Xu, Xin; Farber, Joshua M; Avanesian, Valentina; Baquir, Beverlie; Fu, Yue; French, Samuel W; Edwards, John E; Spellberg, Brad

    2009-12-01

    We sought to define protective mechanisms of immunity to Staphylococcus aureus and Candida albicans bloodstream infections in mice immunized with the recombinant N-terminus of Als3p (rAls3p-N) vaccine plus aluminum hydroxide (Al(OH(3)) adjuvant, or adjuvant controls. Deficiency of IFN-gamma but not IL-17A enhanced susceptibility of control mice to both infections. However, vaccine-induced protective immunity against both infections required CD4+ T-cell-derived IFN-gamma and IL-17A, and functional phagocytic effectors. Vaccination primed Th1, Th17, and Th1/17 lymphocytes, which produced pro-inflammatory cytokines that enhanced phagocytic killing of both organisms. Vaccinated, infected mice had increased IFN-gamma, IL-17, and KC, increased neutrophil influx, and decreased organism burden in tissues. In summary, rAls3p-N vaccination induced a Th1/Th17 response, resulting in recruitment and activation of phagocytes at sites of infection, and more effective clearance of S. aureus and C. albicans from tissues. Thus, vaccine-mediated adaptive immunity can protect against both infections by targeting microbes for destruction by innate effectors.

  20. Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.

    PubMed

    Gaudieri, Silvana; Rauch, Andri; Park, Lawrence P; Freitas, Elizabeth; Herrmann, Susan; Jeffrey, Gary; Cheng, Wendy; Pfafferott, Katja; Naidoo, Kiloshni; Chapman, Russell; Battegay, Manuel; Weber, Rainer; Telenti, Amalio; Furrer, Hansjakob; James, Ian; Lucas, Michaela; Mallal, Simon A

    2006-11-01

    Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level. PMID:17071929

  1. Artificial Immune System Approaches for Aerospace Applications

    NASA Technical Reports Server (NTRS)

    KrishnaKumar, Kalmanje; Koga, Dennis (Technical Monitor)

    2002-01-01

    Artificial Immune Systems (AIS) combine a priori knowledge with the adapting capabilities of biological immune system to provide a powerful alternative to currently available techniques for pattern recognition, modeling, design, and control. Immunology is the science of built-in defense mechanisms that are present in all living beings to protect against external attacks. A biological immune system can be thought of as a robust, adaptive system that is capable of dealing with an enormous variety of disturbances and uncertainties. Biological immune systems use a finite number of discrete "building blocks" to achieve this adaptiveness. These building blocks can be thought of as pieces of a puzzle which must be put together in a specific way-to neutralize, remove, or destroy each unique disturbance the system encounters. In this paper, we outline AIS models that are immediately applicable to aerospace problems and identify application areas that need further investigation.

  2. Macrophage defense mechanisms against intracellular bacteria

    PubMed Central

    Weiss, Günter; Schaible, Ulrich E

    2015-01-01

    Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics. PMID:25703560

  3. Macrophage defense mechanisms against intracellular bacteria.

    PubMed

    Weiss, Günter; Schaible, Ulrich E

    2015-03-01

    Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics. PMID:25703560

  4. Selection for brain size impairs innate, but not adaptive immune responses

    PubMed Central

    Kotrschal, Alexander; Kolm, Niclas; Penn, Dustin J.

    2016-01-01

    Both the brain and the immune system are energetically demanding organs, and when natural selection favours increased investment into one, then the size or performance of the other should be reduced. While comparative analyses have attempted to test this potential evolutionary trade-off, the results remain inconclusive. To test this hypothesis, we compared the tissue graft rejection (an assay for measuring innate and acquired immune responses) in guppies (Poecilia reticulata) artificially selected for large and small relative brain size. Individual scales were transplanted between pairs of fish, creating reciprocal allografts, and the rejection reaction was scored over 8 days (before acquired immunity develops). Acquired immune responses were tested two weeks later, when the same pairs of fish received a second set of allografts and were scored again. Compared with large-brained animals, small-brained animals of both sexes mounted a significantly stronger rejection response to the first allograft. The rejection response to the second set of allografts did not differ between large- and small-brained fish. Our results show that selection for large brain size reduced innate immune responses to an allograft, which supports the hypothesis that there is a selective trade-off between investing into brain size and innate immunity. PMID:26962144

  5. Artificial immune system based on adaptive clonal selection for feature selection and parameters optimisation of support vector machines

    NASA Astrophysics Data System (ADS)

    Sadat Hashemipour, Maryam; Soleimani, Seyed Ali

    2016-01-01

    Artificial immune system (AIS) algorithm based on clonal selection method can be defined as a soft computing method inspired by theoretical immune system in order to solve science and engineering problems. Support vector machine (SVM) is a popular pattern classification method with many diverse applications. Kernel parameter setting in the SVM training procedure along with the feature selection significantly impacts on the classification accuracy rate. In this study, AIS based on Adaptive Clonal Selection (AISACS) algorithm has been used to optimise the SVM parameters and feature subset selection without degrading the SVM classification accuracy. Several public datasets of University of California Irvine machine learning (UCI) repository are employed to calculate the classification accuracy rate in order to evaluate the AISACS approach then it was compared with grid search algorithm and Genetic Algorithm (GA) approach. The experimental results show that the feature reduction rate and running time of the AISACS approach are better than the GA approach.

  6. Evolution of the CRISPR-Cas adaptive immunity systems in prokaryotes: models and observations on virus-host coevolution.

    PubMed

    Koonin, Eugene V; Wolf, Yuri I

    2015-01-01

    CRISPR-Cas is an adaptive immunity system in prokaryotes that functions via a unique mechanism which involves incorporation of foreign DNA fragments into CRISPR arrays and subsequent utilization of transcripts of these inserts (known as spacers) as guide RNAs to cleave the cognate selfish element genome. Multiple attempts have been undertaken to explore the coevolution of viruses and microbial hosts carrying CRISPR-Cas using mathematical models that employ either systems of differential equations or an agent-based approach, or combinations thereof. Analysis of these models reveals highly complex co-evolutionary dynamics that ensues from the combination of the heritability of the CRISPR-mediated adaptive immunity with the existence of different degrees of immunity depending on the number of cognate spacers and the cost of carrying a CRISPR-Cas locus. Depending on the details of the models, a variety of testable, sometimes conflicting predictions have been made on the dependence of the degree of immunity and the benefit of maintaining CRISPR-Cas on the abundance and diversity of hosts and viruses. Some of these predictions have already been directly validated experimentally. In particular, both the reality of the virus-host arms race, with viruses escaping resistance and hosts reacquiring it through the capture of new spacers, and the fitness cost of CRISPR-Cas due to the curtailment of beneficial HGT have been reproduced in the laboratory. However, to test the predictions of the models more specifically, detailed studies of coevolving populations of microbes and viruses both in nature and in the laboratory are essential. Such analyses are expected to yield disagreements with the predictions of the current, oversimplified models and to trigger a new round of theoretical developments.

  7. The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections

    PubMed Central

    Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R.; Huppler, Anna R.; Conti, Heather R.; Ghilardi, Nico; Mamo, Anna J.

    2014-01-01

    Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate “type 17” cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9−/− mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9−/− mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses. PMID:24379290

  8. Evaluation of specific humoral immune response in pigs vaccinated with cell culture adapted classical swine fever vaccine

    PubMed Central

    Nath, Mrinal K.; Sarma, D. K.; Das, B. C.; Deka, P.; Kalita, D.; Dutta, J. B.; Mahato, G.; Sarma, S.; Roychoudhury, P.

    2016-01-01

    Aim: To determine an efficient vaccination schedule on the basis of the humoral immune response of cell culture adapted live classical swine fever virus (CSFV) vaccinated pigs and maternally derived antibody (MDA) in piglets of vaccinated sows. Materials and Methods: A cell culture adapted live CSFV vaccine was subjected to different vaccination schedule in the present study. Serum samples were collected before vaccination (day 0) and 7, 14, 28, 42, 56, 180, 194, 208, 270, 284 and 298 days after vaccination and were analyzed by liquid phase blocking enzyme-linked immunosorbent assay. Moreover, MDA titre was detected in the serum of piglets at 21 and 42 days of age after farrowing of the vaccinated sows. Results: On 28 days after vaccination, serum samples of 83.33% vaccinated pigs showed the desirable level of antibody titer (log10 1.50 at 1:32 dilution), whereas 100% animals showed log10 1.50 at 1:32 dilution after 42 days of vaccination. Animals received a booster dose at 28 and 180 days post vaccination showed stable high-level antibody titre till the end of the study period. Further, piglets born from pigs vaccinated 1 month after conception showed the desirable level of MDA up to 42 days of age. Conclusion: CSF causes major losses in pig industry. Lapinised vaccines against CSFV are used routinely in endemic countries. In the present study, a cell culture adapted live attenuated vaccine has been evaluated. Based on the level of humoral immune response of vaccinated pigs and MDA titer in piglets born from immunized sows, it may be concluded that the more effective vaccination schedule for prevention of CSF is primary vaccination at 2 months of age followed by booster vaccination at 28 and 180 days post primary vaccination and at 1 month of gestation. PMID:27057117

  9. Research progress on the mollusc immunity in China.

    PubMed

    Wang, Lingling; Qiu, Limei; Zhou, Zhi; Song, Linsheng

    2013-01-01

    The economical and phylogenic importance of mollusc has led an increasing number of investigations giving emphasis to immune defense mechanism. This review discusses the advances in immunological study of mollusc in China, with special reference to dominant aquaculture species over the past decades. As an invertebrate group, molluscs lack adaptive immunity and consequently they have evolved sophisticated strategies of innate immunity for defense against pathogens. This review aims to present the various immunologically significant pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), lectins, lipopolysaccharide and β-1, 3-glucan binding protein (LGBP), scavenger receptors (SRs) employed by mollucans. This work also highlights immune proteolytic cascade, TLR signaling pathway and an extensive repertoire of immune effectors including antimicrobial peptide, lysozyme, antioxidant enzyme and heat shock protein. Further, the review presents the preliminary progress made on the catecholaminergic neuroendocrine system in scallop and its immunomodulation function to throw light into neuroendocrine-immune regulatory network in lower invertebrates.

  10. Divergent selection on locally adapted major histocompatibility complex immune genes experimentally proven in the field

    PubMed Central

    Eizaguirre, Christophe; Lenz, Tobias L; Kalbe, Martin; Milinski, Manfred

    2012-01-01

    Although crucial for the understanding of adaptive evolution, genetically resolved examples of local adaptation are rare. To maximize survival and reproduction in their local environment, hosts should resist their local parasites and pathogens. The major histocompatibility complex (MHC) with its key function in parasite resistance represents an ideal candidate to investigate parasite-mediated local adaptation. Using replicated field mesocosms, stocked with second-generation lab-bred three-spined stickleback hybrids of a lake and a river population, we show local adaptation of MHC genotypes to population-specific parasites, independently of the genetic background. Increased allele divergence of lake MHC genotypes allows lake fish to fight the broad range of lake parasites, whereas more specific river genotypes confer selective advantages against the less diverse river parasites. Hybrids with local MHC genotype gained more body weight and thus higher fitness than those with foreign MHC in either habitat, suggesting the evolutionary significance of locally adapted MHC genotypes. PMID:22583762

  11. Duration of immunity engendered by a single dose of a cold-adapted strain of Avian pneumovirus

    PubMed Central

    2006-01-01

    Abstract The duration of immunity after a single dose of a cold-adapted strain of Avian pneumovirus (APV) was studied. Turkeys were vaccinated at 1 wk of age and challenged with virulent virus 3, 7, 10, and 14 wk later. Nonvaccinated groups were also challenged at the same times. No clinical signs were observed in the vaccinated birds after vaccination or after any challenge. No viral RNA was shed by the vaccinated birds after any challenge. The nonvaccinated birds shed viral RNA after all challenges. Avian pneumovirus-specific humoral antibodies were detected in the vaccinated birds until 14 wk after vaccination. The results of this preliminary study indicate that inoculation with a single dose of a cold-adapted strain of APV at 1 wk of age provides protection until 15 wk of age. PMID:16548335

  12. Genital Chlamydia trachomatis: Understanding the Roles of Innate and Adaptive Immunity in Vaccine Research

    PubMed Central

    Vasilevsky, Sam; Greub, Gilbert; Nardelli-Haefliger, Denise

    2014-01-01

    SUMMARY Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide, and despite significant advances in chlamydial research, a prophylactic vaccine has yet to be developed. This Gram-negative obligate intracellular bacterium, which often causes asymptomatic infection, may cause pelvic inflammatory disease (PID), ectopic pregnancies, scarring of the fallopian tubes, miscarriage, and infertility when left untreated. In the genital tract, Chlamydia trachomatis infects primarily epithelial cells and requires Th1 immunity for optimal clearance. This review first focuses on the immune cells important in a chlamydial infection. Second, we summarize the research and challenges associated with developing a chlamydial vaccine that elicits a protective Th1-mediated immune response without inducing adverse immunopathologies. PMID:24696438

  13. Role of Innate and Adaptive Immunity in Cardiac Injury and Repair

    PubMed Central

    Epelman, Slava; Liu, Peter P.; Mann, Douglas L.

    2015-01-01

    Despite significant advances, cardiovascular disease is the leading cause of world-wide mortality, highlighting an important yet unmet clinical need. Understanding the pathophysiological basis underlying cardiovascular tissue injury and repair in therefore of prime importance. Following cardiac tissue injury, the immune system plays an important and complex role throughout the acute inflammatory response and regenerative response. This review will summarize the role of the immune system in cardiovascular disease, and focus on the idea that the immune system evolved to promote tissue homeostasis following tissue injury and/or infection, and that the inherent cost of this evolutionary development is unwanted inflammatory mediated damage. While inflammation induced tissue damage is of little evolutionary consequence in organisms that have limited life spans, as will be discussed below, inflammation plays a major role in the development of cardiovascular disease worldwide in humans. PMID:25614321

  14. Pressure Induced Changes in Adaptive Immune Function in Belugas (Delphinapterus leucas); Implications for Dive Physiology and Health

    PubMed Central

    Thompson, Laura A.; Romano, Tracy A.

    2016-01-01

    Increased pressure, associated with diving, can alter cell function through several mechanisms and has been shown to impact immune functions performed by peripheral blood mononuclear cells (PBMC) in humans. While marine mammals possess specific adaptations which protect them from dive related injury, it is unknown how their immune system is adapted to the challenges associated with diving. The purpose of this study was to measure PBMC activation (IL2R expression) and Concanavalin A induced lymphocyte proliferation (BrdU incorporation) in belugas following in vitro pressure exposures during baseline, Out of Water Examination (OWE) and capture/release conditions. Beluga blood samples (n = 4) were obtained from animals at the Mystic Aquarium and from free ranging animals in Alaska (n = 9). Human blood samples (n = 4) (Biological Specialty Corporation) were run for comparison. In vivo catecholamines and cortisol were measured in belugas to characterize the neuroendocrine response. Comparison of cellular responses between controls and pressure exposed cells, between conditions in belugas, between belugas and humans as well as between dive profiles, were run using mixed generalized linear models (α = 0.05). Cortisol was significantly higher in Bristol Bay belugas and OWE samples as compared with baseline for aquarium animals. Both IL2R expression and proliferation displayed significant pressure induced changes, and these responses varied between conditions in belugas. Both belugas and humans displayed increased IL2R expression, while lymphocyte proliferation decreased for aquarium animals and increased for humans and Bristol Bay belugas. Results suggest beluga PBMC function is altered during diving and changes may represent dive adaptation as the response differs from humans, a non-dive adapted mammal. In addition, characteristics of a dive (i.e., duration, depth) as well as neuroendocrine activity can alter the response of beluga cells, potentially impacting the

  15. Standardized extract of Tinospora crispa stimulates innate and adaptive immune responses in Balb/c mice.

    PubMed

    Ahmad, Waqas; Jantan, Ibrahim; Kumolosasi, Endang; Bukhari, Syed Nasir Abbas

    2016-03-01

    Standardized extract of Tinospora crispa has been shown to exhibit immunostimulatory effects on innate immune responses in Wistar-Kyoto rats by enhancing neutrophil and T cell-mediated immunity. In this study the immunostimulatory effects of T. crispa were further investigated on the cellular immune response by determining its effect on nitric oxide (NO) production ability, peritoneal macrophage phagocytosis and delayed type hypersensitivity (DTH), whereas the humoral immune response was evaluated through the measurement of serum immunoglobulins (IgG and IgM) and serum lysozyme levels. Male Balb/c mice were immunized with 200 μL of 5 × 10(9) sheep red blood cells (sRBCs) per mL on day 0 and orally administered with 50, 100 and 200 mg per kg of ethanol extract of T. crispa for 14 days. Syringin and magnoflorine were qualitatively and quantitatively analyzed in the extract as chemical markers by using a validated reversed-phase high performance liquid chromatography method. T. crispa extract (TCE) considerably improved the peritoneal macrophages' ability to engulf FITC-labeled E. coli in a dose-dependent manner. TCE also dose-dependently promoted NO production in peritoneal macrophages activated by a lipopolysaccharide (LPS) and markedly potentiated the sRBS-induced swelling rate of the mice paw in DTH. The extract significantly enhanced the level of serum immunoglobulins, showing maximum activity at 100 mg kg(-1). Compared to the control groups, the serum lysozyme level and myeloperoxidase (MPO) activity were significantly higher in extract-treated groups. These findings suggest that T. crispa possesses strong immunostimulatory activities and might act as a natural immunomodulator as well as a potential nutraceutical for the modulation of the immune response. PMID:26839149

  16. Standardized extract of Tinospora crispa stimulates innate and adaptive immune responses in Balb/c mice.

    PubMed

    Ahmad, Waqas; Jantan, Ibrahim; Kumolosasi, Endang; Bukhari, Syed Nasir Abbas

    2016-03-01

    Standardized extract of Tinospora crispa has been shown to exhibit immunostimulatory effects on innate immune responses in Wistar-Kyoto rats by enhancing neutrophil and T cell-mediated immunity. In this study the immunostimulatory effects of T. crispa were further investigated on the cellular immune response by determining its effect on nitric oxide (NO) production ability, peritoneal macrophage phagocytosis and delayed type hypersensitivity (DTH), whereas the humoral immune response was evaluated through the measurement of serum immunoglobulins (IgG and IgM) and serum lysozyme levels. Male Balb/c mice were immunized with 200 μL of 5 × 10(9) sheep red blood cells (sRBCs) per mL on day 0 and orally administered with 50, 100 and 200 mg per kg of ethanol extract of T. crispa for 14 days. Syringin and magnoflorine were qualitatively and quantitatively analyzed in the extract as chemical markers by using a validated reversed-phase high performance liquid chromatography method. T. crispa extract (TCE) considerably improved the peritoneal macrophages' ability to engulf FITC-labeled E. coli in a dose-dependent manner. TCE also dose-dependently promoted NO production in peritoneal macrophages activated by a lipopolysaccharide (LPS) and markedly potentiated the sRBS-induced swelling rate of the mice paw in DTH. The extract significantly enhanced the level of serum immunoglobulins, showing maximum activity at 100 mg kg(-1). Compared to the control groups, the serum lysozyme level and myeloperoxidase (MPO) activity were significantly higher in extract-treated groups. These findings suggest that T. crispa possesses strong immunostimulatory activities and might act as a natural immunomodulator as well as a potential nutraceutical for the modulation of the immune response.

  17. Diversity of CRISPR-Cas-Mediated Mechanisms of Adaptive Immunity in Prokaryotes and Their Application in Biotechnology.

    PubMed

    Savitskaya, E E; Musharova, O S; Severinov, K V

    2016-07-01

    CRISPR-Cas systems of adaptive immunity in prokaryotes consist of CRISPR arrays (clusters of short repeated genomic DNA fragments separated by unique spacer sequences) and cas (CRISPR-associated) genes that provide cells with resistance against bacteriophages and plasmids containing protospacers, i.e. sequences complementary to CRISPR array spacers. CRISPR-Cas systems are responsible for two different cellular phenomena: CRISPR adaptation and CRISPR interference. CRISPR adaptation is cell genome modification by integration of new spacers that represents a unique case of Lamarckian inheritance. CRISPR interference involves specific recognition of protospacers in foreign DNA followed by introduction of breaks into this DNA and its destruction. According to the mechanisms of action, CRISPR-Cas systems have been subdivided into two classes, five types, and numerous subtypes. The development of techniques based on CRISPR interference mediated by the Type II system Cas9 protein has revolutionized the field of genome editing because it allows selective, efficient, and relatively simple introduction of directed breaks into target DNA loci. However, practical applications of CRISPR-Cas systems are not limited only to genome editing. In this review, we focus on the variety of CRISPR interference and CRISPR adaptation mechanisms and their prospective use in biotechnology. PMID:27449612

  18. How the innate immune system trains immunity: lessons from studying atopic dermatitis and cutaneous bacteria.

    PubMed

    Skabytska, Yuliya; Kaesler, Susanne; Volz, Thomas; Biedermann, Tilo

    2016-02-01

    The skin is the largest organ at the interface between environment and host. It plays a major protective role against pathogens as physical barrier, as site of first recognition, and as orchestrator of consecutive immune responses. In this process, immunological crosstalk between skin-resident and immune cells is required, and fixed innate immune responses were previously believed to orchestrate adaptive immunity of B and T lymphocytes. Today, we understand that diverse qualities of immune responses to different microbes need to be regulated by also varying responses at the level of first microbe recognition through receptors of the innate immune system. Only fine-tuning of the innate immune system allows for the orchestration of immune responses to the microbiota in the absence of inflammation as well as to pathogens in the context of protective responses including inflammation. Understanding how innate immunity precisely adapts is also important for diseases such as atopic dermatitis (AD) with chronic inflammation. In this review, we present data on how the innate immune system actually fine-tunes its responses with special focus on the immunological consequences of cutaneous innate immune sensing through TLR2. These new insights are highly relevant for understanding microbiota-associated state of health, immune defense, and the pathogenesis underlying chronic cutaneous inflammation as seen in AD.

  19. Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.

    PubMed

    Quach, Hélène; Rotival, Maxime; Pothlichet, Julien; Loh, Yong-Hwee Eddie; Dannemann, Michael; Zidane, Nora; Laval, Guillaume; Patin, Etienne; Harmant, Christine; Lopez, Marie; Deschamps, Matthieu; Naffakh, Nadia; Duffy, Darragh; Coen, Anja; Leroux-Roels, Geert; Clément, Frederic; Boland, Anne; Deleuze, Jean-François; Kelso, Janet; Albert, Matthew L; Quintana-Murci, Lluis

    2016-10-20

    Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

  20. Lymphocyte-derived ACh regulates local innate but not adaptive immunity

    PubMed Central

    Reardon, Colin; Duncan, Gordon S.; Brüstle, Anne; Brenner, Dirk; Tusche, Michael W.; Olofsson, Peder S.; Rosas-Ballina, Mauricio; Tracey, Kevin J.; Mak, Tak W.

    2013-01-01

    Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4+ T-cell population that is stimulated by norepinephrine to release ACh, ChAT+ B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT+ B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT+ B cells controlling the local recruitment of neutrophils. PMID:23297238

  1. Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines.

    PubMed

    Guo, Zhenhong; Zhang, Minghui; Tang, Hua; Cao, Xuetao

    2005-09-15

    Dendritic cells (DCs) and chemokines are important in linking innate and adaptive immunity. We previously reported that Fas ligation induced interleukin 1beta (IL-1beta)-dependent maturation and IL-1beta-independent survival of DCs, with extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-kappaB) signaling pathways involved, respectively. We describe here that Fas ligation induced DCs to rapidly produce both CXC and CC chemokines, including macrophage inflammatory protein 2 (MIP-2), MIP-1alpha, MIP-1beta, monocyte chemoattractant protein 1 (MCP-1), RANTES (regulated on activation normal T cell expressed and secreted), and TARC (thymus and activation-regulated chemokine), resulting in enhanced chemoattraction of neutrophils and T cells by Fas-ligated DCs in vivo or by its supernatant in vitro. These chemokines work synergistically in chemoattraction of neutrophils and T cells with MIP-2 more important for neutrophils, MIP-1alpha and TARC more important for T cells. Moreover, Fas-ligated DCs increased endocytosis by neutrophils and activation and proliferation of antigen-specific naive T cells. Fas ligation-induced DC secretion of chemokines involves Ras/Raf/mitogen-activated protein kinase kinase (MEK)/ERK activation and is ERK, but not NF-kappaB, dependent. Activation of caspases, including caspase 1, but not IL-1 autocrine action, is involved in this process. These data indicate that Fas signaling provides a key link between innate response and adaptive immunity by promoting DC chemokine production.

  2. [Advances in molecular mechanisms of adaptive immunity mediated by type I-E CRISPR/Cas system--A review].

    PubMed

    Sun, Dongchang; Qiu, Juanping

    2016-01-01

    To better adapt to the environment, prokaryocyte can take up exogenous genes (from bacteriophages, plasmids or genomes of other species) through horizontal gene transfer. Accompanied by the acquisition of exogenous genes, prokaryocyte is challenged by the invasion of 'selfish genes'. Therefore, to protect against the risk of gene transfer, prokaryocyte needs to establish mechanisms for selectively taking up or degrading exogenous DNA. In recent years, researchers discovered an adaptive immunity, which is mediated by the small RNA guided DNA degradation, prevents the invasion of exogenous genes in prokaryocyte. During the immune process, partial DNA fragments are firstly integrated.to the clustered regularly interspaced short palindromic repeats (CRISPR) located within the genome DNA, and then the mature CRISPR RNA transcript and the CRISPR associated proteins (Cas) form a complex CRISPR/Cas for degrading exogenous DNA. In this review, we will first briefly describe the CRISPR/Cas systems and then mainly focus on the recent advances of the function mechanism and the regulation mechanism of the type I-E CRISPR/Cas system in Escherichia coli.

  3. Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity.

    PubMed

    Broadley, Steven P; Plaumann, Ann; Coletti, Raffaele; Lehmann, Christin; Wanisch, Andreas; Seidlmeier, Amelie; Esser, Knud; Luo, Shanshan; Rämer, Patrick C; Massberg, Steffen; Busch, Dirk H; van Lookeren Campagne, Menno; Verschoor, Admar

    2016-07-13

    Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity.

  4. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.

    PubMed

    Thiele, Kristin; Solano, M Emilia; Huber, Samuel; Flavell, Richard A; Kessler, Timo; Barikbin, Roja; Jung, Roman; Karimi, Khalil; Tiegs, Gisa; Arck, Petra C

    2015-10-01

    Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans. PMID:26254283

  5. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

    PubMed Central

    Graham, Deborah S Cunninghame; Pinder, Christopher L; Tombleson, Philip; Behrens, Timothy W; Martín, Javier; Fairfax, Benjamin P; Knight, Julian C; Chen, Lingyan; Replogle, Joseph; Syvänen, Ann-Christine; Rönnblom, Lars; Graham, Robert R; Wither, Joan E; Rioux, John D; Alarcón-Riquelme, Marta E; Vyse, Timothy J

    2015-01-01

    Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE. PMID:26502338

  6. Stepping Out of the Cytosol: AIMp1/p43 Potentiates the Link Between Innate and Adaptive Immunity.

    PubMed

    Liang, D; Halpert, M M; Konduri, V; Decker, W K

    2015-01-01

    As a structural component of the multi-aminoacyl tRNA synthetase (mARS) complex, AIMp1, also known as p43, hasn't until recently been recognized for its prominent immunological functions. Together with other nonenzymatic mARS structural components AIMp2/38 and AIMp3/p18, it participates in the machinery responsible for cell-cycle control and tumor suppression. Novel studies also show that AIMp1/p43 can be released by certain cancer cells under conditions of stress. Extracellularly, AIMp1 promotes the proliferation and migration of fibroblasts/endothelial cells and importantly, pro-inflammatory gene expression in monocytes/macrophages and dendritic cells. AIMp1/p43 deficiency is also correlated with spontaneous Type-2 airway hypersensitivity in mice, indicating a potential role in skewing toward T-helper type-1 (T(H)1) immunity. Vaccination strategies in which dendritic cells receive dual MHC class I and MHC class II antigens of homologous origins (i.e., that share overlapping class I and II binding epitopes) boost downstream T(H)1 immunity in a manner that appears to be wholly dependent upon dendritic cell AIMp1 release. Here we underscore the importance of AIMp1/p43 as a pro-inflammatory cytokine when it is released from cytosol to extracellular space and discuss future directions by which the mechanisms that regulate this process might be better characterized, further elucidating the link between innate and adaptive immunity. PMID:26325028

  7. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.

    PubMed

    Thiele, Kristin; Solano, M Emilia; Huber, Samuel; Flavell, Richard A; Kessler, Timo; Barikbin, Roja; Jung, Roman; Karimi, Khalil; Tiegs, Gisa; Arck, Petra C

    2015-10-01

    Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

  8. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

    PubMed

    Bentham, James; Morris, David L; Cunninghame Graham, Deborah S; Pinder, Christopher L; Tombleson, Philip; Behrens, Timothy W; Martín, Javier; Fairfax, Benjamin P; Knight, Julian C; Chen, Lingyan; Replogle, Joseph; Syvänen, Ann-Christine; Rönnblom, Lars; Graham, Robert R; Wither, Joan E; Rioux, John D; Alarcón-Riquelme, Marta E; Vyse, Timothy J

    2015-12-01

    Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE. PMID:26502338

  9. Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity.

    PubMed

    Broadley, Steven P; Plaumann, Ann; Coletti, Raffaele; Lehmann, Christin; Wanisch, Andreas; Seidlmeier, Amelie; Esser, Knud; Luo, Shanshan; Rämer, Patrick C; Massberg, Steffen; Busch, Dirk H; van Lookeren Campagne, Menno; Verschoor, Admar

    2016-07-13

    Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity. PMID:27345696

  10. Selective and hyperactive uptake of foreign DNA by adaptive immune systems of an archaeon via two distinct mechanisms

    PubMed Central

    Erdmann, Susanne; Garrett, Roger A

    2012-01-01

    Central to the disparate adaptive immune systems of archaea and bacteria are clustered regularly interspaced short palindromic repeats (CRISPR). The spacer regions derive from invading genetic elements and, via RNA intermediates and associated proteins, target and cleave nucleic acids of the invader. Here we demonstrate the hyperactive uptake of hundreds of unique spacers within CRISPR loci associated with type I and IIIB immune systems of a hyperthermophilic archaeon. Infection with an environmental virus mixture resulted in the exclusive uptake of protospacers from a co-infecting putative conjugative plasmid. Spacer uptake occurred by two distinct mechanisms in only one of two CRISPR loci subfamilies present. In two loci, insertions, often multiple, occurred adjacent to the leader while in a third locus single spacers were incorporated throughout the array. Protospacer DNAs were excised from the invading genetic element immediately after CCN motifs, on either strand, with the secondary cut apparently produced by a ruler mechanism. Over a 10-week period, there was a gradual decrease in the number of wild-type cells present in the culture but the virus and putative conjugative plasmid were still propagating. The results underline the complex dynamics of CRISPR-based immune systems within a population infected with genetic elements. PMID:22834906

  11. MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses

    PubMed Central

    Yu, Jong W.; Hoffman, Sandy; Beal, Allison M.; Dykon, Angela; Ringenberg, Michael A.; Hughes, Anna C.; Dare, Lauren; Anderson, Amber D.; Finger, Joshua; Kasparcova, Viera; Rickard, David; Berger, Scott B.; Ramanjulu, Joshi; Emery, John G.; Gough, Peter J.; Bertin, John; Foley, Kevin P.

    2015-01-01

    CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo. PMID:25965667

  12. Allergic Host Defenses

    PubMed Central

    Palm, Noah W.; Rosenstein, Rachel K.

    2012-01-01

    Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macro-parasites. Here we present argum